3,079
Views
9
CrossRef citations to date
0
Altmetric
Research Papers

Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights

, , , , , , & show all
Pages 1227-1240 | Received 26 Feb 2022, Accepted 30 Mar 2022, Published online: 26 Apr 2022

References

  • American Cancer Society. Cancer facts & figures. 2020.
  • Manning G, Whyte DB, Martinez R, et al. The protein kinase complement of the human genome. Science 2002;298:1912–34.
  • Parang K, G, Sun Protein kinase inhibitors drug discovery. In: Gad SC ed. Drug discovery handbook. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:1191–1257.
  • Roskoski R. Jr, Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res 2016;103:26–48.
  • Allam HA, Aly EE, Farouk A, et al. Design and Synthesis of some new 2,4,6-trisubstituted quinazoline EGFR inhibitors as targeted anticancer agents. Bioorg Chem 2020;98:103726.
  • Al-Sanea MM, Elkamhawy A, Paik S, et al. Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights. Bioorg Med Chem 2020;28:115525.
  • Alonso A, Sasin J, Bottini N, et al. Protein tyrosine phosphatases in the human genome. Cell 2004;117:699–711.
  • Bononi A, Agnoletto C, De Marchi E, et al. Protein kinases and phosphatases in the control of cell fate. Enzyme Res 2011;2011:329098.
  • Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009;9:28–39.
  • Fabbro D, Ruetz S, Buchdunger E, et al. Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther 2002;93:79–98.
  • Pearson M, C, García-Echeverría, D, Fabbro Protein tyrosine kinases as targets for cancer and other indications. In: Fabbro D, Mc Cormick F, eds. Protein tyrosine kinases – From Inhibitors to Useful Drugs. Totowa, NJ: Humana Press Inc.; 2006:1–29.
  • Sedlacek HH. Kinase inhibitors in cancer therapy: a look ahead. Drugs 2000;59:435–76.
  • Weinstein IB, Joe AK. Mechanisms of disease: Oncogene addiction-a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006;3:448–57.
  • Padma VV. An overview of targeted cancer therapy. BioMedicine 2015;5:19.
  • Aggarwal S. Targeted cancer therapies. Nat Rev Drug Discov 2010;9:427–8.
  • Topcul M, Cetin I. Endpoint of cancer treatment: targeted therapies. Asian Pac J Cancer Prev 2014;15:4395–403.
  • Malumbres M. Physiological relevance of cell cycle kinases. Physiol Rev 2011;91:973–1007.
  • Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci 2005;30:630–41.
  • Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009;8:547–66.
  • Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015;14:130–46.
  • Horiuchi D, Huskey NE, Kusdra L, et al. Chemical-genetic analysis of cyclin dependent kinase 2 function reveals an important role in cellular transformation by multiple oncogenic pathways. Proc Natl Acad Sci USA 2012;109:E1019–1027.
  • He X, Xiang H, Zong X, et al. CDK2-AP1 inhibits growth of breast cancer cells by regulating cell cycle and increasing docetaxel sensitivity in vivo and in vitro. Cancer Cell Int 2014;14:130.
  • Alexander A, Karakas C, Chen X, et al. Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer. Oncotarget 2017;8:14897–911.
  • Ding L, Cao J, Lin W, et al. The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer. Int J Mol Sci 2020;21(6):1960.
  • Harwell RM, Porter DC, Danes C, Keyomarsi K. Processing of cyclin E differs between normal and tumor breast cells. Cancer Res 2000;60:481–9.
  • Cooley A, Zelivianski S, Jeruss JS. Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines. Cell Cycle 2010;9:4900–7.
  • Luk KC, Simcox ME, Schutt A, et al. A new series of potent oxindole inhibitors of CDK2. Bioorg Med Chem Lett 2004;14:913–7.
  • Chohan TA, Qayyum A, Rehman K, et al. An insight into the emerging role of cyclin-dependent kinase inhibitors as potential therapeutic agents for the treatment of advanced cancers. Biomed Pharmacother 2018;107:1326–41.
  • Chohan TA, Qian H, Pan Y, Chen JZ. Cyclin-dependent kinase-2 as a target for cancer therapy: progress in the development of CDK2 inhibitors as anti-cancer agents. Curr Med Chem 2015;22:237–63.
  • Abd El-Karim SS, Syam YM, El Kerdawy AM, Abdelghany TM. New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis, CDK2 inhibition, QSAR and molecular docking studies. Bioorg Chem 2019;86:80–96.
  • Marak BN, Dowarah J, Khiangte L, Singh VP. A comprehensive insight on the recent development of Cyclic Dependent Kinase inhibitors as anticancer agents. Eur J Med Chem 2020;203:112571.
  • Ali S, Heathcote DA, Kroll SH, et al. The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity. Cancer Res 2009;69:6208–15.
  • Węsierska-Gądek J, Gritsch D, Zulehner N, et al. Roscovitine, a selective CDK inhibitor, reduces the basal and estrogen-induced phosphorylation of ER-α in human ER-positive breast cancer cells. J Cell Biochem 2011;112:761–72.
  • Johnson N, Bentley J, Wang LZ, et al. Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells. Br J Cancer 2010;102:342–50.
  • Alexander LT, Mobitz H, Drueckes P, et al. Type II Inhibitors Targeting CDK2. ACS Chem Biol 2015;10:2116–25.
  • Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nature Chemical Biology 2006;2:358–64.
  • Eldehna WM, Abou-Seri SM, El Kerdawy AM, et al. Increasing the binding affinity of VEGFR-2 inhibitors by extending their hydrophobic interaction with the active site: Design, synthesis and biological evaluation of 1-substituted-4-(4-methoxybenzyl)phthalazine derivatives. Eur J Med Chem 2016;113:50–62.
  • Eldehna WM, El Kerdawy AM, Al-Ansary GH, et al. Type IIA - Type IIB protein tyrosine kinase inhibitors hybridization as an efficient approach for potent multikinase inhibitor development: Design, synthesis, anti-proliferative activity, multikinase inhibitory activity and molecular modeling of novel indolinone-based ureides and amides. Eur J Med Chem 2019;163:37–53.
  • Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase inhibitors: Multi-targeted or single-targeted? World J Clin Oncol 2011;2:80–93.
  • Cheng W, Yang Z, Wang S, et al. Recent development of CDK inhibitors: An overview of CDK/inhibitor co-crystal structures. Eur J Med Chem 2019;164:615–39.
  • H. KhanamShamsuzzaman Bioactive Benzofuran derivatives: A review. Eur J Med Chem 2015;97:483–504.
  • Miao Y-h, Hu Y-h, Yang J, et al. Natural source, bioactivity and synthesis of benzofuran derivatives. RSC Adv 2019;9:27510–40.
  • Hassan GS, Georgey HH, George RF, Mohamed ER. Aurones and furoaurones: Biological activities and synthesis. Bull Fac Pharm Cairo Univ 2018;56:121–7.
  • Eldehna WM, Al-Rashood ST, Al-WAr˗Hi T, et al. Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies. J Enzyme Inhib Med Chem 2021;36:270–85.
  • Eldehna WM, Nocentini A, Elsayed ZM, et al. Benzofuran-Based Carboxylic Acids as Carbonic Anhydrase Inhibitors and Antiproliferative Agents against Breast Cancer. ACS Med Chem Lett 2020;11:1022–7.
  • Gaisina IN, Gallier F, Ougolkov AV, et al. From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3beta inhibitors that suppress proliferation and survival of pancreatic cancer cells. J Med Chem 2009;52:1853–63.
  • Salomé C, Narbonne V, Ribeiro N, et al. Benzofuran derivatives as a novel class of inhibitors of mTOR signaling. Euro J Med Chem 2014;74:41–9.
  • Salomé C, Ribeiro N, Chavagnan T, et al. Benzofuran derivatives as anticancer inhibitors of mTOR signaling. Euro J Med Chem 2014;81:181–91.
  • Xiang Y, Hirth B, Asmussen G, et al. The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors. Bioorg Med Chem Lett 2011;21:3050–6.
  • Abd El-Karim SS, Anwar MM, Mohamed NA, et al. Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran-pyrazole derivatives as anticancer agents. Bioorg Chem 2015;63:1–12.
  • Finlay MR, Acton DG, Andrews DM, et al. Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode. Bioorg Med Chem Lett 2008;18:4442–6.
  • Ananda Kumar CS, Benaka Prasad SB, Vinaya K, et al. Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines. Eur J Med Chem 2009;44:1223–9.
  • WALAYAT K, MOHSIN N-u-A, ASLAM S, AHMAD M. An insight into the therapeutic potential of piperazine-based anticancer agents. Turk J Chem 2019;43:1–23.
  • Chen P, Lee NV, Hu W, et al. Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance. Mol Cancer Ther 2016;15:2273–81.
  • Shaquiquzzaman M, Verma G, Marella A, et al. Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents. Eur J Med Chem 2015;102:487–529.
  • Rathi AK, Syed R, Shin HS, Patel RV. Piperazine derivatives for therapeutic use: a patent review (2010-present). Expert Opin Ther Pat 2016;26:777–97.
  • Yu Z, Wang R, Xu L, et al. β-Elemene piperazine derivatives induce apoptosis in human leukemia cells through downregulation of c-FLIP and generation of ROS. PLoS One 2011;6:e15843.
  • Vianello P, Botrugno OA, Cappa A, et al. Discovery of a novel inhibitor of histone lysine-specific demethylase 1A (KDM1A/LSD1) as orally active antitumor agent. J Med Chem 2016;59:1501–17.
  • Chung KS, Han G, Kim BK, et al. A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROS‑mediated c‑Abl/p38 MAPK signaling. Cancer Chemother Pharmacol 2013;72:1315–24.
  • Torrente E, Parodi C, Ercolani L, et al. Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy. J Med Chem 2015;58:5900–15.
  • Chetan B, Bunha M, Jagrat M, et al. Design, synthesis and anticancer activity of piperazine hydroxamates and their histone deacetylase (HDAC) inhibitory activity. Bioorg Med Chem Lett 2010;20:3906–10.
  • Sharath Kumar KS, Hanumappa A, Hegde M, et al. Synthesis and antiproliferative effect of novel 4-thiazolidinone-, pyridine- and piperazine-based conjugates on human leukemic cells. Eur J Med Chem 2014;81:341–9.
  • Arnatt CK, Adams JL, Zhang Z, et al. Design, syntheses, and characterization of piperazine based chemokine receptor CCR5 antagonists as anti prostate cancer agents. Bioorg Med Chem Lett 2014;24:2319–23.
  • Wang KR, Qian F, Sun Q, et al. Substituent Effects on Cytotoxic Activity, Spectroscopic Property, and DNA Binding Property of Naphthalimide Derivatives. Chem Biol Drug Des 2016;87:664–72.
  • Dessole G, JONES P, BUFI L,, et al. 1,2,4-oxadiazole substituted piperidine and piperazine derivatives as SMO Antagonists - WO/2010/013037. 2010.
  • Jones P, Ontoria Ontoria JM. Piperidine and piperazine derivatives as SMO Antagonists - WO/2011/036478. 2011.
  • FAJAS L, BENFODDA Z, FRITZ V. Novel inhibitors of stearoyl-coa-desaturase-1 and their uses - WO/2011/030312. 2011.
  • S, Wang, H, Zhou, J, Chen, et al., Bcl-2/bcl-xl inhibitors and therapeutic methods using the same - US20120189539A1. 2012.
  • Reiner T, Keliher EJ, Weissleder R. Compositions and methods for in vivo imaging - WO2012074840. 2012.
  • Rosell R, Gettinger SN, Bazhenova LA, et al. 1330: Brigatinib efficacy and safety in patients (Pts) with anaplastic lymphoma kinase (ALK)-positive (ALK+) non-small cell lung cancer (NSCLC) in a phase 1/2 trial. J Thorac Oncol 2016;11:S114.
  • Druker BJ. STI571 (Gleevec™) as a paradigm for cancer therapy. Trends Mol Med 2002;8:S14–S18.
  • De Falco V, Buonocore P, Muthu M, et al. Ponatinib (AP24534) is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer. J Clin Endocrinol Metab 2013;98:E811–819.
  • Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015;372:1700–9.
  • El-Miligy MM, Abd El Razik HA, Abu-Serie MM. Synthesis of piperazine-based thiazolidinones as VEGFR2 tyrosine kinase inhibitors inducing apoptosis. Fut Med Chem 2017;9:1709–29.
  • Sun J, Ren SZ, Lu XY, et al. Discovery of a series of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton as potential FAK inhibitors. Bioorg Med Chem 2017;25:2593–600.
  • Gao J, Fang C, Xiao Z, et al. Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9. Medchemcomm 2015;6:444–54.
  • Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev 2016;45:129–38.
  • Cherukupalli S, Chandrasekaran B, Krystof V, et al. Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors. Bioorg Chem 2018;79:46–59.
  • Oakes V, Wang W, Harrington B, et al. Cyclin A/Cdk2 regulates Cdh1 and claspin during late S/G2 phase of the cell cycle. Cell Cycle 2014;13:3302–11.
  • Martin A, Odajima J, Hunt SL, et al. Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1). Cancer Cell 2005;7:591–8.
  • Gorczyca W. Cytometric analyses to distinguish death processes. Endocr Relat Cancer 1999;6:17–9.
  • Mahajan P, Chashoo G, Gupta M, et al. Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors. J Chem Inf Model 2017;57:1957–69.
  • Shaldam M, Eldehna WM, Nocentini A, et al. Development of novel benzofuran-based SLC-0111 analogs as selective cancer-associated carbonic anhydrase isoform IX inhibitors. Eur J Med Chem 2021;216:113283.
  • Wasson BK, Hamel P, Rooney CS. A synthesis of 6-hydroxy-1-benzoxepin-3, 5 (2H, 4H)-dione. J Org Chem 1977;42:4265–6. no.
  • Coaviche-Yoval A, Luna H, Tovar-Miranda R, et al. Synthesis and biological evaluation of novel 2,3-disubstituted Benzofuran Analogues of GABA as Neurotropic Agents. Med Chem 2019;15:77–86.
  • Eldehna WM, El Hassab MA, Abo-Ashour MF, et al. Development of isatin-thiazolo[3,2-a]benzimidazole hybrids as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological and molecular dynamics investigations. Bioorg. Chem 2021;110:104748.
  • Eldehna W, Fares M, Ibrahim H, et al. Synthesis and cytotoxic activity of biphenylurea derivatives containing indolin-2-one moieties. Molecules 2016;21:762.
  • Abdel-Aziz HA, Ghabbour HA, Eldehna WM, et al. Synthesis, crystal structure, and biological activity of cis/trans amide rotomers of (Z)-N’-(2-oxoindolin-3-ylidene)formohydrazide. J Chem 2014;2014:1–7.
  • Sabt A, Eldehna WM, Al-Warhi T, et al. Discovery of 3,6-disubstituted pyridazines as a novel class of anticancer agents targeting cyclin-dependent kinase 2: synthesis, biological evaluation and in silico insights. J Enzyme Inhib Med Chem 2020;35:1616–30.