Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase

Madak, Joseph T.; Cuthbertson, Christine R.; Miyata, Yoshinari; Tamura, Shuzo; Petrunak, Elyse M.; Stuckey, Jeanne A.; Han, Yanyan; He, Miao; Sun, Duxin; Showalter, Hollis D.; Neamati, Nouri

doi:10.1021/acs.jmedchem.7b01862

Title: Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase

Journal Article · Thu May 04 00:00:00 EDT 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b01862· OSTI ID:1499737

^[1]; Cuthbertson, Christine R. ^[1]; Miyata, Yoshinari ^[1]; Tamura, Shuzo ^[1]; Petrunak, Elyse M. ^[1]; Stuckey, Jeanne A. ^[1]; Han, Yanyan ^[1]; He, Miao ^[1]; Sun, Duxin ^[1]; Showalter, Hollis D. ^[1];

^[1]

Univ. of Michigan, Ann Arbor, MI (United States)

In this work, we pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinarbinding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinolinebased analogues 41 (DHODH IC₅₀ = 9.71 ± 1.4 nM) and 43 (DHODH IC₅₀ = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7- naphthyridine 46 (DHODH IC₅₀ = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability ($$F$$ = 56%) and an elimination $$t_{1/2}$$ = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor

Grant/Contract Number:: AC02-06CH11357; 085P1000817

OSTI ID:: 1499737

Journal Information:: Journal of Medicinal Chemistry, Vol. 61, Issue 12; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 41 works

Citation information provided by
Web of Science

References (53)

On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses Munier-Lehmann, Hélène; Vidalain, Pierre-Olivier; Tangy, Frédéric Journal of Medicinal Chemistry, Vol. 56, Issue 8 https://doi.org/10.1021/jm301848w	journal	March 2013
Recent Developments in the Medicinal Chemistry and Therapeutic Potential of Dihydroorotate Dehydrogenase (DHODH) Inhibitors K. Vyas, V.; Ghate, M. Mini-Reviews in Medicinal Chemistry, Vol. 11, Issue 12 https://doi.org/10.2174/138955711797247707	journal	October 2011
Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells Mohamad Fairus, A. K.; Choudhary, B.; Hosahalli, S. Biochimie, Vol. 135 https://doi.org/10.1016/j.biochi.2017.02.003	journal	April 2017
The dihydroorotate dehydrogenases: Past and present Reis, Renata A. G.; Calil, Felipe Antunes; Feliciano, Patricia Rosa Archives of Biochemistry and Biophysics, Vol. 632 https://doi.org/10.1016/j.abb.2017.06.019	journal	October 2017
Use of human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors in Autoimmune Diseases and New Perspectives in Cancer Therapy Lolli, Marco L.; Sainas, Stefano; Pippione, Agnese C. Recent Patents on Anti-Cancer Drug Discovery, Vol. 13, Issue 1 https://doi.org/10.2174/1574892812666171108124218	journal	January 2018
Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer Brown, Kristin K.; Spinelli, Jessica B.; Asara, John M. Cancer Discovery, Vol. 7, Issue 4 https://doi.org/10.1158/2159-8290.CD-16-0611	journal	March 2017
Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells Sharma, Arishya; Janocha, Allison J.; Hill, Brian T. Molecular Cancer Research, Vol. 12, Issue 9 https://doi.org/10.1158/1541-7786.MCR-14-0124	journal	July 2014
Leflunomide Induces Apoptosis in Fludarabine-Resistant and Clinically Refractory CLL Cells Dietrich, Sascha; Krämer, Oliver H.; Hahn, Esther Clinical Cancer Research, Vol. 18, Issue 2 https://doi.org/10.1158/1078-0432.CCR-11-1049	journal	November 2011
Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis He, T.; Haapa-Paananen, S.; Kaminskyy, V. O. Oncogene, Vol. 33, Issue 27 https://doi.org/10.1038/onc.2013.313	journal	September 2013
PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition Mathur, Deepti; Stratikopoulos, Elias; Ozturk, Sait Cancer Discovery, Vol. 7, Issue 4 https://doi.org/10.1158/2159-8290.CD-16-0612	journal	March 2017
DHODH modulates transcriptional elongation in the neural crest and melanoma White, Richard Mark; Cech, Jennifer; Ratanasirintrawoot, Sutheera Nature, Vol. 471, Issue 7339 https://doi.org/10.1038/nature09882	journal	March 2011
Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia Sykes, David B.; Kfoury, Youmna S.; Mercier, François E. Cell, Vol. 167, Issue 1 https://doi.org/10.1016/j.cell.2016.08.057	journal	September 2016
Multicenter Phase II Study of Brequinar Sodium in Patients with Advanced Breast Cancer Cody, Robert; Stewart, David; DeForni, Marcel American Journal of Clinical Oncology, Vol. 16, Issue 6 https://doi.org/10.1097/00000421-199312000-00014	journal	January 1993
Phase II trial with Brequinar (DUP-785, NSC 368390) in patients with metastatic colorectal cancer: A study of the Early Clinical Trials Group of the EORTC Dodion, P. F.; Wagener, Th.; Stoter, G. Annals of Oncology, Vol. 1, Issue 1 https://doi.org/10.1093/oxfordjournals.annonc.a057680	journal	January 1990
Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck Urba, Susan; Doroshow, James; Cripps, Christine Cancer Chemotherapy and Pharmacology, Vol. 31, Issue 2 https://doi.org/10.1007/BF00685106	journal	January 1992
Multicenter phase II study of brequinar sodium in patients with advanced gastrointestinal cancer Moore, Malcolm; Maroun, Jean; Robert, Francisco Investigational New Drugs, Vol. 11, Issue 1 https://doi.org/10.1007/BF00873913	journal	February 1993
Multicenter phase II study of brequinar sodium in patients with advanced lung cancer Maroun, Jean; Ruckdeschel, John; Natale, Ronald Cancer Chemotherapy and Pharmacology, Vol. 32, Issue 1 https://doi.org/10.1007/BF00685878	journal	January 1993
Short report: Multicenter phase II trial of brequinar sodium in patients with advanced melanoma Natale, R.; Wheeler, R.; Moore, M. Annals of Oncology, Vol. 3, Issue 8 https://doi.org/10.1093/oxfordjournals.annonc.a058298	journal	September 1992
Self-Association and Solubility Behaviors of a Novel Anticancer Agent, Brequinar Sodium King, Shang-Ying P.; Basista, Ann M.; Torosian, George Journal of Pharmaceutical Sciences, Vol. 78, Issue 2 https://doi.org/10.1002/jps.2600780204	journal	February 1989
Phase I Safety and Pharmacokinetic Studies of Brequinar Sodium after Single Ascending Oral Doses in Stable Renal, Hepatic, and Cardiac Allograft Recipients Joshi, Amita S.; King, Shang-Ying P.; Zajac, Barbara A. The Journal of Clinical Pharmacology, Vol. 37, Issue 12 https://doi.org/10.1002/j.1552-4604.1997.tb04296.x	journal	December 1997
Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases Fragoso, Yara Dadalti; Brooks, Joseph Bruno Bidin Expert Review of Clinical Pharmacology, Vol. 8, Issue 3 https://doi.org/10.1586/17512433.2015.1019343	journal	February 2015
Aryl hydrocarbon receptor agonist, leflunomide, protects the ischemic-reperfused kidney: role of Tregs and stem cells Baban, Babak; Liu, Jun Yao; Mozaffari, Mahmood S. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 303, Issue 11 https://doi.org/10.1152/ajpregu.00315.2012	journal	December 2012
Role of the aryl hydrocarbon receptor in drug metabolism Ramadoss, Preeti; Marcus, Craig; Perdew, Gary H. Expert Opinion on Drug Metabolism & Toxicology, Vol. 1, Issue 1 https://doi.org/10.1517/17425255.1.1.9	journal	June 2005
Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds Sainas, Stefano; Pippione, Agnese C.; Giorgis, Marta European Journal of Medicinal Chemistry, Vol. 129 https://doi.org/10.1016/j.ejmech.2017.02.017	journal	March 2017
Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents Liu, Shenping; Neidhardt, Edie A.; Grossman, Trudy H. Structure, Vol. 8, Issue 1 https://doi.org/10.1016/S0969-2126(00)00077-0	journal	January 2000
Structure-activity relationship of quinoline carboxylic acids Shih-Fong, Chen; Papp, Lisa M.; Ardecky, Robert J. Biochemical Pharmacology, Vol. 40, Issue 4 https://doi.org/10.1016/0006-2952(90)90305-5	journal	August 1990
Histidine to alanine mutants of human dihydroorotate dehydrogenase Davis, June P.; Copeland, Robert A. Biochemical Pharmacology, Vol. 54, Issue 4 https://doi.org/10.1016/S0006-2952(97)00197-4	journal	August 1997
Dual Binding Mode of a Novel Series of DHODH Inhibitors Baumgartner, Roland; Walloschek, Markus; Kralik, Martin Journal of Medicinal Chemistry, Vol. 49, Issue 4 https://doi.org/10.1021/jm0506975	journal	February 2006
A Medicinal Chemist’s Guide to Molecular Interactions Bissantz, Caterina; Kuhn, Bernd; Stahl, Martin Journal of Medicinal Chemistry, Vol. 53, Issue 14 https://doi.org/10.1021/jm100112j	journal	July 2010
The role of ligand efficiency metrics in drug discovery Hopkins, Andrew L.; Keserü, György M.; Leeson, Paul D. Nature Reviews Drug Discovery, Vol. 13, Issue 2 https://doi.org/10.1038/nrd4163	journal	January 2014
The Pfitzinger Reaction. (Review) Shvekhgeimer, M. G. -A. Chemistry of Heterocyclic Compounds, Vol. 40, Issue 3 https://doi.org/10.1023/B:COHC.0000028623.41308.e5	journal	March 2004
AlCl ₃ /PCC-SiO ₂ -Promoted Oxidation of Azaindoles and Indoles Sriram, Rekulapally; Sesha Sai Pavan Kumar, Chebolu Naga; Raghunandan, Nerella Synthetic Communications, Vol. 42, Issue 23 https://doi.org/10.1080/00397911.2011.584008	journal	August 2012
Use of Pyridinium Chlorochromate and Reusable Polyaniline Salt Catalyst Combination for the Oxidation of Indoles Kumar, Chebolu; Devi, Chebrolu; Rao, Vaidya Synlett, Vol. 2008, Issue 13 https://doi.org/10.1055/s-2008-1077974	journal	July 2008
Synthesis of novel 1,7-naphthyridines by Friedländer condensation of pyridine substrates Stockmann, Vegar; Fiksdahl, Anne Journal of Heterocyclic Chemistry, Vol. 48, Issue 6 https://doi.org/10.1002/jhet.657	journal	August 2011
Direct Access to 4-Carboxy-1,8-naphthyridines and Related Compounds through Pfitzinger-Type Chemistry Zong, Ruifa; Zhou, Hui; Thummel, Randolph P. The Journal of Organic Chemistry, Vol. 73, Issue 11 https://doi.org/10.1021/jo800456r	journal	May 2008
Regiospecific electrophilic substitution of aminopyridines: ortho lithiation of 2-, 3-, and 4-(pivaloylamino)pyridines Turner, James A. The Journal of Organic Chemistry, Vol. 48, Issue 20 https://doi.org/10.1021/jo00168a007	journal	October 1983
A general method for the synthesis of isatins: Preparation of regiospecifically functionalized isatins from anilines Hewawasam, Piyasena; Meanwell, Nicholas A. Tetrahedron Letters, Vol. 35, Issue 40 https://doi.org/10.1016/0040-4039(94)85299-5	journal	October 1994
Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390) Peters, G. J.; Sharma, S. L.; Laurensse, E. Investigational New Drugs, Vol. 5, Issue 3 https://doi.org/10.1007/BF00175293	journal	January 1987
Improvement in Aqueous Solubility in Small Molecule Drug Discovery Programs by Disruption of Molecular Planarity and Symmetry Ishikawa, Minoru; Hashimoto, Yuichi Journal of Medicinal Chemistry, Vol. 54, Issue 6 https://doi.org/10.1021/jm101356p	journal	March 2011
SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug Metabolism Rydberg, Patrik; Gloriam, David E.; Zaretzki, Jed ACS Medicinal Chemistry Letters, Vol. 1, Issue 3 https://doi.org/10.1021/ml100016x	journal	March 2010
Teriflunomide encourages cytostatic and apoptotic effects in premalignant and malignant cutaneous keratinocytes Hail, Numsen; Chen, Ping; Rower, Joseph Apoptosis, Vol. 15, Issue 10 https://doi.org/10.1007/s10495-010-0518-4	journal	June 2010
SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity Das, Priyabrata; Deng, Xiaoyi; Zhang, Liang ACS Medicinal Chemistry Letters, Vol. 4, Issue 6 https://doi.org/10.1021/ml300464h	journal	April 2013
The Structures of Human Dihydroorotate Dehydrogenase with and without Inhibitor Reveal Conformational Flexibility in the Inhibitor and Substrate Binding Sites ^† Walse, Björn; Dufe, Veronica Tamu; Svensson, Bo Biochemistry, Vol. 47, Issue 34 https://doi.org/10.1021/bi8003318	journal	August 2008
Synthesis of ortho -substituted aminopyridines. Metalation of pivaloylamino derivatives Estel, L.; Linard, F.; Marsais, F. Journal of Heterocyclic Chemistry, Vol. 26, Issue 1 https://doi.org/10.1002/jhet.5570260119	journal	January 1989
Design, Synthesis, and Biological Evaluation of 3-[4-(2-Hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4- b ]pyrazin-2(1 H )-one, a Potent, Orally Active, Brain Penetrant Inhibitor of Phosphodiesterase 5 (PDE5) Hughes, Robert O.; Rogier, D. Joseph; Jacobsen, E. Jon Journal of Medicinal Chemistry, Vol. 53, Issue 6 https://doi.org/10.1021/jm901781q	journal	March 2010
AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading Trott, Oleg; Olson, Arthur J. Journal of Computational Chemistry https://doi.org/10.1002/jcc.21334	journal	January 2009
Design, Synthesis, and Characterization of Brequinar Conjugates as Probes to Study DHODH Inhibition Madak, Joseph T.; Cuthbertson, Christine R.; Chen, Wenmin Chemistry - A European Journal, Vol. 23, Issue 56 https://doi.org/10.1002/chem.201702999	journal	September 2017
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
electronic Ligand Builder and Optimization Workbench ( eLBOW ): a tool for ligand coordinate and restraint generation Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10 https://doi.org/10.1107/S0907444909029436	journal	September 2009
Phase I and pharmacokinetic study of brequinar (DUP 785; NSC 368390) in cancer patients de Forni, M.; Armand, J. -P.; Fontana, X. European Journal of Cancer, Vol. 29, Issue 7 https://doi.org/10.1016/S0959-8049(05)80206-0	journal	January 1993

Cited By (5)

A novel series of human dihydroorotate dehydrogenase inhibitors discovered by in vitro screening: inhibition activity and crystallographic binding mode Zeng, Ting; Zuo, Zeping; Luo, Youfu FEBS Open Bio, Vol. 9, Issue 8 https://doi.org/10.1002/2211-5463.12658	journal	May 2019
An unexpected synthesis and application of ethyl 2,4-bis(chloromethyl)-6-iodoquinoline-3-carboxylate Li, Yang; Dong, Shiyu; Tang, Bingyue Research on Chemical Intermediates, Vol. 46, Issue 4 https://doi.org/10.1007/s11164-020-04088-w	journal	January 2020
Hydrothermal preparation, crystal structure, a series of properties and theoretical calculation of a novel cadmium compound Wang, Yin-Feng; Yi, Xiu-Guang; Fang, Xiao-Niu Inorganic and Nano-Metal Chemistry, Vol. 50, Issue 11 https://doi.org/10.1080/24701556.2020.1735430	journal	March 2020
New Quinoline-Based Heterocycles as Anticancer Agents Targeting Bcl-2 Hamdy, Rania; Elseginy, Samia; Ziedan, Noha Molecules, Vol. 24, Issue 7 https://doi.org/10.3390/molecules24071274	journal	April 2019
Discovery of 8-Amino-Substituted 2-Phenyl-2,7-Naphthyridinone Derivatives as New c-Kit/VEGFR-2 Kinase Inhibitors Sun, Haiyan; Zhuo, Linsheng; Dong, Huan Molecules, Vol. 24, Issue 24 https://doi.org/10.3390/molecules24244461	journal	December 2019

Similar Records

Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Journal Article · Wed Jan 20 00:00:00 EST 2010 · J. Biol. Chem. · OSTI ID:1499737

Deng, Xiaoyi; Gujjar, Ramesh; El Mazouni, Farah; +5 more

Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265

Journal Article · Tue Oct 30 00:00:00 EDT 2018 · ACS Infectious Diseases · OSTI ID:1499737

White, John; Dhingra, Satish K.; Deng, Xiaoyi; +10 more

Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model

Journal Article · Mon Nov 22 00:00:00 EST 2010 · J. Biol. Chem. · OSTI ID:1499737

Booker, Michael L; Bastos, Cecilia M; Kramer, Martin L; +26 more

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
High-performance liquid chromatography
Ethanol
Mixtures
Inhibitors
Alkyls

Title: Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase

Citation Formats

References (53)

Cited By (5)

Similar Records

Related Subjects