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  • Design and analysis of EphA2-SAM peptide ligands: a multi-disciplinary screening approach
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-08
    Flavia Anna Mercurio, Concetta Di Natale, Luciano Pirone, Daniela Marasco, Enrica Calce, Marian Vincenzi, Emilia Maria Pedone, Stefania De Luca, Marilisa Leone

    EphA2 receptor plays a critical and debatable function in cancer and is considered a target in drug discovery. Lately, there has been a growing interest in its cytosolic C-terminal SAM domain (EphA2-SAM) as it engages protein modulators of receptor endocytosis and stability. Interestingly, EphA2-SAM binds the SAM domain from the lipid phosphatase Ship2 (Ship2-SAM) mainly producing pro-oncogenic outcomes. In an attempt to discover novel inhibitors of the EphA2-SAM/Ship2-SAM complex with possible anticancer properties, we focused on the central region of Ship2-SAM (known as Mid-Loop interface) responsible for its binding to EphA2-SAM. Starting from the amino acid sequence of the Mid-Loop interface virtual peptide libraries were built through ad hoc inserted mutations with either L- or D- amino acids and screened against EphA2-SAM by docking techniques. A few virtual hits were synthesized and experimentally tested by a variety of direct and competition-type interaction assays relying on NMR (Nuclear Magnetic Resonance), SPR (Surface Plasmon Resonance), MST (Microscale Thermophoresis) techniques. These studies guided the discovery of an original EphA2-SAM ligand antagonist of its interaction with Ship2-SAM.

    更新日期:2018-12-08
  • Antibody recognition by a novel microgel photonic crystal
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-05
    Na Sai, Zhong Sun, Yuntang Wu, Guowei Huang

    In this study, a easy-to-prepare biosensor for the sensitive detection of the antibody (Ab) protein was developed using a novel microgel photonic crystal (MPC). The MPC was fabricated by the spin-coated self-assembly method with the monodisperse Ab-sensitive poly (methyl methacrylate-acrylamide-glutaraldehyde-hapten) (P(MMA-AM-GA-HP)) microgels. Morphology characterization showed that the P(MMA-AM-GA-HP) microgels possessed round shapes and the large specific surface area, and the formed MPC had a highly ordered three dimensional (3D) periodically-ordered structure with the desired structural color. The Ab-response event of the P(MMA-AM-GA-HP) microgels can be directly transferred into a readable optical signal through a change in Bragg reflection of the periodic structure of the MPC. With the sensory system, the sensitive and selective detection of Ab was achieved without labeling techniques and expensive instruments. Therefore, this easy and sensitive detection system has great potential for next generation of the bioassay platform for clinical diagnosis and other applications.

    更新日期:2018-12-06
  • One-pot four-component synthesis of thiazolidin-2-imines using CuI/ZnII dual catalysis: a new class of acetylcholinesterase inhibitors
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-05
    Syeda Aaliya Shehzadi, Imtiaz Khan, Aamer Saeed, Fayaz Ali Larik, Pervaiz Ali Channar, Mubashir Hassan, Hussain Raza, Qamar Abbas, Sung-Yum Seo

    An efficient one-pot four-component strategy involving aldehydes, amines, alkynes and isothiocyanates has been developed to access a novel series of thiazolidine-2-imines (5a-x). This process operates under the action of a cooperative catalysis composed of Cu(I) and Zn(II) delivering the desired five-membered heterocyclic compounds in good to excellent yields. Notably, this transformation avoids the use of pre-formed imines or propargylamines and proceeds via an intramolecular 5-exo-dig hydrothiolation reaction of the in situ formed propargyl thiourea. Furthermore, the biological application of these motifs was demonstrated in terms of their strong acetylcholinesterase (AChE) inhibitory activity where compound 5s was identified as the lead AChE inhibitor with an IC50 value of 0.0023 ± 0.0002 μM, 88-folds stronger inhibition than standard drug (neostigmine methyl sulphate; IC50 = 0.203 ± 0.004 μM). Molecular docking analysis reinforced the in vitro biological activity results revealing the formation of several useful interactions of the potent lead with amino acid residues in the active site of the enzyme.

    更新日期:2018-12-06
  • A New Class of Diamide Scaffold: Design, Synthesis and Biological Evaluation As Potent Antimitotic Agents, Tubulin Polymerization Inhibition and Apoptosis Inducing Activity Studies
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-05
    Khaled O. Mohamed, Islam Zaki, Ibrahim M. El-Deen, Mohammed K. Abdelhameid

    A new series of diamide functional compounds has been designed, synthesized and confirmed by spectroscopic methods and elemental analyses. All the synthesized compounds were evaluated for their antiproliferative activity on HepG2 cell line. Compounds 3k and 3l were proved to have potent anticancer activity equipotent or more potent than reference compound Combretastatin A-4. The results of DNA flow cytometry analysis demonstrated cell cycle arrest at G2/M phase. The extent of apoptosis induced by 3k and 3l was also determined. Moreover, the compounds produced a significant reduction in cellular microtubules for microtubule loss and potently inhibited the binding of [3H]colchicine to tubulin. Compounds 3k and 3l were proved to upregulate expression of proteins triggering apoptosis, such as p53, Bax, and decreased Bcl-2 overexpression as well as increased the expression of effector caspase- 3/7.

    更新日期:2018-12-05
  • N-Alkyl-1,5-Dideoxy-1,5-Imino-L-Fucitols as Fucosidase Inhibitors: Synthesis, Molecular Modelling and Activity Against Cancer Cell Lines
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-04
    Jian Zhou, Arvind Negi, Styliana I. Mirallai, Rolf Warta, Christel Herold-Mende, Michael P. Carty, Xin-Shan Ye, Paul V. Murphy

    1,5-Dideoxy-1,5-imino-L-fucitol (1-deoxyfuconojirimycin, DFJ) is an iminosugar that inhibits fucosidases. Herein, N-alkyl DFJs have been synthesised and tested against the α-fucosidases of T. maritima (bacterial origin) and B. taurus (bovine origin). The N-alkyl derivatives were inactive against the bacterial fucosidase, while inhibiting the bovine enzyme. Docking of inhibitors to homology models, generated for the bovine and human fucosidases, was carried out. N-Decyl-DFJ was toxic to cancer cell lines and was more potent than the other N-alkyl DFJs studied.

    更新日期:2018-12-04
  • Hydrolases-mediated transformation of oleuropein into demethyloleuropein
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-04
    Luca Cariati, Manuela Oliverio, Francesco G. Mutti, Sonia Bonacci, Tanja Knaus, Paola Costanzo, Antonio Procopio

    Phenolic compounds present in extra virgin olive oil have recently attracted considerable attention due to their pharmacological activities. Among them oleacein (3,4-DHPEA-EDA), structurally related to oleochantal (4-HPEA-EDA), is one of the most studied. 3,4-DHPEA-EDA has been synthesized through decarboxylation of demethyloleuropein catalyzed by Er(OTf)3. Demethyloleuropein is extracted from black olives drupes in very limited amounts and only in particular periods of the year. The availability of demethyloleuropein could be increased by a selective hydrolysis of the methyl ester moiety of oleuropein, a secoiridoid present in large amount in olive leaves. In this work we describe a new enzymatic method for carrying out a selective hydrolysis of oleuropein via the screening of a panel of hydrolases (lipases, esterases and proteases). Among all the enzymes tested the best results was obtained using α-chymotrypsyn from bovine pancreas as biocatalyst, thus revealing a classic example of catalytic enzyme promiscuity.

    更新日期:2018-12-04
  • Fluorescent labeling of ursolic acid with FITC for investigation of its cytotoxic activity using confocal microscopy
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-04
    Tatiana S. Frolova, Alla V. Lipeeva, Dmitry S. Baev, Sergey I. Baiborodin, Кonstantin E. Orishchenko, Alexey V. Kochetov, Olga I. Sinitsyna

    Fluorescent labeling is a widely-used approach in the study of intracellular processes. This method is becoming increasingly popular for studying small bioactive molecules of natural origin; it allows us to estimate the vital intracellular changes which occur under their influence. We propose a new approach for visualization of the intracellular distribution of triterpene acids, based on fluorescent labeling by fluoresceine isothiocyanate. As a model compound we took the most widely-used and best-studied acid in the ursane series – ursolic acid, as this enabled us to compare the results obtained during our research with the available data, in order to evaluate the validity of the proposed method. Experimental tracing of the dynamics of penetration and distribution of the labeled ursolic acid has shown that when the acid enters the cell, it initially localizes on the inner membranes where the predicted target Akt1/protein kinase B – a protein that inhibits apoptosis – is located.

    更新日期:2018-12-04
  • Synthesis, ADME, Docking Studies and in vivo Anti-Hyperglycaemic Potential Estimation of Novel Schiff Base Derivatives from Octadec-9-enoic Acid
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-04
    Garima Kapoor, Dharam Pal Pathak, Rubina Bhutani, Asif Husain, Sandeep Jain, Md. Azhar Iqbal

    A new series of octadec-9-enoic acid schiff base entities (S1-S30) were designed and synthesized targeting peroxisome proliferator activated receptor-gamma for agonist action. Molinspiration software (online) was used to estimate drug like molecular properties of the metabolites. Docking disquisition on co-crystallized protein of PPAR-γ (PDB ID 1FM9) was carried out which showed S21, S10 and S7 as best situated in the vital sites of receptor having docking scores -9.19, -8.68 and -8.64 respectively. Free binding energy measured using model of Maestro 9.0 and was in range of from -40.01 and -80.54 kcal/mol, significant when compared with pioglitazone (-51.58 Kcal/mol). Seven best docked derivatives were assessed for in-vivo oral glucose tolerance on normal rats and anti-hyperglycaemic activity by streptozotocin induced diabetes model. S21 unveiled to be the best measured analogue among all the synthesized entities. Encouraging outcomes motivates fatty acids for further development of more effective and safer compounds.

    更新日期:2018-12-04
  • Eight new glycosides with hepatoprotective activity isolated from the aerial parts of Morinda parvifolia
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-03
    Xianming Su, Li Li, Hua Sun, Fan Zhang, Changkang Li, Fenghua Li, Hongqing Wang, Baoming Li, Ruoyun Chen, Jie Kang

    Eight new glycosides, morindaparvins P–W, were isolated from the butanol extract of the aerial parts of Morinda parvifolia. These new structures were elucidated by comprehensive spectroscopic analysis and by comparing the experimental and calculated electronic circular dichroism spectra. The butanol extract was observed to significantly reduce the levels of alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase in the sera of mice with concanavalin A-induced hepatitis. At a concentration of 10 μM, five compounds (1, and 4–7) isolated from the butanol extract possessed hepatoprotective activities against the damage induced by acetaminophen in human HepG2 liver cancer cells.

    更新日期:2018-12-04
  • Xanthenone-based hydrazones as potent α-glucosidase inhibitors: synthesis, solid state self-assembly and in silico studies
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-30
    Qamar-un-Nisa Tariq, Sana Malik, Ajmal Khan, Muhammad Moazzam Naseer, Shafi Ullah Khan, Abida Ashraf, Muhammad Ashraf, Muhammad Rafiq, Khalid Mahmood, Muhammad Nawaz Tahir, Zahid Shafiq

    Xanthenone based hydrazone derivatives (5a-n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a-n) are characterized by their FTIR, 1HNMR, 13C-NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC50 = 375.38±0.12 µM). Amongst the series, compound 5l (IC50= 62.25±0.11µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.

    更新日期:2018-12-01
  • Synthesis of a new disulfide Fmoc monomer for creating biologically susceptible linkages in peptide nucleic acid oligomers
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-01
    Brandon Campbell, Taylor Hood, Nathaniel Shank

    Peptide nucleic acids (PNA) are one of many synthetic mimics of DNA and RNA that have found applications as biological probes, as nano-scaffold components, and in diagnostics. In an effort to use PNA as constructs for cellular delivery we investigated the possibility of installing a biologically susceptible disulfide bond in the backbone of a PNA oligomer. Here we report the synthesis of a new abasic Fmoc monomer containing a disulfide bond that can be incorporated into a PNA oligomer (DS-PNA) using standard solid phase peptide synthesis. The disulfide bond survives cleavage from the resin and DS-PNA forms duplexes with complementary PNA oligomers. Initial studies aimed at determining if the disulfide bond is cleavable to reducing agents while in a duplex are explored using UV thermal analysis and HPLC.

    更新日期:2018-12-01
  • Artemisianins A-D, New Stereoisomers of Seco-guaianolide Involved Heterodimeric [4+2] Adducts from Artemisia argyi Induce Apoptosis via Enhancement of Endoplasmic Reticulum Stress
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-12-01
    Gui-Min Xue, Dong-Rong Zhu, Chao Han, Xiao-Bing Wang, Jian-Guang Luo, Ling-Yi Kong

    Artemisianins A-D (1-4), four stereoisomers of sesquiterpenoid dimers, forming via [4+2] cycloaddition from a 1, 10-seco-guaianolide dienophile and a guaianolide diene, along with two biosynthetically related precurors 5 and 6, were isolated from the famous traditional Chinese medicine Artemisia argyi. The structures of 1-4, including their absolute configurations, were elucidated by extensive spectroscopic data and ECD/TDDFT calculation analysis. Compounds 1-4 exhibited cytotoxicity with IC50 values ranging from 7.2 to 23.3 μM. The accumulation of Ca2+ in cytoplasm and enlarged endoplasmic reticulum (ER) indicated that 1 mediated HT-29 cancer cell apoptosis through improvement of ER-stress, which was further proved by unfolded protein response (UPR) pathway on basis of the upregulation of IRE1α, p-PERK, ATF6, and CHOP.

    更新日期:2018-12-01
  • The Synthesis and Anticancer Activities of Chiral Epoxy-substituted Chromone Analogs
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-30
    Hyunji Cho, Seung Hee Seo, Younghwa Na, Youngjoo Kwon

    Human DNA topoisomerases (topos) have been recognized as a good target molecule for the development of anticancer drugs because they play an important role in solving DNA topological problems caused by DNA strand separation during replication and transcription. In this study, we designed and synthesized 11 novel chromone backbone compounds possessing epoxy and halohydrin substituents with chirality. In the topos inhibition test, compounds 2, 9, 10, and 11 showed comparable topo I inhibitory activity at concentration of 100 μM compared to camptothecin, and all of the synthesized compounds showed moderate topo IIα inhibitory activity. Among them, compounds 9, 10 and 11 were more potent than the others in both topo I and IIα inhibitory activity. Compound 11 showed the most potent cell antiproliferative activity against all tested cancer cell lines with particularly strong inhibition (an IC50 of 0.04 µM) of K562 myelogenous leukemia cancer cell proliferation. In the brief structure-activity relationship analysis, there was no clear correlation between stereochemistry and topos inhibitory and cytotoxic activity. 5(R),7(S)-bisepoxy-substituted compound 11 was the most potent DNA cross-linker and induced G2/M arrest in a cell cycle assay in a dose- and time-dependent manner. After the treatment time period induced apoptosis in K562 cells without increasing G2/M-phase cells. Overall, compound 11 showed good consistent inhibitory biological activity related to cancer cell proliferation.

    更新日期:2018-12-01
  • Multi-target inhibitors of Alzheimer disease derived from 3-hydrazinyl 1,2,4- triazine scaffold containing pendant phenoxy methyl- 1,2,3-triazole: Design, synthesis and biological evaluation
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-29
    Mahnaz Yazdani, Najmeh Edraki, Rashid Badri, Mehdi Khoshneviszadeh, Aida Iraji, Omidreza Firuzi

    Alzheimer's disease (AD) is a complex neurological disorder with diverse underlying pathological processes. Several lines of evidence suggest that BACE1 is a key enzyme in the pathogenesis of AD and its inhibition is of particular importance in AD treatment. Ten new 3-hydrazinyl-1,2,4-triazine bearing pendant aryl phenoxy methyl-1,2,3-triazole as multifunctional ligands against AD. We show that compounds containing Cl and NO2 groups at the para position of the phenyl ring, namely compounds 7c (IC50= 8.55 ± 3.37 µM) and 7d (IC50= 11.42 ± 2.01 µM), demonstrate promising BACE1 inhibitory potential. Furthermore, we assessed the neuroprotective activities of 7c and 7d derivatives in the PC12 neuronal cell line, which showed moderate protection against amyloid β peptide toxicity. In addition, compound 7d demonstrated metal chelating activity and moderate antioxidant potential (IC50= 44.42 ± 7.33 µM). Molecular docking studies of these molecules revealed high-affinity binding to several amino acids of BACE1, which are essential for efficient inhibition. These results demonstrate that 1,2,4-triazine derivatives bearing an aryl phenoxy methyl-1,2,3-triazole have promising properties as therapeutic agents for AD.

    更新日期:2018-11-30
  • Synthesis, molecular docking and cholinesterase inhibitory activity of hydroxylated 2-phenylbenzofuran derivatives
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-29
    Antonella Fais, Amit Kumar, Rosaria Medda, Francesca Pintus, Francesco Delogu, Maria J. Matos, Benedetta Era, Giovanna L. Delogu

    We have designed, synthesized and evaluated a series of hydroxylated 2-phenylbenzofuran derivatives as potential cholinesterase inhibitors. Starting from a series of 2-phenylbenzofurans previously published, in this paper we present a complete synthesis and the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring and highlight the importance of position of hydroxyl groups. Moreover, simultaneous introduction of halogen at position 7 of the benzofuran scaffold resulted in an improved inhibitory activity against the enzyme. To further provide molecular insight and to identify the most probable ligand-binding site of the protein, docking studies were performed for the top-ranked compounds. Docking results revealed conserved ligand-binding residues and supported the role of catalytic site residues in enzyme inhibition.

    更新日期:2018-11-29
  • 3D-QSAR assisted identification of FABP4 inhibitors: an effective scaffold hopping analysis/QSAR evaluation
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-29
    Giuseppe Floresta, Agostino Cilibrizzi, Vincenzo Abbate, Ambra Spampinato, Chiara Zagni, Antonio Rescifina

    Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC50 values between 3.70 and 5.59 μM, with a high level of agreement with the predicted values.

    更新日期:2018-11-29
  • Design, synthesis, DNA assessment and molecular docking study of novel 2-(pyridin-2-ylimino)thiazolidin-4-one derivatives as potent antifungal agents
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-28
    Nadia Hanafy Metwally, Ibrahim Taha Radwan, Walaa Salah El-Serwy, Mohamed Ahmed Mohamed

    A series of novel 2-imino-4-thiazolidinone derivatives 4a,b was synthesized through reaction of unsymmetrical thioureas 3a,b with chloroacetic acid. Condensation of 4a,b with aromatic aldehydes 5a-eyielded the corresponding 5-arylidene derivatives6a-j. In addition, the reaction of 4a,b with 4-arylazo-3-hydroxybenzaldehydes 8a-c furnished the respective mono-arylazo-4-thiazolidinones10a-f. All the newly synthesized compounds were confirmed by their elemental analysis and spectral data. The antifungal activity of the newly synthesized compounds was assessed and the compounds 6d, 6e, 6i, 6j, 9a,b and 10a-frevealedhigher antifungal activity towards Alternaria solani than to the standard Ridomil gold plus. Moreover, the DNA toxicity of 4-thiazolidinone derivatives 6d, 9a, 10b, 10c and 10f on the nucleic acid of Alternaria solani (KT354939) was performed and the results showed qualitatively more than 70% cleavage. Also, compounds 6i, 6j, 9b, 10c and 10f were docked inside the active site of 1ZOYenzyme and suitable binding with the active site of amino acids,were displayedaccording to their bond lengths, angles and conformational energy.

    更新日期:2018-11-29
  • Synthesis, bioactivity and molecular modeling studies on potential anti-Alzheimer piperidinehydrazide-hydrazones
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-28
    Sulunay Parlar, Gozde Sayar, Ayse Hande Tarikogullari, Sumru Sozer Karadağli, Vildan Alptuzun, Ercin Erciyas, Ulrike Holzgrabe

    A group of N-benzylpiperidine-3/4-carbohydrazide-hydrazones were designed, synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities, Aβ42 self-aggregation inhibitory potentials, and antioxidant capacities, in vitro. All of the compounds displayed eeAChE and huAChE inhibitory activity in a range of IC50= 5.68-11.35 µM and IC50= 8.80-74.40 µM, respectively and most of the compounds exhibited good to moderate inhibitory activity on BuChE enzyme. Kinetic analysis and molecular modeling studies were also performed for the most potent compounds (1g and 1j). Not only the molecular modeling studies but also the kinetic analysis suggested that these compounds might be able to interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of the enzymes. In the light of the results, compound 1g and compound 1j may be suggested as lead compounds for multifunctional therapy of AD.

    更新日期:2018-11-28
  • Synthesis and identification of novel pryidazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-28
    Syed Usama Bin Farrukh, Ibrahim Javed, Abdul Qayyum Ather, Abdul-Hamid Emwas, Meshari Alazmi, Xin Gao, Ghayoor Abbas Chotana, Thomas P. Davis, Pu Chun Ke, Rahman Shah Zaib Saleem

    We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pryidazinylpyrazolone molecules for their ability to modulate the amyloidogenic self-assembly of human islet amyloid polypeptide (hIAPP). hIAPP is a 37-residue peptide which is involved in glycemic control along with insulin. Its extracellular fibrillar assemblies in pancreatic β-cells are responsible for type 2 diabetes. A three-step synthetic scheme was used to prepare these novel compounds using 2-(6-chloropyridazin-3-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one as a key intermediate that was reacted with various diazo electrophiles to generate a library of compounds with yields ranging from 64 to 85%. The effect of the compounds on hIAPP amyloid fibril formation was evaluated with a thioflavin T (ThT) fluorescence-based kinetic assay. Furthermore, TEM imaging was carried out to corroborate the interactions of the compounds with hIAPP and subsequent hIAPP inhibition at the different level of fibrillization. The CD Spectroscopy showed that upon incubation with SSE15314 for 12 h, the percentage of α-helices was maintained to a level of hIAPP at 0 h. The current study presents identification and characterization of SSE15314 as the hit, which completely inhibited the fibril formation and can be further optimized into a lead compound.

    更新日期:2018-11-28
  • New tirucallane triterpenoids from Picrasma quassioides with their potential antiproliferative activities on hepatoma cells
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-28
    Wen-Yu Zhao, Jing-Jie Chen, Chun-Xin Zou, Ying-Ying Zhang, Guo-Dong Yao, Xiao-Bo Wang, Xiao-Xiao Huang, Bin Lin, Shao-Jiang Song

    Seven new tirucallane-type triterpenoids (1-7), kumuquassin A-G, along with 20 known analogues (8-27) were isolated from the stems of Picrasma quassioides. The structures and the absolute configurations of new compounds were elucidated by spectroscopic data, electronic circular dichroism (ECD) spectroscopic analyses and quantum ECD calculations. Notably, kumuquassin A (1) contains a rare Δ17, 20 double bond, kumuquassin B (2) is the first example of tirucallane triterpenoid possessing a 5/3 biheterocyclic ring system at the side chain. All the compounds were screened for the cytotoxicity against two human hepatoma cell lines, HepG2 and Hep3B, and several compounds exhibited promising activity. The most potential compound 3 was selected for cell cycle analysis, which showed that 3 could cause an accumulation of HepG2 cells at subG1 peak. Annexin V-FITC/PI staining further confirmed that compound 3 caused death of hepatoma cells through apoptosis induction.

    更新日期:2018-11-28
  • Anti-proliferative 3-deoxysphingomyelin analogs: Design, synthesis, biological evaluation and molecular docking of pyrrolidine-based 3-deoxysphingomyelin analogs as anticancer agents
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-26
    Ahmed H.E. Hassan, Hye Rim Park, Yoon Mi Yoon, Hye In Kim, Sung Yeun Yoo, Kun Won Lee, Yong Sup Lee

    Sphingomyelins and glycerophospholipids are structurally related phospholipids. Nevertheless, glycerophospholipids analogs are known as antitumor agents while sphingomyelin analogs were reported as cytoprotective agents. Herein, we have addressed the development of 3–deoxysphingomyelin analogs as cytotoxic agents possessing modified sphingobases. Thus, pyrrolidine-based 3–deoxysphingomyelin analogs were synthesized and evaluated against a panel of cell lines representing four major types of cancers. Compounds 3d, 4d and 6d elicited better GI50 values than the FDA approved drug miltefosine. Investigation of their impact on Akt phosphorylation as a possible mechanism for the antiproliferative activity of this class of compounds revealed that these compounds might elicit a concentration-dependent mechanism acting via inhibition of Akt phosphorylation at the lower concentration and possibly via disruption of membranes at the higher concentration. Molecular docking predicted their binding modes to Akt to involve polar head binding to the Pleckstrin homology domain and hydrophobic tail extension into a hydrophobic pocket connecting the Pleckstrin homology domain and the kinase domain. As a whole, the described work suggests compounds 3d, 4d and 6d as promising pyrrolidine-based 3–deoxysphingomyelin analogs for development of novel cancer therapies.

    更新日期:2018-11-28
  • Phenylpropanoids and lignans from Prunus tomentosa seeds as efficient β-amyloid (Aβ) aggregation inhibitors
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-26
    Qingbo Liu, Jie Wang, Bin Lin, Zhuo-Yang Cheng, Ming Bai, Shaochun Shi, Xiao-Xiao Huang, Shao-Jiang Song

    Alzheimer’s disease (AD) is characterized by the progressive accumulation of extracellular β-amyloid (Aβ) aggregates. Recently, lignans and phenylpropanoids are attracting increasing attention to discovery useful agents of inhibition on Aβ aggregation. In the present study, to develop potential agents for slowing the progression of AD, Prunus tomentosa seeds were selected as a raw material for bioactive compounds, which led to the separation of two pairs of new enantiomeric lignans and phenylpropanoids using chiral HPLC. The planar structures of these compounds were elucidated by spectroscopic data analyses. And their absolute configurations were determined by comparing of experimental and calculated electronic circular dichroism (ECD). The biosynthesis pathway was also discussed. Additionally, the inhibitory activity on Aβ aggregation of all optical pure compounds was tested by thioflavin T (ThT) assay. The isolates (1a, 1b, 2a and 2b) showed more potent inhibitory activity than positive control curcumin with inhibitory rate of 73.89±3.41% 78.69±1.50%, 63.25±2.68%, and 67.13±0.90% at 20 μM, respectively. More importantly, the inhibition profiles were explained by molecular dynamics and docking simulation studies.

    更新日期:2018-11-28
  • Combined Molecular Modeling and Cholinesterase Inhibition Studies on Some Natural and Semisynthetic O-Alkylcoumarin Derivatives
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-26
    Ilkay Erdogan Orhan, F. Sezer Senol Deniz, Ramin Ekhteiari Salmas, Serdar Durdagi, Francesco Epifano, Salvatore Genovese, Serena Fiorito

    Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer’s disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC50= 46.58 ± 0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC50= 7.01 ± 0.28 µM - 43.31 ± 3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC50= 7.01 ± 0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC50= 8.18 ± 0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug analysis and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies.

    更新日期:2018-11-28
  • Synthesis and computer-aided analysis of the role of linker for novel ligands of the 5-HT6 serotonin receptor among substituted 1,3,5-triazinylpiperazines
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-26
    Dorota Łażewska, Rafał Kurczab, Małgorzata Więcek, Grzegorz Satała, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik

    A series of 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazines was designed based on previously published 2-amino-4-benzyl-(4-methylpiperazin-1-yl)-1,3,5-triazines in order to evaluate the role of a linker between the triazine moiety and an aromatic substituent for the human serotonin 5-HT6 receptor affinity. As new linkers two carbon atoms (ethyl or ethenyl) or an oxyalkyl chain (methoxy, 2-ethoxy, 2-propoxy) were introduced. Affinities of the compounds for the 5-HT6R as the main target, and for the 5-HT1AR, 5-HT7R and D2R as competitive ones, were determined in the radioligand binding assays. Docking to the 5-HT6R homology model was performed to support SAR analysis. Results showed that the branching of the methoxyl linker increased affinity for the human 5-HT6R whereas an unsaturated bond within the linker dramatically reduced desirable activity. Both experimental and theoretical studies confirmed the previously postulated beneficial role of the aromatic size for interaction with the 5-HT6R. Thus, the largest naphthyl moiety yielded the highest activity. In particular, 4-(4-Methylpiperazin-1-yl)-6-(1-(naphthalen-1-yloxy)ethyl)-1,3,5-triazin-2-amine (24), the most potent 5-HT6R agent found (Ki = 23 nM), can be a new lead structure for further search and development.

    更新日期:2018-11-28
  • TDP-43 Specific Reduction Induced by Di-hydrophobic tags conjugated peptides
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-27
    Na Gao, Yun-Peng Huang, Ting-Ting Chu, Qian-Qian Li, Bing Zhou, Yong-Xiang Chen, Yu-Fen Zhao, Yan-Mei Li

    TAR DNA binding protein 43 (TDP-43) is a key target in amyotrophic lateral sclerosis (ALS) treatment. Here, based on hydrophobic tagging strategy, we designed and synthesized a series of single or double hydrophobic tags conjugated peptides D1-D8. Among them, it was found that D4 displayed strongest ability to induce TDP-43 degradation in cells. D4 could reduce TDP-43 induced cytotoxicity. Besides, D4 could reduce TDP-43 levels in a transgenic drosophila model.

    更新日期:2018-11-28
  • Synthesis of 8-hydroxyquinoline glyoconjugates and preliminary assay of their β1,4-GalT inhibitory and anti-cancer properties
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-24
    Monika Krawczyk, Gabriela Pastuch-Gawolek, Anna Mrozek-Wilczkiewicz, Michal Kuczak, Magdalena Skonieczna, Robert Musiol

    8-Hydroxyquinoline scaffold is a privileged structure used in designing a new active agents with therapeutic potential. Its connections with the sugar unit is formed to improve the pharmacokinetic properties. The broad spectrum of activity of quinoline derivatives, especially glycoconjugates, is often associated with the ability to chelate metal ions or with the ability to intercalate into DNA. Simple and effective methods of synthesis glycoconjugates of 8-hydroxyquinoline and 8-hydroxyquinaldine derivatives, containing an O-glycosidic bond or a 1,2,3-triazole linker in their structure, have been developed. The obtained glycoconjugates were tested for their ability to inhibit β-1,4-Galactosyltransferase, as well as inhibit cancer cell proliferation. It was found that used glycoconjugation strategy influenced both improvement of activity and improvement of the bioavailability of 8-HQ derivatives. Their activity depends on type of attached sugar, presence of protecting groups in sugar moiety and presence of a linker between sugar and quinolone aglycone.

    更新日期:2018-11-26
  • 1-(2-Hydroxy-5-((trimethylsilyl)ethynyl)phenyl)ethanone based α,β-unsaturated derivatives an alternate to non-sulfonamide carbonic anhydrase II inhibitors, synthesis via Sonogashira coupling, binding analysis, Lipinsk’s rule validation
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-24
    Jamaluddin Mahar, Aamer Saeed, Kevin D. Belfield, Fayaz Ali Larik, Pervaiz Ali Channar, Mehar Ali Kazi, Qamar Abbas, Mubashir Hassan, Hussain Raza, Sung-Yum Seo

    A novel series of silyl-yne containing chalcone derivatives 5a-5j was synthesized by exploiting Sonogashira coupling reaction and Claisen-Schimdt condensation reaction. The synthesized derivative were characterized by spectroscopic and elemental analysis. The selective inhibition of carbonic anhydrases is considered critical in the field of medicinal chemistry because carbonic anhydrases exits in several isoforms. Synthesized compounds were subjected to carbonic anhydrase –II assay. Except 5j, the other derivatives exhibited better potential than standard acetazolamide. Compound 5e was found to be potent derivative in the series with IC50 value 0.054±0.001µM. Binding analysis revealed that most potent derivative 5e binds in the active site of CA-II and single π-π stacking interaction was observed between ring structure of ligand and Phe129 having bond length 4.90Å. Pharmacokinetics elicited that compounds obey Lipinski’s rule and show significant drug score.

    更新日期:2018-11-26
  • Antitrypanosomal activity of epi-polygodial from Drimys brasiliensis and its effects in cellular membrane models at the air-water interface
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-24
    Giulia Elisa Guimarães Gonçalves, Thiago Rahal Morais, Kaio Santos Gomes, Thais Alves Costa-Silva, Andre Gustavo Tempone, João Henrique Ghilardi Lago, Luciano Caseli

    Epi-polygodial, a drimane sesquiterpene was isolated from Drimys brasiliensis (Winteraceae). This compound demonstrated high parasite selectivity towards Trypanosoma cruzi trypomastigotes (IC50 = 5.01 μM) with a selectivity index higher than 40. These results were correlated with the effects observed when this compound was incorporated in cellular membrane models of protozoans, represented by Langmuir monolayers of dipalmitoylphosphoethanolamine (DPPE). Surface pressure-area isotherms showed that epi-polygodial expands DPPE monolayers at higher areas and condenses them at lower areas, which was attributed to the preferential interaction with the polar heads of the lipid. This mechanism of action could be corroborated with Polarization-Modulation Reflection-Absorption Spectroscopy and Brewster Angle Microscopy. These results pointed to the fact that the interaction of epi-polygodial with DPPE monolayers at the air-water interface affects the physical chemical properties of the mixed film, which may be important to comprehend the interaction of this drug with cellular membranes at the molecular level.

    更新日期:2018-11-26
  • Encapsulation of ciprofloxacin within modified xanthan gum- chitosan based hydrogel for drug delivery
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Demiana H. Hanna, Gamal R. Saad

    The aim of the present work was to investigate the preparation of polyelectrolyte hydrogel as potential drug carrier for antibacterial Ciprofloxacin drug (CFX), intended for controlled release formulation. Hydrogel of N -trimehtyl chitosan (TMC)/sodium carboxymethyl xanthan gum (CMXG) was prepared and ciprofloxacin was employed as a model drug to investigate the loading and release performance of the prepared hydrogel. FTIR, DSC, TGA and SEM analysis were used to characterize the TMC/CMXG hydrogel and its CFX loaded hydrogel. The results showed that the ciprofloxacin was successfully incorporated and released from the prepared hydrogel without the loss of structural integrity or the change in its functionality. The encapsulation efficiency of CFX within the prepared hydrogel was found to be increased with increasing the concentration of drug reaching about 93.8 ±2.1 % with concentration of CFX 250 µg/ml. It was shown also that the drug is entrapped within the gel without significant interaction as confirmed from FTIR spectra and DSC analysis. In vitro release study in phosphate buffer saline (PBS), indicated the steady rise in cumulative drug release with the highest release amount, reaching about 96.1 ±1.8 % up to 150 min, whereby the gel with high drug loading efficiency (3.52 ±0.07 %) displayed faster and higher release rate than that of gel containing a smaller amount of drug (0.44 ±0.01%). The release kinetics of loaded drug followed zero-order kinetics. CFX drug loaded hydrogel showed high activity against the gram positive and gram negative bacterial strains due to the successful released of CFX from the CFX loaded hydrogel into the tested bacterial strains with the highest diameter of inhibition zone against Escherichia coli (67.0 ±1.0) as compared to reference antibiotic, Gentamicin (28 ±0.5). Cytotoxicity of the prepared hydrogel was examined in vitro using lung human normal cell lines and showed the highest cell viability (97 ±0.5 %) at concentration up to 50 µg/ml. Consequently, TMC/CMXG hydrogel can be proposed as new controlled release drug delivery system.

    更新日期:2018-11-24
  • Synthesis and anti-inflammatory activity of sulfonamides and carboxylates incorporating trimellitimides: dual cyclooxygenase/carbonic anhydrase inhibitory actions
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Alaa A.M. Abdel-Aziz, Andrea Angeli, Adel S. El-Azab, Mohammed E.A. Hammouda, Magda A. El-Sherbeny, Claudiu T. Supuran

    Trimellitimides 6-21 were prepared and investigated in vivo for anti-inflammatory and ulcerogenic effects and in vitro for cytotoxicity. They were subjected to in vitro cyclooxygenase (COX-1/2) and carbonic anhydrase inhibition protocols. Compounds 6-11 and 18 exhibited anti-inflammatory activities and had median effective doses (ED50) of 34.3–49.8 mg kg-1 and 63.6-86.6% edema inhibition relative to the reference drug celecoxib (ED50: 33.9 mg kg-1 and 85.2% edema inhibition). Compounds 6-11 and 18 were weakly cytotoxic at 10 μM against 59 cell lines compared with the reference standard 5-fluorouracil (5-FU). Compounds 6-11 had optimal selectivity against COX-2. The selectivity index (SI) range was > 200−490 and was comparable to that for celecoxib [COX-2 (SI) > 416.7]. In contrast, compounds 12, 13, and 16-18 were nonselective COX inhibitors with a selectivity index range of 0.92-0.25. The carbonic anhydrase inhibition assay showed that sulfonamide incorporating trimellitimides 6-11 inhibited the cytosolic isoforms hCA I and hCA II, and tumor-associated isoform hCA IX. They were relatively more susceptible to inhibition by compounds 8, 9, and 11. The KI ranges were 54.1−81.9 nM for hCA I, 25.9–55.1 nM for hCA II, and 46.0–348.3 nM for hCA IX. © 2018 Elsevier Science. All rights reserved.

    更新日期:2018-11-24
  • Novel salicylamide derivatives as potent multifunctional agents for the treatment of Alzheimer's disease: design, synthesis and biological evaluation
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Qing Song, Yan Li, Zhongcheng Cao, Xiaoming Qiang, Zhenghuai Tan, Yong Deng

    A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced Aβ1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC50 value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced Aβ1-42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu2+-induced Aβ1-42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.

    更新日期:2018-11-24
  • 1,3,4-Oxadiazole/chalcone hybrids: Design, synthesis, and inhibition of leukemia cell growth and EGFR, Src, IL-6 and STAT3 activities
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Marwa Ali A. Fathi, Amer Ali Abd El-Hafeez, Dalia Abdelhamid, Samar H. Abbas, Monica M. Montano, Mohamed Abdel-Aziz

    A new series of 1,3,4-oxadiazole/chalcone hybrids was designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as inhibitors of EGFR, Src, and IL-6. The synthesized compounds showed promising anticancer activity, particularly against leukemia, with 8v being the most potent. The synthesized compounds exhibited strong to moderate cytotoxic activities against K-562, KG-1a, and Jurkat leukemia cell lines in MTT assays. Compound 8v showed the strongest cytotoxic activity with IC50 of 1.95 µM, 2.36 µM and 3.45 µM against K-562, Jurkat and KG-1a leukemia cell lines, respectively. Moreover; the synthesized compounds inhibited EGFR, Src, and IL-6. Compound 8v was most effective at inhibiting EGFR (IC50= 0.24 μM), Src (IC50= 0.96 μM), and IL-6 (% of control= 20%). Additionally, most of the compounds decreased STAT3 activation.

    更新日期:2018-11-24
  • Ebsulfur as a potent scaffold for inhibition and labelling of New Delhi Metallo-β-lactamase-1 in vitro and in vivo
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Jianpeng Su, Jiayun Liu, Cheng Chen, Yuejuan Zhang, Kewu Yang

    The superbug infection caused by New Delhi metallo-β-lactamase (NDM-1) has grown into an emerging threat, labelling and inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. Here, we report a potent covalent scaffold, ebsulfur, for targeting the protein in vitro and in vivo. Enzymatic kinetic study indicated that eighteen ebsulfurs gained except 1a-b and 1f inhibited NDM-1, exhibiting an IC50 value ranging of 0.16-9 μM, and 1g was found to be the best, dose- and time-dependent inhibitor with an IC50 of 0.16 μM. Also, these ebsulfurs effectively restored the antibacterial activity of cefazolin against E. coli expressing NDM-1, and the best effect was observed to be from 1g, 1i and 1n, resulting in an 256-fold reduction in MIC of the antibiotic at a dose of 16 μg/mL. The equilibrium dialysis study implied that the ebsulfur disrupted the coordination of one Zn(II) ion at active site of NDM-1. Labelling of NDM-1 using a constructed fluorescent ebsulfur Ebs-R suggested that the inhibitor covalently bound to the target through SDS-PAGE analysis in vitro. Also, labelling NDM-1 in living E. coli cells with Ebs-R by confocal microscopic imaging showed the real-time distribution change process of intracellular recombinant protein NDM-1. Moreover, the cytotoxicity of these ebsulfurs against L929 mouse fibroblastic cells was tested, and their capability to restore antibacterial activity of antibiotic against clinical strains E.coli EC08 producing NDM-1 was determined. The ebsulfur scaffold proposed here is valuable for development of the covalent irreversible inhibitors of NDM-1, and also for labelling the target in vitro and in vivo.

    更新日期:2018-11-24
  • Biological Evaluation and Structure activity relationship of 9-methyl-1-phenyl-9H-pyrido[3,4-b]indole derivatives as anti-leishmanial agents
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Penta Ashok, Subhash Chander, Terry K. Smith, Rajnish Prakash Singh, Prabhat Nath Jha, Murugesan Sankaranarayanan

    A series of piperazinyl-β-carboline-3-carboxamide derivatives were designed through a molecular hybridization approach. Designed analogues were synthesized, characterized and evaluated for anti-leishmanial activity against Leishmania infantum and Leishmania donovani. In L. infantum inhibition assay, compounds 7d, 7g and 7c displayed potent inhibition of promastigotes (EC50 1.59, 1.47 and 3.73 µM respectively) and amastigotes (EC50 1.4, 1.9 and 2.6 µM respectively). SAR studies revealed that, para substitution of methoxy, chloro groups and methyl group on ortho position favored anti-leishmanial activity against L. infantum. Among these analogues 7d, 7h, 7n and 7g exhibited potent inhibition against L. donovani promastigotes (EC50 0.91, 4.0, 4.57 and 5.02 µM respectively), axenic amastigotes (EC50 0.9, 3.5, 2.2 and 3.8 µM respectively) and intracellular amastigotes (EC50 1.3, 7.8, 5.6 and 6.3 µM respectively). SAR studies suggested that, para substitution of methoxy group, para and meta substitution of chloro groups and benzyl replacement recommended for significant anti-leishmanial against L. donovani.

    更新日期:2018-11-24
  • 1,4-Dihydroquinazolin-3(2H)-yl benzamide derivatives as anti-inflammatory and analgesic agents with an improved gastric profile: Design, synthesis, COX-1/2 inhibitory activity and molecular docking study
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Asmaa Sakr, Hend Kothayer, Samy M. Ibrahim, Mohamed M. Baraka, Samar Rezq

    The design and synthesis of a new series of 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives (4a-o) as anti-inflammatory and analgesic agents and COX-1/2 inhibitors are reported. The target compounds (4a-o) were synthesized using a two-step scheme, and their chemical structures were confirmed with 1H NMR, 13C NMR, and mass spectra and elemental analysis. Compounds 4b, 4d, 4h, 4l, 4n and 4o showed the best in vitro COX-2 inhibitory activity (IC50 0.04-0.07 μM), which was nearly the same as that of the reference drug celecoxib (IC50 0.049 μM), but had a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory inhibition assay, compounds 4b, 4c, 4e, 4f, 4m and 4o showed better oedema inhibition percentages, ranging from 38.1% to 54.1%, than did diclofenac sodium (37.8%). An in vivo analgesic assay revealed that compounds 4b and 4n had a potential analgesic effect 4- to 21-fold more potent than that of indomethacin and diclofenac sodium. All the tested compounds showed an improved ulcerogenic index when compared to indomethacin. In the synthesized series, compound 4b showed the best biological activity in all the experiments. The docking study results agreed with the in vitro COX inhibition assay results. Moreover, the predicted in silico studies of all the compounds support their potential as drug candidates.

    更新日期:2018-11-24
  • Evaluation of blood-brain barrier penetration and examination of binding to human serum albumin of 7-O-arylpiperazinylcoumarins as potential antipsychotic agents
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Teresa Żołek, Orsolya Dömötör, Kinga Ostrowska, Éva A. Enyedy, Dorota Maciejewska

    The delivery of drugs to the brain is complicated by the multiple factors including low blood–brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT1A and 5-HT2A with particular analysis of the requirements for the CNS chemotherapeutics. The binding constants to human serum albumin (HSA) were determined at physiological pH using fluorescence spectroscopy, and then their mode of action was explained by analysis of theoretical HSA complexes. Dynamic simulation of systems allowed for reliable evaluation of the interaction strength. The analyzed coumarins were able to pass BBB, and they present good drug likeness properties. They showed high affinities to HSA (log KQ = 5.3 – 6.0 which corresponds to -8.12 – -7.15 kcal/mol of Gibbs free energy). The changes of the emission intensity upon binding to HSA were scrutinized showing the different mode of action for 4-phenylpiperazinylcoumarins. The values of computed Gibbs free energy and determined on the basis of experimentally obtained binding constants log KQ coincide suggesting a good quality of the theoretical model. Overall the 8-acetyl-7-O-arylpiperazinyl-4-methylcoumarin derivatives represent valuable lead compounds to be further tested in various preclinical assays as a possible chemotherapeutics against CNS diseases. Studied coumarins can be metabolized by cytochrome P450 to aldehydes and hydroxy derivatives. The existence of other binding sites inside HSA than Sudlow’s site 1 was postulated. The longer aliphatic linker between coumarin and piperazine moieties favored binding to HSA in other than Sudlow site 1 pocket.

    更新日期:2018-11-24
  • Discovery of a novel cathepsin inhibitor with dual autophagy-inducing and metastasis-inhibiting effects on breast cancer cells
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Lei Yuan, Jun Liu, Wenhui He, Youmei Bao, Lei Sheng, Chunyang Zou, Baichun Hu, Wentao Ge, Yang Liu, Jian Wang, Bin Lin, Yanchun Li, Enlong Ma

    Drug resistance and cancer cells metastasis have been the leading causes of chemotherapy failure and cancer-associated death in breast cancer patients. In present, various active molecules either exhibiting novel mechanism of action such as inducing autophagy or inhibiting metastasis have been developed to address these problems. However, the compounds exhibiting such dual functions have rarely been described. Previous work in our group showed that TSA, as a synthetic analog of asperphenamate, induced autophagic cell death in breast cancer cells instead of apoptosis. Furthermore, the target enzyme of TSA was predicted to be cathepin L (Cat L) by natural product consensus pharmacophore strategy. Accumulated evidences have shown that cathepsins are closely associated with migration and invasion of breast cancer cells. It seemed likely that TSA-like molecules may possess the dual functions of inducing autophagy and inhibiting metastasis. Therefore, sixty optically active derivatives were firstly designed and synthesized by replacing the A-ring moiety of TSA with other substituted-phenyl sulfonyl groups. Further cathepsin inhibitory activity assay showed that (S, S) and (S, R) isomers displayed no activity against four kinds of cathepsins (L, S, K, B), while all derivatives tested were inactive toward K and B subtypes. Compound 6a with meta-bromo substituent displayed the greatest inhibitory activity, and its inhibitory capability against Cat L and S was 3.9 and 11.5-fold more potent than that of TSA, respectively. Molecular docking also exhibited that 6a formed more hydrogen bonds or π-π contacts with Cat L or S than TSA. In order to determine whether 6a could play dual roles, its anti-cancer mechanism was further investigated. On the one hand, MDC staining experiment and western blotting analysis validated that 6a can induce autophagy in MDA-MB-231 cells. On the other hand, its metastatic inhibitory ability was also confirmed by wound healing and transwell chamber experiment.

    更新日期:2018-11-24
  • Heterocyclic cellular lipid peroxidation inhibitors inspired by the marine antioxidant barettin
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-22
    Christophe Labrière, Jeanette H Andersen, Marte Albrigtsen, Jørn H Hansen, Johan Svenson

    The marine environment remains a rich source for the discovery and development of novel bioactive compounds. The present paper describes the design, synthesis and biological evaluation of a library of small molecule heterocyclic mimetics of the marine 2,5-diketopiperazine barettin which is a powerful natural antioxidant. By mainly focusing on the influence from the brominated indole and heterocyclic core of barettin, a library of 19 compounds was prepared. The compounds comprised a heterocyclic core, either a 2,5 diketopiperazine, an imidazolidinedione or a thioxothiazolidinone, which were mainly monosubstituted with ranging bulky substituents. The prepared compounds were screened for activity in a cellular lipid peroxidation assay using HepG2 cells. Several of the synthetic compounds showed antioxidant properties superior to the positive control barettin. Two of the prepared compounds displayed inhibitory activity similar to commercial antioxidants with significant inhibition at low µg/mL concentrations. The toxicity of the compounds was also investigated against MRC-5 lung fibroblasts and none of the included compounds displayed any toxicity at 50 µg/mL.

    更新日期:2018-11-24
  • An alkali tolerant α-l-rhamnosidase from Fusarium moniliforme MTCC-2088 used in de-rhamnosylation of natural glycosides
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-20
    Dhirendra Kumar, Sarita Yadav, Sudha Yadava, K.D.S. Yadav

    Analkali tolerant α-L-rhamnosidase has been purified to homogeneity from the culture filtrate of a new fungal strain, Fusarium moniliforme MTCC-2088,using concentration by ultrafiltration and cation exchange chromatography on CM cellulose column. The molecular mass of the purified enzyme has been found to be 36.0 kDa using SDS-PAGE analysis. The Km value using p-nitrophenyl-α-L-rhamnopyranosideas the variable substrate in 0.2M sodium phosphate buffer pH10.5 at50 0C was 0.50 mM. The catalytic rate constant was15.6 s-1giving the values of kcat/Kmis 3.12x 104M-1s-1. The pH and temperature optima of the enzyme were 10.5 and 50°C, respectively. The purified enzyme had better stability at 10°C in basic pH medium. The enzyme derhamnosylated natural glycosides like naringin to prunin, rutin to isoquercitrin and hesperidin to hesperetin glucoside. The purified α-L-rhamnosidase has potential for enhancement of wine aroma.

    更新日期:2018-11-24
  • The first target specific, highly diastereoselective synthesis, design and characterization of pyranoquinolinyl acrylic aciddiasteromers as potential α-glucosidase inhibitors
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-20
    G. Lavanya, K. Venkatapathy, C.J. Magesh, M. Ramanathan, R. Jayasudha

    In the present investigation we report the first target specific, highly diastereoselective synthesis of new class of pyranoquinolinyl/furoquinolinyl-acrylic acid diastereomers and evaluation of their invitro α-glucosidase inhibitory activity. All the products were thoroughly characterized by 1H-NMR, 13C-NMR, FT-IR, Mass spectral and CHN analysis. A highly diastereoselective target specific route of synthesis for the biologically active diastereomers were developed by usingchiral catalyst Europium tris[3-heptafluoropropylhydroxyl methylene]-(-)-camporate (A) or Europiumtris[3-(trifluoromethyl)hydroxylmethylene]-(+)-camporate (B). It was found that among a set of 4 diastereomeric products obtained, exodiasteromers of pyranoquinolinyl acrylic acid adducts exhibited relatively high α-glucosidase inhibitory activity. The newly synthesized compounds exhibited IC50 values in the range of (0.40 ± 0.02 - 30.3 ± 0.84μM) as compared to standard acarbose (IC50=0.65± 0.02μM). It was found that compounds 11a, 11c, 11d and 12d were found to be more active than standard acarbose. It was also found that unsubstituted compound (11a) or compounds with chlorine or methoxy substituent (11c, 11d, 12d) showed potential α-glucosidase inhibitory activity. However a reversal in activity was observed with Nitro substituent (11b, 13b) wherein the endodiastereomers were found to be more active than exodiastereomers. Molecular docking studies were used for design of the compound and understand the mode of binding between the compound and target enzyme. A plausible mechanism for the diastereoselective synthesis was also proposed.

    更新日期:2018-11-24
  • Design, Synthesis and Structure-Activity Relationship Optimization of Phenanthridine Derivatives as New Wnt/β-catenin Signalling Pathway Agonists
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-19
    Duo-zhi Chen, Bi-juan Yang, Xiao-li He, Shi-rui Fan, Jie-yun Cai, Chen-xu Jing, HengZhang, Yu Zhang, Lin Li, Xiao-jiang Hao

    Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/β-catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/β-catenin signalling pathway,HLY78 is insufficient for further pharmacological study. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships (SARs) of HLY78-derived phenanthridine derivatives as agonists of the Wnt/β-catenin signalling pathway are presented. In this work, 36 derivatives were designed and synthesized with some derivatives exhibiting stronger Wnt activity than the activity of HLY78.In particular, one of them, 8-((1,3-dimethy-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro-phenanthridin-9-ol, exhibited strong Wnt active activity and is 10 times more potent than HLY78. The following SAR analysis suggests that a pyrazole group, especially at the C-8 position, is important for Wnt activation; a methyl group at the C-4position seems to be more beneficial for Wnt activation than ethyl; and oxidation of the C-6 position reduces the Wnt activation.

    更新日期:2018-11-24
  • Design, synthesis and cytotoxicity of chimeric Erlotinib-Alkylphospholipid hybrids
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-19
    Md. Maqusood Alam, Ahmed H.E. Hassan, Kun Won Lee, Min Chang Cho, Ji Seul Yang, Jiho Song, Kyung Hoon Min, Jongki Hong, Dong-Hyun Kim, Yong Sup Lee

    Two series of erlotinib-alkylphospholipid hybrids were prepared and evaluated for their antiproliferative activities against a panel of four cell lines representing lung, breast, liver and skin cancers using erlotinib and miltefosine as reference standards. Amide analogs elicited more enhanced cytotoxic activity than analogous esters. Amide derivatives 8d and 8e exhibited promising broad-spectrum antiproliferative activity and higher efficacy than reference erlotinib and miltefosine. Their cellular GI50 values was in the ranges of 24.7∼46.9 μM and 26.8∼43.1 μM for 8e and 8d respectively. Assay results of the inhibitory activity of the prepared compounds on EGFR kinase reaction and Akt phosphorylation in conjugation with statistical correlation analysis indicated that other mechanisms might contribute to their elicited cytotoxicities. In addition, statistical correlation analysis revealed that mechanisms of elicited cytotoxicities for amide series might be different from ester series. In addition, correlation analysis indicated variations in the mechanisms according to the types of cell line.

    更新日期:2018-11-21
  • Synthesis and biological evaluation of 7-(aminoalkyl)pyrazolo[1,5-a]pyrimidine derivatives as cathepsin K inhibitors
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-19
    Nejc Petek, Bogdan Štefane, Marko Novinec, Jurij Svete

    A series of novel 7-aminoalkyl substituted pyrazolo[1,5-a]pyrimidine derivatives were synthesized and tested for inhibition of cathepsin K. The synthetic methodology comprises cyclization of 5-aminopyrazoles with N-Boc-α-amino acid-derived ynones followed by transformation of the ester and the Boc-amino functions. It allows for easy diversification of the pyrazolo[1,5-a]pyrimidine scaffold at various positions. Molecular docking studies with pyrazolo[1,5-a]pyrimidine derivatives were also performed to elucidate the binding mode in the active site of cathepsin K. The synthesized compounds exhibited moderate inhibition activity (Ki ≥ 77 μM).

    更新日期:2018-11-21
  • Anti-melanogenesis potential of a new series of Morita-Baylis-Hillman adducts in B16F10 melanoma cell line
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-19
    Emna Ketata, Haitham Elleuch, Aref Neifar, Wafa Mihoubi, Wajdi Ayadi, Naziha Marrakchi, Farhat Rezgui, Ali Gargouri

    Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyses the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic fields. We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to find out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6-oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10-50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.

    更新日期:2018-11-21
  • Synthesis, molecular modeling and BACE-1 inhibitory study of tetrahydrobenzo[b] pyran derivatives
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-19
    Vijaya Bhaskar, Reshma Chowdary, Sheshagiri R. Dixit, Shrinivas D. Joshi

    β-Secretase (BACE1) has been broadly documented as one of the possible therapeutic targets for the treatment of Alzheimer’s disease. In this paper, we report the synthesis and the for β-secretase (BACE-1) inhibitory activity of new series of tetrahydrobenzo [b] pyran derivatives. One-pot synthesis of tetrahydrobenzo [b] pyrans was carried out by condensing aromatic aldehyde, malononitrile and 1,3-cyclohexanedione using ionic liquid 1-butyl-3-methyl imidazolium chloride ([bmIm]Cl-) in aqueous alcohol media. The addition of alcohol and water in the ratio of 1:2 keeps all the reactants in solution which facilitates the reaction and makes the product formation very easy. The synthesized compounds were subjected to BACE1 inhibition assay and six compounds, 4d, 4e, 4f, 4h, 4i, and 4p have shown significant IC50 values at micromolar level. Among these six active compounds, 4e was a potential inhibitor with its IC50 value in nanomolar range. All the synthesized compounds were docked onto the active site of β-Secretase enzyme.

    更新日期:2018-11-21
  • Immobilized Baliospermum montanum hydroxynitrile lyase catalyzed synthesis of chiral cyanohydrins
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-19
    Nisha Jangir, Santosh Kumar Padhi

    Hydroxynitrile lyase (HNL) catalyzed enantioselective C-C bond formation is an efficient approach to synthesize chiral cyanohydrins which are important building blocks in the synthesis of a number of fine chemicals, agrochemicals and pharmaceuticals. Immobilization of HNL is known to provide robustness, reusability and in some cases also enhances activity and selectivity.We optimized the preparation of immobilization of Baliospermium montanum HNL (BmHNL) by cross linking enzyme aggregate (CLEA) method and characterized it by SEM. Optimization of biocatalytic parameters was performed to obtain highest % conversion and ee of (S)-mandelonitrile from benzaldehyde using CLEA-BmHNL. The optimized reaction parameters were: 20 minutes of reaction time, 7 U of CLEA-BmHNL, 1.2 mM substrate, and 300 mM citrate buffer pH 4.2, that synthesized (S)-mandelonitrile in ∼99% ee and ∼60% conversion. Addition of organic solvent in CLEA-BmHNL biocatalysis did not improve in % ee or conversion of product unlike other CLEA-HNLs. CLEA-BmHNL could be successfully reused for eight consecutive cycles without loss of conversion or product formation and five cycles with a little loss in enantioselectivity. Eleven different chiral cyanohydrins were synthesized under optimal biocatalytic conditions in up to 99% ee and 59% conversion, however the % conversion and ee varied for different products. CLEA-BmHNL has improved the enantioselectivity of (S)-mandelonitrile synthesis compared to the use of purified BmHNL. Nine aldehydes not tested earlier with BmHNL were converted into their corresponding (S)-cyanohydrins for the first time using CLEA-BmHNL. Among the eleven (S)-cyanohydrins syntheses reported here, eight of them have not been synthesized by any CLEA-HNL. Overall, this study showed preparation, characterization of a stable, robust and recyclable biocatalyst i.e. CLEA-BmHNL and its biocatalytic application in the synthesis of different (S)-aromatic cyanohydrins.

    更新日期:2018-11-21
  • Repurposing Approach Identifies New Treatment Options for Invasive Fungal Disease
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-19
    Isis Regina Grenier Capoci, Daniella Renata Faria, Karina Mayumi Sakita, Franciele Abigail Vilugron Rodrigues, Patricia de Souza Bonfim-Mendonça, Tania Cristina Alexandrino Becker, Érika Seki Kioshima, Terezinha Inez Estivalet Svidzinski, Bernard Maigret

    Drug repositioning is the process of discovery, validation and marketing of previously approved drugs for new indications. Our aim was drug repositioning, using ligand-based and structure-based computational methods, of compounds that are similar to two hit compounds previously selected by our group that show promising antifungal activity. Through the ligand-based method, 100 compounds from each of three databases (MDDR, DrugBank and TargetMol) were selected by the Tanimoto coefficient, as similar to LMM5 or LMM11. These compounds were analyzed by the scaffold trees, and up to 10 compounds from each database were selected. The structure-based method (molecular docking) using thioredoxin reductase as the target drug was performed as a complementary approach, resulting in six compounds that were tested in an in vitro assay. All compounds, particularly raltegravir, showed antifungal activity against the genus Paracoccidioides. Raltegravir, an antiviral drug, showed promising antifungal activity against the experimental murine paracoccidioidomycosis, with significant reduction of the fungal burden and decreased alterations in the lung structure of mice treated with 1 mg/kg of raltegravir. In conclusion, the combination of two in silico methods for drug repositioning was able to select an antiviral drug with promising antifungal activity for treatment of paracoccidioidomycosis.

    更新日期:2018-11-21
  • Nitric oxide inhibitory limonoids as potential anti-neuroinflammatory agents from Swietenia mahagoni
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-19
    Zhaoyu Shi, Lijun An, Xueyuan Yang, Yaru Xi, Chenyue Zhang, Yuan Shuo, Jie Zhang, Da-Qing Jin, Yasushi Ohizumi, Dongho Lee, Jing Xu, Yuanqiang Guo

    Recent studies have revealed that there is a close relationship between neuroinflammation and Alzheimer's disease (AD) and compounds with anti-neuroinflammatory effects are potentially useful for the treatment of AD. A phytochemical investigation to obtain new neuroinflammatory inhibitors resulted in the isolation of four new and three known limonoids from Swietenia mahagoni. The structures of these limonoids were established by NMR, MS, and electronic circular dichroism (ECD) data analysis. Compounds 1−3 feature complicated polycyclic caged structures of limonoid orthoester and represent new examples of phragmalin-type limonoids. All of the isolates showed anti-neuroinflammatory activities by inhibiting nitric oxide (NO) release in LPS-induced murine microglial BV-2 cells with compounds 1 and 3−6 having IC50 values of 26.8, 26.1, 26.0, 37.1, and 16.5 μM, respectively. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the inducible nitric oxide synthase (iNOS) protein.

    更新日期:2018-11-20
  • Synthesis and Biological Evaluation of New Pyrazolone Schiff Bases as Monoamine Oxidase and Cholinesterase Inhibitors
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-17
    Fatih Tok, Bedia Koçyiğit-Kaymakçıoğlu, Begüm Nurpelin Sağlık, Serkan Levent, Yusuf Özkay, Zafer Asım Kaplancıklı

    In the current work, Schiff base derivatives of antipyrine were synthesized. The chemical characterization of the compounds was confirmed using IR, 1H-NMR, 13C-NMR and mass spectroscopies. The inhibitory potency of synthesized compounds was investigated towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes. Some of the compounds displayed significant inhibitory activity against AChE and MAO-B enzymes, respectively. According to AChE enzyme inhibition assay, compounds 3e and 3g were found as the most potent derivatives with IC50 values of 0.285 µM and 0.057 µM, respectively. Also, compounds 3a (IC50 = 0.114 µM), 3h (IC50 = 0.049 µM), and 3i (IC50 =0.054 µM) were the most active derivatives against MAO-B enzyme activity. So as to understand inhibition type, enzyme kinetics studies were carried out. Furthermore, molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) permeability predictions were applied to estimate pharmacokinetic profiles of synthesized compounds.

    更新日期:2018-11-17
  • Switching of Trp-214 intrinsic rotamer population in Human Serum Albumin: An insight into the aftermath of embracing therapeutic bioorganic luminophore Azapodophyllotoxin into Sudlow site I
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-16
    Soham Mukherjee, Kapil Ganorkar, Ajay Kumar, Naina Sehra, Sujit Kumar Ghosh

    Human serum albumin is perceived to be the most abundant protein in human blood plasma and functions as a major carrier of different enzymes and drugs inside human body. The present article puts in an effort to demonstrate the attitude adopted by human serum albumin towards a potential therapeutic luminophore 4-(2-Hydroxyethyl)-10-phenyl-3,4,6,7,8,10-hexahydro-1H-cyclopenta[g]furo[3,4-b]quinoline-1-one (HPFQ). HPFQ is a prodigy from azapodophyllotoxin class of compounds, which have been synthesized from the perspective of improved bioactivity than its prologue podophyllotoxins. While, HPFQ has proved to be highly bioactive against most cancer cell lines with best GI50 values of < 0.1 µM for a major number of cell lines; it also showed terrific fluorescent properties throughout the polarity scale, worthy of a promising imaging agent. The binding mechanism of HPFQ with HSA has been established by combining in vitro spectroscopic techniques, in silico molecular docking and induced fit docking (IFD). The competitive site-binding studies demonstrated that the otherwise anion-receptor sudlow site I of HSA nurtures neutral HPFQ with prudent affinity (Binding constant, K b = 0.74 x 105 M-1). The time-resolve fluorescence studies reveal an appreciable reduction in HSA average radiative lifetime against an increase in HPFQ concentration and provided evidence for Forster’s resonance energy transfer (FRET) being responsible for the dominant quenching mechanism, escorted by minor structural deformations in the backbone of protein structure. HPFQ institutes itself near Trp-214 within protein matrix, and subsequently the “hydrophobic amino acids” dominated cybotactic environment of Trp-214 experiences a reduction in the micropolarity. The allosteric modulation triggered by the stronger association of HPFQ with HSA leads towards minor deformation in secondary structure of protein. Sudlow site I of HSA proficiently embraces a favourable conformation like malleable dough to furnish space for arriving bioactive HPFQ molecule. HPFQ is also believed to administer the conformational regulation in HSA domain by affecting inter-conversion of HSA rotamers, which may prove to be an enlightening area to decode the preferable interaction between them. The juxtaposed spectroscopic research described herein is expected to embolden design of azapodophyllotoxin based anti-proliferative clinical agents for efficient in vivo bio-distribution employing HSA-centred drug delivery and administration systems.

    更新日期:2018-11-17
  • Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-16
    Zhong-Rui Li, Feng-Zhi Suo, Bo Hu, Yan-Jia Guo, Dong-Jun Fu, Bin Yu, Yi-Chao Zheng, Hong-Min Liu

    Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC50 of 3.98 ± 0.3 μM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting.

    更新日期:2018-11-16
  • SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-14
    Wagdy M. Eldehna, Mahmoud F. Abo-Ashour, Emanuela Berrino, Daniela Vullo, Hazem A. Ghabbour, Sara T. Al-Rashood, Ghada S. Hassan, Hamad M. Alkahtani, Abdulrahman A. Almehizia, Amal Alharbi, Hatem A. Abdel-Aziz, Claudiu T. Supuran

    SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (KIs: 0.21 – 7.1 nM), with 6- to 21-fold enhanced activity than SLC-0111 (KI = 45 nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 – >35714), hCA II (SI: 2 – 1689) and hCA IV (SI: 11 – >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.

    更新日期:2018-11-14
  • Synthesis and antioxidant activity of new lipophilic dihydropyridines
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-13
    Diego da Costa Cabrera, Eduarda Santa-Helena, Heloisa P. Leal, Renata Rodrigues de Moura, Luiz Eduardo Maia Nery, Carla Amorim Neves Gonçalves, Dennis Russowsky, Marcelo G. Montes D'Oca

    Dihydropyridines (DHPs) obtained from Hantzsch multicomponent reactions are an important pharmaceutical class of compounds marketed as antihypertensive (e.g., nifedipine, nitrendipine, and amlodipine) drugs. This study synthesized new symmetrical and unsymmetrical long-chain fatty DHPs using multicomponent reactions under metal-free conditions with sulfamic acid as a catalyst. The DHPs were tested for antioxidant activity using three different methods. The insertion of a long chain into the DHP core contributed to antioxidant potential, and compounds derived from nitro aldehydes have better antioxidant potential than the antihypertensive drug nifedipine. In addition, fatty analogs to nifedipine derived from palmitic and oleic chains showed similar antioxidant activity to the common standards butylated hydroxytoluene and vitamin E. These results showed that our new synthesized products may find novel applications as antioxidant additives or for tools for use in drug discovery.

    更新日期:2018-11-14
  • Neuroprotective effects of triterpenoid saponins from Medicago sativa L. against H2O2-induced oxidative stress in SH-SY5Y cells
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-13
    Xue-Gui Liu, Yu-Qiu Sun, Jun Bian, Ting Han, Dan-Dan Yue, Dan-Qi Li, Pin-Yi Gao

    Medicago sativa L. is a forage legume plant widely distributed in all continents. Six new triterpenoid saponins, Medicagoside A-F (1-6) and five known ones (7-11) were isolated from M. sativa. Their structures were determined via HRESIMS, 1D and 2D NMR analysis. Biologically, all the isolates displayed neuroprotective activities against H2O2-induced damage in SH-SY5Y cells. Among them, compounds 1, 3-5 and 10 exhibited striking neuroprotective activities at 100 μM, restoring cell viability range from 79.66% to 89.03%, relative to 79.46% (100 μM) of Trolox used as the positive control.

    更新日期:2018-11-13
  • Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer’s agents
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-13
    Naeimeh Salehi, Bi Bi Fatemeh Mirjalili, Hamid Nadri, Zahra Abdolahi, Hamid Forootanfar, Alireza Samzadeh-Kermani, Tuba Tüylü Küçükkılınç, Beyza Ayazgok, Saeed Emami, Ismaeil Haririan, Mohammad Sharifzadeh, Alireza Foroumadi, Mehdi Khoobi

    A novel series of benzylpyridinium-based benzoheterocycles (benzimidazole, benzoxazole or benzothiazole) were designed as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The title compounds 4a-q were conveniently synthesized via condensation reaction of 1,2-phenylenediamine, 2-aminophenol or 2-aminothiophenol with pyridin-4-carbalehyde, followed by N-benzylation using various benzyl halides. The results of in vitro biological assays revealed that most of them, especially 4c and 4g, had potent anticholinesterase activity comparable or more potent than reference drug, donepezil. The kinetic study demonstrated that the representative compound 4c inhibits AChE in competitive manner. According to the ligand-enzyme docking simulation, compound 4c occupied the active site at the vicinity of catalytic triad. The compounds 4c and 4g were found to be inhibitors of Aβ self-aggregation as well as AChE-induced Aβ aggregation. Meanwhile, these compounds could significantly protect PC12 cells against H2O2-induced injury and showed no toxicity against HepG2 cells. As multi-targeted structures, compounds 4c and 4g could be considered as promising candidate for further lead developments to treat Alzheimer’s disease.

    更新日期:2018-11-13
  • Introduction of Z-GP scaffold into procarbazine reduces spermatoxicity and myelosuppression
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-12
    Rikang Wang, Chao Zhang, Chaojun Zheng, Huilan Li, Xinshu Xie, Yi Jin, Zhijun Liu, Heru Chen

    Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or β position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-α (FAPα). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPα or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by α-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb.

    更新日期:2018-11-12
  • Design, synthesis, and biological activities of 1-aryl-(3-(2-styryl)phenyl)prop-2-en-1-ones
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-10
    Soon Young Shin, Junho Lee, Jihyun Park, Youngshim Lee, Seunghyun Ahn, Ji Hye Lee, Dongsoo Koh, Young Han Lee, Yoongho Lim
    更新日期:2018-11-10
  • Synthesis and evaluation of new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives as potent antibacterial agents effective against multidrug resistant Staphylococcus aureus
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-08
    Srikanth Gatadi, Jitendra Gour, Manjulika Shukla, Grace Kaul, Swetarka das, Arunava Dasgupta, Y.V. Madhavi, Sidharth Chopra, Srinivas Nanduri
    更新日期:2018-11-09
  • 更新日期:2018-11-08
  • Potential bioisosteres of β-uracilalanines derived from 1H-1,2,3-triazole-C-carboxylic acids
    Bioorgan. Chem. (IF 3.929) Pub Date : 2018-11-07
    Ewa Mironiuk-Puchalska, Włodzimierz Buchowicz, Piotr Grześkowiak, Patrycja Wińska, Monika Wielechowska, Olena Karatsai, Maria Jolanta Rędowicz, Maria Bretner, Mariola Koszytkowska-Stawińska
    更新日期:2018-11-08
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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