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Discovery and structure-activity relationship of novel 2,3-dihydrobenzofuran-7-carboxamide and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide derivatives as poly(ADP-ribose)polymerase-1 inhibitors.

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<div class='caption-title'>Synthesis of 5-Substituted 2,3-Dihydrobenzofuran-7-carboxamideDerivatives</div>
Patel MR, Bhatt A, Steffen JD, Chergui A, Murai J, Pommier Y, Pascal JM, Trombetta LD, Fronczek FR, Talele TT
OpenAccess logo J Med Chem 57 5579-601 (2014)
Related entries: 4opx, 4oqb

Cited: 21 times
EuropePMC logo PMID: 24922587

Abstract

Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3',4'-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4'-hydroxyl/4'-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.

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  1. Rational discovery of dual-indication multi-target PDE/Kinase inhibitor for precision anti-cancer therapy using structural systems pharmacology. Lim H, He D, Qiu Y, Krawczuk P, Sun X, Xie L. PLoS Comput Biol 15 e1006619 (2019)
  2. Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening. Shi D, Pang Q, Qin Q, Yao X, Yao X, Yu Y. Front Pharmacol 13 1026306 (2022)


Reviews citing this publication (5)

  1. PARP1: Structural insights and pharmacological targets for inhibition. Spiegel JO, Van Houten B, Durrant JD. DNA Repair (Amst) 103 103125 (2021)
  2. G4-quadruplex-binding proteins: review and insights into selectivity. Meier-Stephenson V. Biophys Rev 14 635-654 (2022)
  3. PARP inhibitors as antitumor agents: a patent update (2013-2015). Yuan Z, Chen J, Li W, Li D, Chen C, Gao C, Jiang Y. Expert Opin Ther Pat 27 363-382 (2017)
  4. Poly(ADP-ribose)--a unique natural polymer structural features, biological role and approaches to the chemical synthesis. Drenichev MS, Mikhailov SN. Nucleosides Nucleotides Nucleic Acids 34 258-276 (2015)
  5. A comprehensive look of poly(ADP-ribose) polymerase inhibition strategies and future directions for cancer therapy. Kumar C, Rani N, Velan Lakshmi PT, Arunachalam A. Future Med Chem 9 37-60 (2017)

Articles citing this publication (14)

  1. Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer. Fu L, Wang S, Wang X, Wang P, Zheng Y, Yao D, Guo M, Zhang L, Ouyang L. Sci Rep 6 3 (2016)
  2. AutoGrow4: an open-source genetic algorithm for de novo drug design and lead optimization. Spiegel JO, Durrant JD. J Cheminform 12 25 (2020)
  3. Early Treatment with Poly(ADP-Ribose) Polymerase-1 Inhibitor (JPI-289) Reduces Infarct Volume and Improves Long-Term Behavior in an Animal Model of Ischemic Stroke. Kim Y, Kim YS, Kim HY, Noh MY, Kim JY, Lee YJ, Kim J, Park J, Kim SH. Mol Neurobiol 55 7153-7163 (2018)
  4. Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy. Yuan Z, Chen S, Sun Q, Wang N, Li D, Miao S, Gao C, Chen Y, Tan C, Jiang Y. Bioorg Med Chem 25 4100-4109 (2017)
  5. Autonomous molecule generation using reinforcement learning and docking to develop potential novel inhibitors. Jeon W, Kim D. Sci Rep 10 22104 (2020)
  6. Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors. Yao H, Ji M, Zhu Z, Zhou J, Cao R, Chen X, Xu B. Bioorg Med Chem 23 681-693 (2015)
  7. New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy. Zhou Z, Zhou Z, Huang F, Shrivastava I, Zhu R, Luo A, Hottiger M, Bahar I, Liu Z, Cristofanilli M, Wan Y. EMBO Mol Med 12 e12391 (2020)
  8. Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity. Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT. J Med Chem 62 5330-5357 (2019)
  9. Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy. Yuan Z, Chen S, Chen C, Chen J, Chen C, Dai Q, Gao C, Jiang Y. Eur J Med Chem 138 1135-1146 (2017)
  10. A toolset of functionalized porphyrins with different linker strategies for application in bioconjugation. Staegemann MH, Gräfe S, Haag R, Wiehe A. Org Biomol Chem 14 9114-9132 (2016)
  11. Deciphering the functional mechanism of zinc ions of PARP1 binding with single strand breaks and double strand breaks. Sun S, Wang X, Lin R, Wang K. RSC Adv 12 19029-19039 (2022)
  12. How ligands regulate the binding of PARP1 with DNA: Deciphering the mechanism at the molecular level. Wang K, Wu Y, Lai L, Wang X, Sun S. PLoS One 18 e0290176 (2023)
  13. PARP1pred: a web server for screening the bioactivity of inhibitors against DNA repair enzyme PARP-1. Lerksuthirat T, Chitphuk S, Stitchantrakul W, Dejsuphong D, Malik AA, Nantasenamat C. EXCLI J 22 84-107 (2023)
  14. Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1 inhibitors. Shao X, Pak S, Velagapudi UK, Gobbooru S, Kommaraju SS, Low WK, Subramaniam G, Pathak SK, Talele TT. Bioorg Chem 102 104075 (2020)


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