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  • Regio- and stereoselective synthesis of dispirooxindole-pyrrolocarbazole hybrids via 1,3-dipolar cycloaddition reactions: Cytotoxic activity and SAR studies
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-20
    Karunanidhi Murali, Hazel A. Sparkes, Karnam Jayarampillai Rajendra Prasad

    A library of novel dispiro compounds containing oxindole-pyrrolo-carbazole hybrid frame works has been synthesized in a fully regio- and stereoselective fashion by the three-component 1,3-dipolar cycloaddition of azomethineylides generated in situ from the condensation of isatins and benzylamine with 2-arylidene/heteroarylidene-2,3,4,9-tetrahydro-1H-carbazole-1-one. The structures of the compounds were established by FT-IR, 1H NMR, 13C NMR, X-ray diffraction and elemental analysis. The synthesized dispiro heterocycles have been screened for in vitro cytotoxic activity by MTT assay and displayed enviable growth inhibition on both the cancer cell lines i.e. breast cancer cell line MCF-7 and lung cancer cell line A-549. Morphological changes and apoptosis induction have been studied by inverted light microscopic, fluorescent microscopic techniques and by flow cytometry analyses. The preliminary structure activity relationships were also carried out. Data indicated that among dispiro-carbazole compounds,6-chloro-4'-(thiophen-2-yl)-5′-phenyl-3,4-dihydrodispiro[carbazole-2,3′-pyrrolo-2′,3″-indole]-9(H)-1,2″-dione 7e could be exploited as a significant therapeutic drug against breast cancer as well as lung cancer cell proliferation.

    更新日期:2017-11-20
  • Targeting tubulin polymerization by novel 7-aryl-pyrroloquinolinones: Synthesis, biological activity and SARs
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-20
    Roberta Bortolozzi, Elena Mattiuzzo, Matteo Dal Pra, Mattia Sturlese, Stefano Moro, Ernest Hamel, Davide Carta, Giampietro Viola, Maria Grazia Ferlin

    Earlier studies had confirmed that the 7-phenylpyrroloquinolinone (7-PPyQ) nucleus was an important scaffold for new chemotherapeutic drugs targeting microtubules. For wide-ranging SARs, a series of derivatives were synthesized through a robust procedure. For comparison with the reference 3-ethyl-7-PPyQ 31, the angular geometry and substituents at the 3 and 7 positions were varied to explore interactions inside the colchicine site of tubulin. Of the new compounds synthesized, potent cytotoxicity (low and sub-nanomolar GI50 values) was observed with 21 and 24, both more potent than 31, in both leukemic and solid tumor cell lines. Neither compound 21 nor 24 induced significant cell death in normal human lymphocytes, suggesting that the compounds may be selectively active against cancer cells. In particular, 24 was a potent inducer of apoptosis in the A549 and HeLa cell lines. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, indicating that cells treated with the compounds followed the intrinsic pathway of apoptosis. Moreover, immunoblot analysis revealed that compound 24 even at 50 nM reduced the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1. Finally, molecular docking studies of the newly synthesized compounds demonstrate that active pyrroloquinolinone derivatives strongly bind in the colchicine site of β-tubulin.

    更新日期:2017-11-20
  • Microwave-promoted facile access to 4-Aminoquinoline-phthalimides: Synthesis and anti-plasmodial evaluation
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-16
    Anu Rani, Amandeep Singh, Jiri Gut, Philip J. Rosenthal, Vipan Kumar

    Microwave promoted high yielding synthesis of 4-aminoquinoline-phthalimides was developed with an aim to evaluate their anti-plasmodial potential. The scaffolds with longer spacer length (n = 6, 8) between two pharmacophores and a halogen substituent on the phthalimide ring displayed good antiplasmodial activity. Compound 5w, with an optimum combination of hexyl chain as spacer along with a tetra-bromophthalimide ring proved to be most potent and non-cytotoxic among the series exhibiting an IC50 value of 0.10 μM.

    更新日期:2017-11-20
  • Synthesis and biological evaluation of sulfur-containing shikonin oxime derivatives as potential antineoplastic agents
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-14
    Guang Huang, Hui-Ran Zhao, Qing-Qing Meng, Qi-Jing Zhang, Jin-Yun Dong, Bao-quan Zhu, Shao-Shun Li

    As a continuation of our research on developing potent and potentially safe antineoplastic agents, a set of forty five sulfur-containing shikonin oxime derivatives were synthesized and evaluated for their in vitro cytotoxic activity against human colon cancer (HCT-15), gastric carcinoma (MGC-803), liver (Bel7402), breast (MCF-7) cancer cells and human skin fibroblast (HSF) cells. All the synthesized compounds exhibited potent cytotoxic activity selectively towards HCT-15 cells and did not display apparent toxicity to the normal HSF cells, some of which were more or comparatively effective to the parent compound against HCT-15, MGC-803 and Bel7402 cells. The most active agent 9m displayed high potency against human cancer cells with IC50 ranging from 0.27 ± 0.02 to 9.23 ± 0.12 μM. The structure-activity relationships (SARs) studies suggested that the nature of substituent group in the side chain is important for antitumor potency in vitro. Additionally, nitric oxide release studies revealed that the amount of nitric oxide generated from these oxime derivatives was relatively low. Furthermore, cellular mechanism investigations indicated that compound 9m could arrest cell cycle at G1 phase and induce a strong apoptotic response in HCT-15 cells. Moreover, western blot studies revealed that compound 9m induced apoptosis through the down-regulation of Bcl-2 and up-regulation of Bax, caspase 3 and 9. For all these reasons, compound 9m hold promising potential as antineoplastic agent.

    更新日期:2017-11-15
  • Identification of highly potent BTK and JAK3 dual inhibitors with improved activity for the treatment of B-cell lymphoma
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-01
    Yang Ge, Changyuan Wang, Shijie Song, Jiaxin Huang, Zhihao Liu, Yongming Li, Qiang Meng, Jianbin Zhang, Jihong Yao, Kexin Liu, Xiaodong Ma, Xiuli Sun

    The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors. Among these molecules, approximately two thirds displayed strong inhibitory capacity at less than 10 nM concentration, and four compounds (7e, 7g, 7m and 7n) could significantly inhibit the phosphorylation of BTK and JAK3 enzymes at concentrations lower than 1 nM. Additionally, these pyrimidine derivatives also exhibited enhanced activity to block the proliferation of B-cell lymphoma cells compared with the representative BTK inhibitor ibrutinib. In particular, two structure-specific compounds 7b and 7e displayed stronger activity than reference agents in cell-based evaluation, with IC50 values lower than 10 μM. Further biological studies, including flow cytometric analysis, and a xenograft model for in vivo evaluation, also indicated their efficacy and low toxicity in the treatment of B-cell lymphoma. These findings provide a new insight for the development of novel anti-B-cell lymphoma drugs with multi-target actions.

    更新日期:2017-11-15
  • Recent developments in Anti-Trichomonas research: An update review
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-13
    Veenu Bala, Yashpal S. Chhonker

    Trichomonas vaginalis is a major non-viral sexually-transmitted infection resulted into serious obstetrical and gynecological troubles. The increasing resistance to nitroimidazole therapy and recurrence makes it crucial to develop new drugs against trichomoniasis. Over the past few years, a large number of research articles highlighting the synthetic and natural product research to combat Trichomonas vaginalis have been published. Electronic databases were searched to collect all data from the year 2006 through June 2017 for anti-Trichomonas activity potential of synthetic and natural products. This review article put together the synthetic and natural product research to find out an effective metronidazole alternative to cure trichomoniasis.

    更新日期:2017-11-13
  • 1,2,4-Thiadiazolidin-3,5-diones as novel hydrogen sulfide donors
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-11
    Beatrice Severino, Angela Corvino, Ferdinando Fiorino, Paolo Luciano, Francesco Frecentese, Elisa Magli, Irene Saccone, Paola Di Vaio, Valentina Citi, Vincenzo Calderone, Luigi Servillo, Rosario Casale, Giuseppe Cirino, Valentina Vellecco, Mariarosaria Bucci, Elisa Perissutti, Vincenzo Santagada, Giuseppe Caliendo

    Hydrogen sulfide (H2S) is an endogenous modulator that plays significant physio-pathological roles in several biological systems. In this research field there is a large interest in developing selective CBS and CSE inhibitors and H2S releasing moieties, that could be either used as therapeutic agents or linked to known drugs. One of the major problem is the limited availability of chemicals that ensure a controlled release of H2S in vitro as well in vivo. Aiming to obtain novel H2S donors, whose release properties could be appropriately modulated, we have synthesized a series of 1,2,4-thiadiazolidine-3,5-diones (THIA 1–10) as innovative donors that could release H2S in controlled manner. All the synthesized compounds were evaluated for their H2S releasing properties by an amperometric approach and for their vasorelaxant ability on aorta rings. In order to rationalize the obtained results, a detailed study on the release mechanism has been performed using the most efficient H2S donor, THIA 3 (Cmax 65.4 μM and EC50 1.7 μM).

    更新日期:2017-11-11
  • New metalo-therapeutics of NSAIDs against human breast cancer cells
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-11
    Christina N. Banti, Constantina Papatriantafyllopoulou, Anastasios J. Tasiopoulos, Sotiris K. Hadjikakou

    The non steroidal anti-inflammatory drugs (NSAID's)-silver(I) metallodrugs of aspirin (aspH), salicylic acid (salH2), naproxen (napH) acid or p-hydrobenzoic acid (pHbzaH) and the mitochondriotropic triphenylarsine (tpAs) with the formulae [Ag(asp)(tpAs)3] (1), [Ag(salH)(tpAs)3] (2), [Ag(nap)(tpAs)3] (3) and {[Ag(pHbza)(tpAs)3]∙(dmf)} (4) and [Ag(tpAs)3(NO3)] (5) have been synthesized and characterized by m.p., FT-IR, UV-vis and 1H NMR, spectroscopic techniques and X-ray crystallography. The in vitro cytotoxic activity of 1–5 against human breast adenocarcinoma cancer cells: MCF-7 (positive to estrogen receptors (ERs)) and MDA-MB-231 (negative to estrogen receptors (ERs)) was evaluated. Compound 4 exhibits the stronger activity against MCF-7 (2.5 ± 0.1 μΜ), while 1 the strongest one against MDA-MB-231 (3.2 ± 0.3 μΜ). The IC50 values against normal human fetal lung fibroblast cells lie between 3.0 and 3.7 μΜ. The toxic effect of 1–5 was evaluated against normal human fetal lung fibroblast cells (MRC-5 cells). The IC50 values of 1–5 lie between 2.9 and 3.7 μΜ. The genotoxicity or not of 1–5 against MRC-5 cells was detected from the presence or absence of micronucleus using fluorescence microscopy. The presence of micronucleus in MRC-5 cells (3.0–3.7% in contrast to 1% of the untreated cells) confirms the in vitro toxic behaviour of the compounds. The apoptotic pathway, though the mitochondrion, was confirmed by cell cycle arrest (increasing of the apoptotic cells, in sub-G1 phase (3.5 (5) - 13.3% (4)) in contrast of 1.8% in the control group) and permeabilization of the mitochondrial membrane test (MMP assay). Moreover, the ability of 1–5 to interact with Calf Thymus (CT)-DNA was also studied. Compound 4 exhibits the highest DNA binding constant (Kb= (25.0 ± 9.7) × 104 M−1). The inhibitory activity of 1–5 against the enzyme lipoxygenase (LOX) is also investigated. The activity order is 1 > 4 > 3 > 2,5.

    更新日期:2017-11-11
  • Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-11
    Ilija N. Cvijetić, Tatjana Ž. Verbić, Pedro Ernesto de Resende, Paul Stapleton, Simon Gibbons, Ivan O. Juranić, Branko J. Drakulić, Mire Zloh

    Antimicrobial resistance (AMR) is a major health problem worldwide, because of ability of bacteria, fungi and viruses to evade known therapeutic agents used in treatment of infections. Aryldiketo acids (ADK) have shown antimicrobial activity against several resistant strains including Gram-positive Staphylococcus aureus bacteria. Our previous studies revealed that ADK analogues having bulky alkyl group in ortho position on a phenyl ring have up to ten times better activity than norfloxacin against the same strains. Rational modifications of analogues by introduction of hydrophobic substituents on the aromatic ring has led to more than tenfold increase in antibacterial activity against multidrug resistant Gram positive strains. To elucidate a potential mechanism of action for this potentially novel class of antimicrobials, several bacterial enzymes were identified as putative targets according to literature data and pharmacophoric similarity searches for potent ADK analogues. Among the seven bacterial targets chosen, the strongest favorable binding interactions were observed between most active analogue and S. aureus dehydrosqualene synthase and DNA gyrase. Furthermore, the docking results in combination with literature data suggest that these novel molecules could also target several other bacterial enzymes, including prenyl-transferases and methionine aminopeptidase. These results and our statistically significant 3D QSAR model could be used to guide the further design of more potent derivatives as well as in virtual screening for novel antibacterial agents.

    更新日期:2017-11-11
  • Synthesis and biological evaluation of novel alkylated polyamine analogues as potential anticancer agents
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-11
    Meng Li, Yuxia Wang, Chaochao Ge, Liping Chang, Chaojie Wang, Zhiyong Tian, Senzhen Wang, Fujun Dai, Luyao Zhao, Songqiang Xie

    A new class of polyamine analogues modified by alkylation at the terminal of the polyamine chain has been synthesized and their structures were determined by 1H NMR, 13C NMR, ESI-MS and elemental analysis. As the representative compound, 3f displayed a broad spectrum of anti-cancer effects by MTT assays. Tumor xenograft model and pulmonary metastasis model showed that compound 3f significantly suppressed tumor growth and metastasis in vivo, which was more stronger than the reference drug amonafide. Molecular mechanisms indicated that compound 3f exhibited antiproliferative activities and induced the generation of reactive oxygen species (ROS), which resulted in the occurrence of autophagy. The downregulated expression of MMP-9 and β-catenin by compound 3f accounted for the inhibition of migration. Taken altogether, the in vitro and in vivo biological evaluations corroborated compound 3f to be an effective anticancer agent.

    更新日期:2017-11-11
  • Design, synthesis and biological evaluation of novel benzimidazole amidines as potent multi-target inhibitors for the treatment of non-small cell lung cancer
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-11
    Andrea Bistrović, Luka Krstulović, Anja Harej, Petra Grbčić, Mirela Sedić, Sanja Koštrun, Sandra Kraljević Pavelić, Miroslav Bajić, Silvana Raić-Malić

    A series of novel amidino 2-substituted benzimidazoles linked to 1,4-disubstituted 1,2,3-triazoles were synthesized by implementation of microwave and ultrasound irradiation in click reaction and subsequent condensation of thus obtained 4-(1,2,3-triazol-1-yl)benzaldehyde with o-phenylenediamines. In vitro antiproliferative screening of compounds performed on human cancer cell lines revealed that p-chlorophenyl-substituted 1,2,3-triazolyl N-isopropylamidine 10c and benzyl-substituted 1,2,3-triazolyl imidazoline 11f benzimidazoles had selective and potent cytostatic activities in the low nM range against non-small cell lung cancer cell line A549, which could be attributed to induction of apoptosis and primary necrosis. Additional Western blot analyses showed different mechanisms of cytostatic activity between compounds 10c and 11f that could be associated with the nature of aromatic substituent at 1-(1,2,3-triazolyl) and amidino moiety at C-5 position of benzimidazole ring. Specifically, compound 11f abrogated the activity of several protein kinases including TGM2, CDK9, SK1 and p38 MAPK, whereas compound 10c did not have profound effect on the activities of CDK9 and TGM2, but instead showed moderate downregulation of SK1 activity concomitant with a significant reduction in p38 MAPK. Further in silico structural analysis demonstrated that compound 11f bound slightly better to the ATP binding site of p38 MAPK compared to 10c, which correlated well with observed stronger decrement in the expression level of phospho-p38 MAPK elicited by 11f in comparison with 10c.

    更新日期:2017-11-11
  • Design and synthesis of short amphiphilic cationic peptidomimetics based on biphenyl backbone as antibacterial agents
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-11
    Rajesh Kuppusamy, Muhammad Yasir, Thomas Berry, Charles G. Cranfield, Shashidhar Nizalapur, Eugene Yee, Onder Kimyon, Aditi Taunk, Kitty K.K. Ho, Bruce Cornell, Mike Manefield, Mark Willcox, David StC Black, Naresh Kumar

    Antimicrobial peptides (AMPs) and their synthetic mimics have received recent interest as new alternatives to traditional antibiotics in attempts to overcome the rise of antibiotic resistance in many microbes. AMPs are part of the natural defenses of most living organisms and they also have a unique mechanism of action against bacteria. Herein, a new series of short amphiphilic cationic peptidomimetics were synthesized by incorporating the 3′-amino-[1,1′-biphenyl]-3-carboxylic acid backbone to mimic the essential properties of natural AMPs. By altering hydrophobicity and charge, we identified the most potent analogue 25g that was active against both Gram-positive Staphylococcus aureus (MIC = 15.6 μM) and Gram-negative Escherichia coli (MIC = 7.8 μM) bacteria. Cytoplasmic permeability assay results revealed that 25g acts primarily by depolarization of lipids in cytoplasmic membranes. The active compounds were also investigated for their cytotoxicity to human cells, lysis of lipid bilayers using tethered bilayer lipid membranes (tBLMs) and their activity against established biofilms of S. aureus and E. coli.

    更新日期:2017-11-11
  • Therapeutic potential of songorine, a diterpenoid alkaloid of the genus Aconitum
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-11
    Haroon Khan, Seyed Mohammad Nabavi, Antoni Sureda, Nikolay Mehterov, Diana Gulei, Ioana Berindan-Neagoe, Hiroaki Taniguchi, Atanas G. Atanasov

    Alkaloids are well-studied secondary metabolites, with recent preclinical studies evidencing that many of them exhibit anti-cancer, anti-depressant, anti-nociceptive, anti-inflammatory, anti-pyretic, anti-platelet, anti-oxidant, and anti-bacterial properties. Aconitum is a genus rich of diverse alkaloids. More than 450 alkaloids have been identified in a variety of species. Songorine is a C20 diterpenoid alkaloid and 12-keto analog of napelline, isolated from Aconitum soongaricum and was associated with a heterogeneous panel of biological functions. However, the bioactivity profile of this natural product has not been reviewed up to now. The present manuscript aims to summarize the most important biological activities associated with songorine administration in preclinical models. The most significant data found in the scientific literature were evaluated in order to summarize the potential clinical utility of songorine in a diverse spectrum of pathologies and conditions. Songorine and its derivatives have many pharmacological effects including anti-arrhythmic, anti-cardiac-fibrillation, excitation of synaptic transmission, anxiolytic effects, anti-nociceptive, anti-inflammatory, anti-arthritis effects, and a regenerative effect in a skin excision wound animal model. Despite its outstanding pharmacotherapeutic potential, songorine has never been tested in clinical trials. Therefore, further evaluation is required to better evaluate its clinical utility.

    更新日期:2017-11-11
  • Functionalized 2,1-benzothiazine 2,2-dioxides as new inhibitors of Dengue NS5 RNA-dependent RNA polymerase
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-11
    Rolando Cannalire, Delia Tarantino, Andrea Astolfi, Maria Letizia Barreca, Stefano Sabatini, Serena Massari, Oriana Tabarrini, Mario Milani, Gilles Querat, Eloise Mastrangelo, Giuseppe Manfroni, Violetta Cecchetti

    Over recent years, many RNA viruses have been “re-discovered”, including life-threatening flaviviruses, such as Dengue, Zika, and several encephalitis viruses. Since no specific inhibitors are currently available to treat these infections, there is a pressing need for new therapeutics. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) represents a validated target being essential for viral replication and it has no human analog. To date, few NS5 RdRp inhibitor chemotypes have been reported and no inhibitors are currently in clinical development. In this context, after an in vitro screening against Dengue 3 NS5 RdRp of our in-house HCV NS5B inhibitors focused library, we found that 2,1-benzothiazine 2,2-dioxides are promising non-nucleoside inhibitors of flaviviral RdRp with compounds 8 and 10 showing IC50 of 0.6 and 0.9 μM, respectively. Preliminary structure-activity relationships indicated a key role for the C-4 benzoyl group and the importance of a properly functionalized C-6 phenoxy moiety to modulate potency. Compound 8 acts as non-competitive inhibitor and its proposed pose in the so-called N pocket of the RdRp thumb domain allowed to explain the key contribution of the benzoyl and the phenoxy moieties for the ligand binding.

    更新日期:2017-11-11
  • Design, synthesis, and biological evaluation of new 1,2,3-triazolo-2′-deoxy-2′-fluoro- 4′-azido nucleoside derivatives as potent anti-HBV agents
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-10
    Yuan Liu, Youmei Peng, Jingjing Lu, Jingwen Wang, Haoran Ma, Chuanjun Song, Bingjie Liu, Yan Qiao, Wenquan Yu, Jie Wu, Junbiao Chang

    Novel drugs are urgently needed to combat hepatitis B virus (HBV) infection due to drug-resistant virus. In this paper, a series of novel 4-monosubstituted 2′-deoxy-2′-β-fluoro-4′-azido-β-d-arabinofuranosyl 1,2,3-triazole nucleoside analogues (1a-g) were designed, synthesized and screened for in vitro anti-HBV activity. At 5.0 μM in the cellular model, all the synthetic compounds display activities comparable to that of the positive control, lamivudine at 20 μM. Of the compounds tested, the amide-substituted analogue (1a) shows the most promising anti-HBV activity and low cytotoxicity in the cell model. In particular, it retains excellent activity against lamivudine-resistant HBV mutants. In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (67.4% and 53.3%, respectively) were reduced markedly by the treatment with 1a. Analysis of the structure of HBV polymer/1a-triphosphate (1a-TP) complex shows that 1a-TP is stabilized by specific van der Waals interactions with the enzyme residues arising from 4-amino-1,2,3-triazole and the 4′-azido group.

    更新日期:2017-11-11
  • Molecular docking, design, synthesis and antifungal activity study of novel triazole derivatives
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-03
    Junqi Wu, Tingjunhong Ni, Xiaoyun Chai, Ting Wang, Hongrui Wang, Jindong Chen, Yongsheng Jin, Dazhi Zhang, Shichong Yu, Yuanying Jiang

    The incidence of life-threatening fungal infections has dramatically increased for decades. In order to develop novel antifungal agents, two series of (2R,3R)-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-substitutied)-2-butanols (3a-o, 5a-f, 8a-u), which were analogues of voriconazole, were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS. The MIC80 values showed that the target compounds 3a-o indicated better activities than fluconazole on three important fungal pathogens except for 3i. Significant activity of compounds 3d, 3k, 3n, 3m and 3o was observed on the Aspergillus fumigatus strain (MIC80 range: 1–0.125 μg/ml). Especially, compound 3k had strong activity to inhibit the growth of ten fungal pathogens. But it didn't exhibit good activity in in vivo value. Molecular docking experiments demonstrated that 3k possessed superior affinity with target enzyme by strong hydrogen bond from morpholine ring.

    更新日期:2017-11-11
  • Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-01
    Yan–Xiang Wang, Wei–Qiang Pang, Qing–Xuan Zeng, Zhe–Song Deng, Tian–Yun Fan, Jian–Dong Jiang, Hong–Bin Deng, Dan–Qing Song

    To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty–five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure–activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71–90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation.

    更新日期:2017-11-11
  • Synthesis of new 1-benzyl tetrahydropyridinylidene ammonium salts and their antimicrobial and anticellular activities
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-10
    Noor-ul-Amin Mohsin, Werner Seebacher, Johanna Faist, Patrick Hochegger, Marcel Kaiser, Pascal Mäser, Ferdinand Belaj, Robert Saf, Nadine Kretschmer, Muaaz Alajlani, Ivana Turek, Adelheid Brantner, Rudolf Bauer, Franz Bucar, Robert Weis

    A series of N-benzyl tetrahydropiperidinylidene pyrrolidinium salts have been synthesized and investigated for their antiplasmodial and antitrypanosomal activities as well as for their cytotoxic effects. The antibacterial, antimycobacterial and anticancer potencies of selected compounds were examined, too. Physicochemical parameters were calculated and structure-activity-relationships are discussed.

    更新日期:2017-11-10
  • Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-10
    Ridong Li, Xianling Ning, Shuo Zhou, Zhiqiang Lin, Xingyu Wu, Hong Chen, Xinyu Bai, Xin Wang, Zemei Ge, Runtao Li, Yuxin Yin

    Pyruvate kinase M2 isoform (PKM2) is a crucial protein responsible for aerobic glycolysis of cancer cells. Activation of PKM2 may alter aberrant metabolism in cancer cells. In this study, we discovered a 4-hydroxy-thiazolidine-2-thione compound 2 as a novel PKM2 activator from a random screening of an in-house compound library. Then a series of novel 4-hydroxy-thiazolidine-2-thione derivatives were designed and synthesized for screening as potent PKM2 activators. Among these, some compounds showed higher PKM2 activation activity than lead compound 2 and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound 5w was identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC50 values from 0.46 μM to 0.81 μM against H1299, HCT116, Hela and PC3 cell lines. 5w also showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound 5t was rationalized through docking studies.

    更新日期:2017-11-10
  • Photoresponsive azo-combretastatin A-4 analogues
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-10
    Shiva K. Rastogi, Zhenze Zhao, Scott L. Barrett, Spencer D. Shelton, Martina Zafferani, Hailee E. Anderson, Madeleine O. Blumenthal, Lindsey R. Jones, Lei Wang, Xiaopeng Li, Craig N. Streu, Liqin Du, William J. Brittain

    Colchicine analogues in which an azo group is incorporated into a molecule containing the key pharmacophore of colchicine, have found particular utility as switchable tubulin binding chemotherapeutics. Combretastatin is a related compound containing a stilbene fragment that shows different bioactivity for the cis and trans isomers. We have performed cell assays on 17 new compounds structurally related to a previously reported azo-analogue of combretastatin. One of these compounds showed enhanced potency against HeLa (IC50 = 0.11 μM) and H157 cells (IC50 = 0.20 μM) for cell studies under 400 nm irradiation and the highest photoactivity (IC50 with irradiation/IC50 in dark = 550). We have performed docking and physicochemical studies of this new compound (7). Kinetic studies in water reveal a longer half-life for the cis isomer of 7 which may be one factor responsible for the better IC50 values in cell assays and the improved photoresponsive behavior.

    更新日期:2017-11-10
  • Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-10
    Mao-Chia Yuan, Teng-Kuang Yeh, Chiung-Tong Chen, Jen-Shin Song, Yu-Chen Huang, Tsung-Chih Hsieh, Chung-Yu Huang, Yu-Ling Huang, Min-Hsien Wang, Szu-Huei Wu, Chun-Hsu Yao, Yu-Sheng Chao, Jinq-Chyi Lee

    Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C−N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 μM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 μM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.

    更新日期:2017-11-10
  • Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-10
    Han-Bo Liu, Wei-Wei Gao, Vijai Kumar Reddy Tangadanchu, Cheng-He Zhou, Rong-Xia Geng

    A series of novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents were designed, synthesized and characterized by IR, NMR and HRMS spectra. The biological evaluation in vitro revealed that some of the target compounds exerted good antibacterial and antifungal activity in comparison with the reference drugs. Noticeably, compound 7d could effectively inhibit the growth of A. flavus, E. coli DH52 and MRSA with MIC values of 1, 1 and 8 μg/mL, respectively. Further studies revealed that pyrimidine derivative 7d could exhibit bactericidal mode of action against both Gram positive (S. aureus and MRSA) and Gram negative (P. aeruginosa) bacteria. The active molecule 7d showed low cell toxicity and did not obviously trigger the development of resistance in bacteria even after 16 passages. Furthermore, compound 7d was able to beneficially regulate reactive oxygen species (ROS) generation for an excellent safety profile. Molecular docking study revealed that compound 7d could bind with DNA gyrase by the formation of hydrogen bonds. The preliminary exploration for antimicrobial mechanism disclosed that compound 7d could effectively intercalate into calf thymus DNA to form a steady supramolecular complex, which might further block DNA replication to exert the powerful bioactivities. The binding investigation of compound 7d with human serum albumins (HSA) revealed that this molecule could be effectively transported by HSA.

    更新日期:2017-11-10
  • Synthesis and pharmacological evaluation of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-09
    Yu-Tong Sun, Gui-Fei Wang, Yi-Qiu Yang, Fujun Jin, Yifei Wang, Xiao-Yang Xie, Robert H. Mach, Yun-Sheng Huang

    Increasing evidences have implicated that sigma-2 receptor is a biomarker and significantly over-expressed in many proliferative cancer cells with no or low expression in normal cells. Sigma-2 receptor selective ligands have been successfully used as valuable tools to study its pharmacological functions, tumor imaging, and cancer therapeutics or adjuvants. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolinylalkyl benzamides are among a few categories of structures that have demonstrated high affinities and selectivities for sigma-2 receptor and been used extensively as study tools in various tumor imaging and therapy. As a continuous effort, we have synthesized a new series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and evaluated their affinities for both sigma-1 and sigma-2 receptors. Most of these newly developed analogs showed good to excellent binding affinities for sigma-2 receptor with no or low affinities for sigma-1 receptor. In particular, compounds 3b, 3e, 4b, and 4e demonstrated Ki values of 5–6 nM affinities and excellent selectivities for sigma-2 receptor. In addition, these analogs also demonstrated moderate anticancer activities against human liver Huh-7 tumor cells and human esophagus KYSE-140 cancer cells. But their cytotoxicities seem not to be correlated with their sigma-2 receptor affinities.

    更新日期:2017-11-10
  • Synthesis, biological evaluation, and metabolic stability of phenazine derivatives as antibacterial agents
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-09
    Maddeboina Krishnaiah, Nathalia Rodrigues de Almeida, Venkatareddy Udumula, Zhongcheng Song, Yashpal Singh Chhonker, Mai M. Abdelmoaty, Valter Aragao do Nascimento, Daryl J. Murry, Martin Conda-Sheridan

    Drug-resistant pathogens are a major cause of hospital- and community-associated bacterial infections in the United States and around the world. These infections are increasingly difficult to treat due to the development of antibiotic resistance and the formation of bacterial biofilms. In the paper, a series of phenazines were synthesized and evaluated for their in vitro antimicrobial activity against Gram positive (methicillin resistant staphylococcus aureus, MRSA) and Gram negative (Escherichia coli, E. coli) bacteria. The compound 6,9-dichloro-N-(methylsulfonyl)phenazine-1-carboxamide (18c) proved to be the most active molecule (MIC = 16 μg/mL) against MRSA whereas 9-methyl-N-(methylsulfonyl)phenazine-1-carboxamide (30e) showed good activity against both MRSA (MIC = 32 μg/mL) and E. coli (MIC = 32 μg/mL). This molecule also demonstrated significant biofilm dispersion and inhibition against S. aureus. Preliminary studies indicate the molecules do not disturb bacterial membranes and there activity is not directly linked to the generation of reactive oxygen species. Compound 18c displayed minor toxicity against mammalian cells. Metabolic stability studies of the most promising compounds indicate stability towards phase I and phase II metabolizing enzymes.<img hspace="2" height="47" border="0" align="middle" width="219" vspace="2" alt="Image 2" title="Full-size image (26 K)" src="http://origin-ars.els-cdn.com/content/image/1-s2.0-S0223523417309212-fx2.sml" data-thumbE data-fullE>Figure options

    更新日期:2017-11-10
  • Synthesis and biological evaluation of a novel β-D-2′-deoxy-2′-α-fluoro-2′-β-C-(fluoromethyl)uridine phosphoramidate prodrug for the treatment of hepatitis C virus infection
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-09
    Ertong Li, Yafeng Wang, Wenquan Yu, Zhigang Lv, Youmei Peng, Bingjie Liu, Shiliang Li, Wenzhe Ho, Qingduan Wang, Honglin Li, Junbiao Chang

    A novel β-D-2′-deoxy-2′-α-fluoro-2′-β-C-(fluoromethyl)uridine phosphoramidate prodrug (1) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC50 = 0.18–1.13 μM) with low cytotoxicity (CC50 > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver.

    更新日期:2017-11-10
  • Camptothecin-psammaplin a hybrids as topoisomerase I and HDAC dual-action inhibitors
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-08
    Raffaella Cincinelli, Loana Musso, Roberto Artali, Mario Guglielmi, Erminia Bianchino, Francesco Cardile, Fabiana Colelli, Claudio Pisano, Sabrina Dallavalle

    Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM487 orthotopically xenografted in CD-1 nude mice and very high tolerability.

    更新日期:2017-11-10
  • Synthesis and bio-evaluation of indole-chalcone based benzopyrans as a promising antiligase and antiproliferative agent
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-07
    Sampa Gupta, Pooja Maurya, Akanksha Upadhyay, Pragati Kushwaha, Shagun Krishna, Mohammad Imran Siddiqi, Koneni V. Sashidhara, Dibyendu Banerjee

    DNA replication and repair are complex processes accomplished by the concerted action of a network of enzymes and proteins. DNA ligases play a crucial role in these processes by catalyzing the nick joining between DNA strands. As compared to normal cells, elevated levels of human DNA ligase I (hLigI) is reported in some cancers. We studied the inhibition of hLigI mediated DNA nick sealing activity followed by the antiproliferative activity of novel indole-chalcone based benzopyran compounds on cancer cells. One molecule called compound 27 showed a notable preference for inhibition of hLigI as compared to other ligases and showed enhanced cytotoxicity against colon cancer (DLD-1) cells as compared to normal cells. Mechanistic studies showed that compound 27 directly interacts with hLigI in a competitive manner and did not interact with the DNA substrate during ligation. This novel and potent hLigI inhibitor showed significant inhibition of both monolayer culture as well as 3D culture of DLD-1 cells that mimic solid tumor. It also affected the migration of DLD-1 cells indicating the potential anti-metastatic activity. This novel hLigI inhibitor could therefore serve as a promising lead for anticancer drug development.

    更新日期:2017-11-10
  • Design, syntheses and lipid accumulation inhibitory activities of novel resveratrol mimics
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-07
    Chanjuan Li, Bao Cheng, Sai Fang, Huihao Zhou, Qiong Gu, Jun Xu

    Hispidine was initially discovered from Ficus Hispida for cardiovascular protection. In this paper, hispidine derivatives, which contain a novel resveratrol-like scaffold, have been designed, synthesized, and assayed as agents against lipid accumulations in 3T3-L1 pre-adipocytes. Six hispidine derivatives have the activity of reducing TG in 3T3-L1 adipocytes in dosage-dependent manner. The most active compound can reduce the lipid accumulation up to 78.4% at 10 μM qPCR and Western blotting results demonstrate that the two most active compounds inhibit both lipodenesis and adipogenesis in 3T3-L1 cells through (1) increasing the phosphorylations of AMPK and ACC, promoting SIRT1 expression. These three proteins are key regulators for lipogenesis and energy metabolism. (2) Decreasing the expressions of PPARγ, sREBP-1c, and FABP4, which are pivotal regulators for adipogenesis. Overall, this work proves that hispidine derivatives diminish the lipid accumulation in 3T3-L1 cell line by downregulating lipogenic and adipogenic pathways.

    更新日期:2017-11-10
  • Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-07
    Daulat Bikram Khadka, Seojeong Park, Yifeng Jin, Jinhe Han, Youngjoo Kwon, Won-Jea Cho

    With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 μM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative 4cc revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit.

    更新日期:2017-11-10
  • Thieno[2,3-b]pyridine derivatives are potent anti-platelet drugs, inhibiting platelet activation, aggregation and showing synergy with aspirin
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-07
    Naif K. Binsaleh, Catherine A. Wigley, Kathryn A. Whitehead, Michelle van Rensburg, Johannes Reynisson, Lisa I. Pilkington, David Barker, Sarah Jones, Nina C. Dempsey-Hibbert

    Drugs which inhibit platelet function are commonly used to prevent blood clot formation in patients with Acute Coronary Syndromes (ACS) or those at risk of stroke. The thieno[3,2-c]pyridine class of therapeutic agents, of which clopidogrel is the most commonly used, target the P2Y12 receptor, and are often used in combination with acetylsalicylic acid (ASA). Six thieno[2,3-b]pyridine were assessed for in vitro anti-platelet activity; all derivatives showed effects on both platelet activation and aggregation, and showed synergy with ASA. Some compounds demonstrated greater activity when compared to clopidogrel. These compounds, therefore, represent potential novel P2Y12 inhibitors for improved treatment for patients.

    更新日期:2017-11-10
  • Design, synthesis and cytotoxic activity of N-Modified oleanolic saponins bearing A glucosamine
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-06
    You-Yu Lin, She-Hung Chan, Yu-Pu Juang, Hsin-Min Hsiao, Jih-Hwa Guh, Pi-Hui Liang

    A series of N-acyl, N-alkoxycarbonyl, and N-alkylcarbamoyl derivatives of 2′-deoxy-glucosyl bearing oleanolic saponins were synthesized and evaluated against HL-60, PC-3, and HT29 tumor cancer cells. The SAR studies revealed that the activity increased in order of conjugation of 2′ -amino group with carbamate > amide > urea derivatives. Lengthening the alkyl chain increased the cytotoxicity, the peak activity was found to around heptyl to nonyl substitutions. 2′-N-heptoxycarbonyl derivative 56 was found to be the most cytotoxic (IC50 = 0.76 μM) against HL-60 cells. Due to the interesting SARs of alkyl substitutions, we hypothesized that their location in the cell was different, and pursued a location study using 2′-(4″-pentynoylamino) 2′-deoxy-glucosyl OA, which suggested that these compounds distributed mainly in the cytosol.

    更新日期:2017-11-10
  • Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to overcome crizotinib-resistant mutants including G1202R
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-06
    Yu Wang, Shaowei Chen, Gang Hu, Jiao Wang, Wenfeng Gou, Daiying Zuo, Yucheng Gu, Ping Gong, Xin Zhai

    Aiming to explore novel anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) dual inhibitors to overcome crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine (DAAP) analogues bearing thiazole or 1,2,3-triazole moieties were designed and synthesized based upon the cocrystal structure of ceritinib with ALKWT (PDB 4MKC) as well as the binding model of ceritinib with ALKG1202R. The cellular and enzymatic assays validated 34c (WY-135) as a promising ALK (IC50 = 1.4 nM) and ROS1 (IC50 = 1.1 nM) dual inhibitor superior to crizotinib and ceritinib. 34c showed significantly inhibitory activities on ALK-dependent cell lines KARPAS299 (IC50 = 21 nM) and H2228 (IC50 = 95 nM) as well as ROS1-positive cell line HCC78 (IC50 = 40 nM). In particular, 34c was potent against a variety of frequently observed crizotinib-resistant mutants, particularly the L1196M mutant (IC50 = 3.1 nM) identified as the “gatekeeper” mutation and the G1202R mutant (IC50 = 8.7 nM) which conferred resistance to all clinical stage ALK inhibitors. Furthermore, 34c was capable of inducing cell apoptosis and strongly inhibiting cellular ALK and ROS1 activity. In addition, the binding models of 34c with ALKWT, ALKL1196M and ALKG1202R provided structural bases for SARs observations.

    更新日期:2017-11-10
  • Design, synthesis and pharmacological evaluation of N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-N-arylmethyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamides as potent Hsp90 inhibitors
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-06
    Chuanpeng Liang, Xingkang Wu, Zhenyu Li, Jing Zhu, Chunhua Lu, Yuemao Shen

    Using diverse arylmethyl groups to replace the benzyl moiety of the lead Hsp90 inhibitor 1 (N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-N-benzyl-1,2,3,4-tetrahydro-3-iso quinolinecarboxamide), thirty four derivatives (10–43) were developed, and exhibited improved Hsp90 inhibitory and antiproliferative activities. SAR analysis indicated that the southeastern aryl substitutions influenced their antiproliferative activities obviously, with the para-pyridyl group (41) outperforming all other substitution patterns. In this regard, compound 41 was selected for further evaluation. CETSA melt and ITDRFCETSA (isothermal dose-response fingerprint) curves for Hsp90α further proved that 41 interacted with intracellular Hsp90α more powerfully. Compared with the lead compound 1, docking and MD refinement of the Hsp90α-41 complex revealed a favorable H-bonding interaction between the side-chain of Tyr139 and the pyridine moiety of 41, which is the first time to be used for resorcinol-based Hsp90 inhibitors. With broad-spectral antitumor activity, compound 41 induced time- and dose-dependent growth inhibition and G0/G1 cell cycle arrest on human breast cancer MDA-MB-453 cell line. In addition, flow cytometry and Western blot analyses confirmed that 41 induced apoptosis of human breast cancer MDA-MB-453 cell line. Via degradation of IKKs and suppression of IKKs activity, compound 41 inhibited TNF-α-induced NF-κB activation. The overall properties warrant compound 41 a promising Hsp90 inhibitor and further biological characterizations. This study provides insights into the chemical evolution of Hsp90 inhibitors, and may facilitate the design of next generation Hsp90 inhibitors for the antitumor drug development.

    更新日期:2017-11-10
  • Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-06
    Junjie Lan, Lan Huang, Huayong Lou, Chao Chen, Tangjingjun Liu, Shengcao Hu, Yao Yao, Junrong Song, Jun Luo, Yazhou Liu, Bin Xia, Lei Xia, Xueyi zeng, Yaacov Ben-David, Weidong Pan

    Tetrandrine is a dibenzyltetrahydroisoquinoline alkaloid, isolated from traditional Chinese medicinal plant Stephania tetrandra, with anti-tumor activity. Our previous study identified several derivatives of tetrandrine showing better activities than parental compound against human hepatocellular carcinoma cells. To increase diversity and cytotoxic activities of the original compound, a series of novel 14-urea-tetrandrine derivatives were synthesized through structural modification of tetrandrine. These derivaties demonstrated a moderate to strong anti-proliferative activities against human cell lines HEL and K562 (Leukemia), prostate (PC3), breast (MDA-MB-231) and melanoma (WM9). Compound 4g showed strongest cytotoxic effect against PC3 cells with IC50 value of 0.64 μM, which was 12-fold, 31-fold and 26-fold lower than the parental tetrandrine, 5-fluorouracil and cisplatin, respectively. Preliminary structure-activity relationship study indicated that urea subsititution was the key pharmacophore for the enhancement of their antitumor activities. Induction of apoprosis by 4g was associated with the activation of pro-apoptotic protein BAX and inhibition of antiapoptosis proteins survivin as well as Bcl-2. Moreover, activation of caspases led to increase cleavage of PARP, which further accelerates apoptotic cell death. These results reveal that the compound 4g may be used as a potential anticancer drug candidate.

    更新日期:2017-11-10
  • Design, synthesis and preliminary biological evaluation of 5,8-dihydropteridine-6,7-diones that induce apoptosis and suppress cell migration
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-05
    Peng-Fei Geng, Cong-Cong Wang, Zhong-Hua Li, Xiao-Ning Hu, Tao-Qian Zhao, Dong-Jun Fu, Bing Zhao, Li-Ping Jiang, Bin Yu, Hong-Min Liu

    Pteridines are an important fused heterocyclic system found in natural products and drug molecules, and have shown diverse biological activities. A focused library of 5,8-dihydropteridine-6,7-dione derivatives was designed and evaluated for their antiproliferative activity against MGC-803, SGC-7901, A549 and PC-3 cancer cell lines. The SARs studies highlighted the importance of the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks for the activity and revealed essential structural elements. Among these compounds, compound 5n displayed the most potent and broad-spectrum proliferative inhibition against the tested cell lines and was sensitive to MGC-803 cell line, slightly more potent than 5-FU. Preliminary mechanistic studies showed that compound 5n could inhibit the colony formation and migration of MGC-803 cells. Besides, flow cytometry analysis showed that compound 5n concentration-dependently induced apoptosis of MGC-803 cells. Our studies suggest the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks may be regarded as new chemotypes for designing effective antitumor agents targeting gastric cancer cells.

    更新日期:2017-11-10
  • Synthesis and biological evaluation of curcumin inspired imidazo[1,2-a]pyridine analogues as tubulin polymerization inhibitors
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-05
    P.V.Sri Ramya, Lalita Guntuku, Srinivas Angapelly, Chander Singh Digwal, Uppu Jaya Lakshmi, Dilep Kumar Sigalapalli, Bathini Nagendra Babu, V.G.M. Naidu, Ahmed Kamal

    With an aim to develop new curcumin inspired analogues as potent anticancer agents, we synthesized a series of (1E,4E)-1-phenyl-5-(3-phenylimidazo[1,2-a]pyridin-2-yl)penta-1,4-dien-3-ones (12a–t) as tubulin polymerization inhibitors. An initial screening was carried out to evaluate their cytotoxic potential on a panel of six cancer cell lines namely, cervical (HeLa), gastric (HGC-27), lung (NCI-H460), prostate (DU-145 and PC-3) and breast (4T1), using MTT assay. Among the compounds tested, compounds 12e, 12r and 12t showed potent growth inhibition and 12t {(1E,4E)-1-(3-(3,4-difluorophenyl)imidazo[1,2-a]pyridin-2-yl)-5-(2,4,6-trimethoxyphenyl)penta-1,4-dien-3-one} being the most active member of the series inhibited the growth of all the tested cell lines with IC50 values varying from 1.7 – 2.97 μM. Moreover, 12t showed promising cytotoxicity on PC-3, HGC-27 and HeLa cell lines with IC50 values of 2.11 ± 0.27 μM, 2.21 ± 0.25 μM and 2.53 ± 0.01 μM respectively. The results from aqueous solubility test showed that compounds 12e and 12t have 1.7 and 2.8 times more aqueous solubility than curcumin. Interestingly, the most active compound 12t was found to be nearly 2 times more selective on PC-3 cells as well as safe on normal human prostate (RWPE-1) cells. In addition, compound 12t efficiently inhibited tubulin polymerization with IC50 value of 8.44 ± 0.13 μM and molecular modelling studies disclosed that 12t binds at the colchicine binding site of the tubulin. Cell cycle analysis revealed that 12t arrests PC-3 cells in G2/M phase in a dose dependant manner. Further, treatment of PC-3 cells with 12t showed typical apoptotic morphology, also led to the impairment of mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS). Altogether, the results from acridine orange/ethidium bromide (AO-EB) and DAPI staining studies, annexin V-FITC/propidium iodide staining assay, analysis of mitochondrial membrane potential (DΨm) and reactive oxygen species (ROS) levels undoubtedly demonstrated the induction of apoptosis in PC-3 cells by compound 12t.

    更新日期:2017-11-10
  • The Novel 4-Phenyl-2-Phenoxyacetamide Thiazoles modulates the tumor hypoxia leading to the crackdown of neoangiogenesis and evoking the cell death
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-04
    Yasser Hussein Eissa Mohammed, Vikas H. Malojirao, Prabhu Thirusangu, Mohammed Al-Ghorbani, B.T. Prabhakar, Shukath Ara Khanum
    更新日期:2017-11-05
  • Novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(1,3,5-triazin-2-ylamino)guanidine derivatives: Inhibition of human carbonic anhydrase cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII, anticancer activity, and molecular modeling studies
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-04
    Beata Żołnowska, Jarosław Sławiński, Krzysztof Szafrański, Andrea Angeli, Claudiu T. Supuran, Anna Kawiak, Miłosz Wieczór, Joanna Zielińska, Tomasz Bączek, Sylwia Bartoszewska
    更新日期:2017-11-05
  • Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-04
    Srinivasa Rao Ramisetti, Manoj K. Pandey, Sang Y. Lee, Deepkamal Karelia, Satya Narayan, Shantu Amin, Arun K. Sharma
    更新日期:2017-11-05
  • Newly designed organotin(IV) carboxylates with peptide linkage: Synthesis, structural elucidation, physicochemical characterizations and pharmacological investigations
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-04
    Muhammad Sirajuddin, Vickie McKee, Muhammad Tariq, Saqib Ali
    更新日期:2017-11-05
  • A green multicomponent synthesis of tocopherol analogues with antiproliferative activities
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-03
    Mariana Ingold, Rosina Dapueto, Sabina Victoria, Germán Galliusi, Carlos Batthyàny, Mariela Bollati-Fogolín, David Tejedor, Fernando García-Tellado, José M. Padrón, Williams Porcal, Gloria V. López
    更新日期:2017-11-05
  • Design, synthesis, biological evaluation and molecular modeling of novel 2-amino-4-(1-phenylethoxy) pyridine derivatives as potential ROS1 inhibitors
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-03
    Yuanxin Tian, Tingting Zhang, Lifan Long, Zhonghuang Li, Shanhe Wan, Guangfa Wang, Yonghuan Yu, Ju Hou, Xiaoyun Wu, Jiajie Zhang
    更新日期:2017-11-05
  • Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of α7 nicotinic receptors with analgesic activity
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-01
    Beatriz Balsera, José Mulet, Salvador Sala, Francisco Sala, Roberto de la Torre, Sara González-Rodríguez, Adrián Plata, Lieve Naesens, Asia Fernández-Carvajal, Antonio Ferrer-Montiel, Manuel Criado, María Jesús Pérez de Vega, Rosario González-Muñiz
    更新日期:2017-11-02
  • Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-11-01
    Laura L. Romero-Hernández, Penélope Merino-Montiel, Socorro Meza-Reyes, José Luis Vega-Baez, Óscar López, José M. Padrón, Sara Montiel-Smith
    更新日期:2017-11-02
  • Biological activity of dihydropyrimidinone (DHPM) derivatives: A systematic review
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-31
    Larizza Hellen Santana Matos, Flávia Teixeira Masson, Luiz Alberto Simeoni, Mauricio Homem-de-Mello
    更新日期:2017-11-01
  • Design and synthesis of sulfonamidophenylethylureas as novel cardiac myosin activator
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-31
    Manoj Manickam, Hitesh B. Jalani, Thanigaimalai Pillaiyar, Pulla Reddy Boggu, Niti Sharma, Eeda Venkateswararao, You-Jung Lee, Eun-Seok Jeon, Min-Jeong Son, Sun-Hee Woo, Sang-Hun Jung
    更新日期:2017-11-01
  • The structural requirements of histone deacetylase inhibitors: C4-modified SAHA analogs display dual HDAC6/HDAC8 selectivity
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-31
    Ahmed T. Negmeldin, Joseph R. Knoff, Mary Kay H. Pflum
    更新日期:2017-11-01
  • DMXAA-pyranoxanthone hybrids enhance inhibition activities against human cancer cells with multi-target functions
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-31
    Jie Liu, Fan Zhou, Lei Zhang, Huailing Wang, Jianrun Zhang, Cao Zhang, Zhenlei Jiang, Yanbing Li, Zhijun Liu, Heru Chen
    更新日期:2017-11-01
  • Design and synthesis of thienopyrimidine urea derivatives with potential cytotoxic and pro-apoptotic activity against breast cancer cell line MCF-7
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-28
    Eman F. Abdelhaleem, Mohammed K. Abdelhameid, Asmaa E. Kassab, Manal M. Kandeel
    更新日期:2017-10-30
  • Green, unexpected synthesis of bis-coumarin derivatives as potent anti-bacterial and anti-inflammatory agents
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-28
    Bahubali M. Chougala, S. Samundeeswari, Megharaja Holiyachi, Nirmala S. Naik, Lokesh A. Shastri, Suneel Dodamani, Sunil Jalalpure, Sheshagiri R. Dixit, Shrinivas D. Joshi, Vinay A. Sunagar
    更新日期:2017-10-28
  • Multivalent oleanolic acid human serum albumin conjugate as nonglycosylated neomucin for influenza virus capture and entry inhibition
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-28
    Yang Yang, Hao-Jie He, Hao Chang, Yao Yu, Mei-Bing Yang, Yun He, Zhen-Chuan Fan, Suri S. Iyer, Peng Yu
    更新日期:2017-10-28
  • Synthesis of bis-indolylmethanes as new potential inhibitors of β-glucuronidase and their molecular docking studies
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-26
    Muhammad Taha, Hayat Ullah, Laode Muhammad Ramadhan Al Muqarrabun, Muhammad Naseem Khan, Fazal Rahim, Norizan Ahmat, Muhammad Ali, Shahnaz Perveen
    更新日期:2017-10-27
  • Synthesis, crystal structure and biological evaluation of a new dasatinib copper(II) complex as telomerase inhibitor
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-25
    Qi-Pin Qin, Ting Meng, Ming-Xiong Tan, Yan-Cheng Liu, Xu-Jian Luo, Bi-Qun Zou, Hong Liang
    更新日期:2017-10-26
  • Synthesis, characterization, and antileishmanial activity of neutral N-heterocyclic carbenes gold(I) complexes
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-24
    Chen Zhang, Sandra Bourgeade Delmas, Álvaro Fernández Álvarez, Alexis Valentin, Catherine Hemmert, Heinz Gornitzka
    更新日期:2017-10-24
  • 1,4-Naphthoquinones potently inhibiting P2X7 receptor activity
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-23
    R.X. Faria, F.H. Oliveira, J.P. Salles, A.S. Oliveira, N.L. von Ranke, M.L. Bello, C.R. Rodrigues, H.C. Castro, A.R. Louvis, D.L. Martins, V.F. Ferreira
    更新日期:2017-10-24
  • Design, synthesis and biological evaluation of new β-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-23
    Jeshma Kovvuri, Burri Nagaraju, V. Lakshma Nayak, Ravikumar Akunuri, M.P. Narasimha Rao, Ayyappan Ajitha, Narayan Nagesh, Ahmed Kamal
    更新日期:2017-10-24
  • Development of 11C-Labeled ω-sulfhydryl fatty acid tracer for myocardial imaging with PET
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-23
    Xiangxiang Wu, Peizhi Wang, Ruixin Liu, Huahui Zeng, Fangfang Chao, Hao Liu, Caiyun Xu, Haifeng Hou, Qiong Yao
    更新日期:2017-10-23
  • Discovery of new potent molecular entities able to inhibit mPGES-1
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-23
    Simone Di Micco, Stefania Terracciano, Vincenza Cantone, Katrin Fischer, Andreas Koeberle, Antonio Foglia, Raffaele Riccio, Oliver Werz, Ines Bruno, Giuseppe Bifulco
    更新日期:2017-10-23
  • Conformationally rigid derivatives of WAY-267,464: Synthesis and pharmacology at the human oxytocin and Vasopressin-1a receptors
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-23
    William T. Jorgensen, Damien W. Gulliver, Timothy A. Katte, Eryn L. Werry, Tristan A. Reekie, Mark Connor, Michael Kassiou
    更新日期:2017-10-23
  • Indole and benzimidazole bichalcophenes: Synthesis, DNA binding and antiparasitic activity
    Eur. J. Med. Chem. (IF 4.519) Pub Date : 2017-10-22
    Abdelbasset A. Farahat, Mohamed A. Ismail, Arvind Kumar, Tanja Wenzler, Reto Brun, Ananya Paul, W. David Wilson, David W. Boykin
    更新日期:2017-10-23
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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