Indenopyrazole as a Privileged Structure in the Development of Anticancer Agents
DOI:
https://doi.org/10.12970/2308-8044.2017.05.01Keywords:
Checkpoint kinase 1, cyclin-dependent kinases, epidermal growth factor receptor, hypoxia-inducible factor 1, indenopyrazoles, inhibitors, platelet-derived growth factor receptor, privileged structures, tubulin polymerization, vascular endothelial growth factor.Abstract
A Privileged structureis a molecular scaffold that can provide potent and selective ligands for a range of different biological targets through modification of functional groups. Indenopyrazole is a three ringed heterocyclic structure consisting of a benzene ring, a central 5-membered ring and a pyrazole ring. As a privileged structure, indenopyrazole has been extensively used in recent years in the design of anticancer agents with versatile targets. A number of indenopyrazole derivatives displayed potent anticancer activities as checkpoint kinase 1, epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, cyclin-dependent kinases, and tubulin polymerization inhibitors, among many others. This review will summarize the recent development of indenopyrazoles as anticancer agents, discuss their SARs.References
Duarte CD, Barreiro EJ, Fraga CA. Privileged structures: a useful concept for the rational design of new lead drug candidates. Mini-Rev Med Chem 2007; 7(11): 1108-1119. http://dx.doi.org/10.2174/138955707782331722
Evans BE, Rittle KE, Bock MG, DiPardo RM, Freidinger RM, Whitter WL, et al. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J Med Chem 1988; 31(12): 2235-2246. http://dx.doi.org/10.1021/jm00120a002
DeSimone RW, Currie KS, Mitchell SA, Darrow JW, Pippin DA. Privileged structures: Applications in drug discovery. Comb Chem High T Scr 2004; 7(5): 473-493. http://dx.doi.org/10.2174/1386207043328544
Boyd GV. Pseudoazulenes containing 2 fused 5- memberedrings. Tetrahedron Lett 1965; 6(19): 1421-1426. http://dx.doi.org/10.1016/S0040-4039(00)90081-9
Lemke TL, Cramer MB, Shanmugam K. Heterocyclic tricycles as potential CNS agents I: 4-Aminoalkylindeno[1,2- c]pyrazoles. J Pharm Sci 1978; 67(10): 1377-1381. http://dx.doi.org/10.1002/jps.2600671012
Ali MA, Bastian S, Ismail R, Choon TS, Ali S, Aubry A, Pandian S, et al. Discovery of novel methanone derivatives acting as antimycobacterial agents. J Enzyme Inhib Med Chem 2011; 26(6): 890-894. http://dx.doi.org/10.3109/14756366.2011.559945
Ahsan MJ, Samy JG, Dutt KR, Agrawal UK, Yadav BS, Vyas S, et al. Design, synthesis and antimycobacterial evaluation of novel 3-substituted-N-aryl-6,7-dimethoxy-3a,4-dihydro-3Hindeno[1,2-c]pyrazole-2-carboxamide analogues. Bioorg Med Chem Lett 2011; 21(15): 4451-4453. http://dx.doi.org/10.1016/j.bmcl.2011.06.018
Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004; 73: 39- 85. http://dx.doi.org/10.1146/annurev.biochem.73.011303.07372 3
Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature 2004; 432(7015): 316-323. http://dx.doi.org/10.1038/nature03097
Zhou BB, Bartek J. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 2004; 4(3): 216-225. http://dx.doi.org/10.1038/nrc1296
Tao Z-F, Lin N-H. Chk1 inhibitors for novel cancer treatment. Anti-Cancer Agents Med Chem 2006; 6(4): 377-388. http://dx.doi.org/10.2174/187152006777698132
Tong Y, Claiborne A, Stewart KD, Park C, Kovar P, Chen Z, et al. Discovery of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of potent and selective checkpoint kinase 1 inhibitors. Bioorg Med Chem 2007; 15(7): 2759-2767. http://dx.doi.org/10.1016/j.bmc.2007.01.012
Tao ZF, Li G, Tong Y, Chen Z, Merta P, Kovar P, et al. Synthesis and biological evaluation of 4'-(6,7-disubstituted2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol as potent Chk1 inhibitors. Bioorg Med Chem Lett 2007; 17(15): 4308- 4315. http://dx.doi.org/10.1016/j.bmcl.2007.05.027
Tong Y, Claiborne A, Pyzytulinska M, Tao ZF, Stewart KD, Kovar P, et al. 1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: extended exploration on phenyl ring substitutions and preliminary ADME/PK studies. Bioorg Med Chem Lett 2007; 17(13): 3618-3623. http://dx.doi.org/10.1016/j.bmcl.2007.04.055
Tao ZF, Li G, Tong Y, Stewart KD, Chen Z, Bui MH, et al. Discovery of 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- benzonitriles and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- pyridine-2'-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors. Bioorg Med Chem Lett 2007; 17(21): 5944-5951. http://dx.doi.org/10.1016/j.bmcl.2007.07.102
Burgess AW. EGFR family: structure physiology signaling and therapeutic targets. Growth Factors 2008; 26(5): 263- 274. http://dx.doi.org/10.1080/08977190802312844
Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett 2012; 318(2): 124-134. http://dx.doi.org/10.1016/j.canlet.2012.01.011
Ciardiello F, Tortora G. Drug therapy: EGFR antagonists in cancer treatment. N Engl J Med 2008; 358(11): 1160-1174. http://dx.doi.org/10.1056/NEJMra0707704
Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol 2010; 7(9): 493-507. http://dx.doi.org/10.1038/nrclinonc.2010.97
Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013; 31(8): 1070-1080. http://dx.doi.org/10.1200/JCO.2012.43.3912
Stuttfeld E, Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life 2009; 61(9): 915-922. http://dx.doi.org/10.1002/iub.234
Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem J 2011; 437(2): 169-183. http://dx.doi.org/10.1042/BJ20110301
Paz K, Zhu Z. Development of angiogenesis inhibitors to vascular endothelial growth factor receptor 2. Current status and future perspective. Front Biosci 2005; 10: 1415-1439. http://dx.doi.org/10.2741/1629
Usui T, Ban HS, Kawada J, Hirokawa T, Nakamura H. Discovery of indenopyrazoles as EGFR and VEGFR-2 tyrosine kinase inhibitors by in silico high-throughput screening. Bioorg Med Chem Lett 2008; 18(1): 285-288. http://dx.doi.org/10.1016/j.bmcl.2007.10.084
Dinges J, Akritopoulou-Zanze I, Arnold LD, Barlozzari T, Bousquet PF, Cunha GA, et al. Hit-to-lead optimization of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of KDR kinase inhibitors. Bioorg Med Chem Lett 2006; 16(16): 4371- 4375. http://dx.doi.org/10.1016/j.bmcl.2006.05.052
Radomska-Lesniewska DM, Skopinski P, Balan BJ, Bialoszewska A, Jozwiak J, Rokicki D, Skopinska-Rozewska E, et al. Angiomodulatory properties of Rhodiola spp. and other natural antioxidants. Centr Eur J Immunol 2015; 40(2): 249-262. http://dx.doi.org/10.5114/ceji.2015.52839
Wang Y, Appiah-Kubi K, Wu M, Yao X, Qian H, Wu Y, Chen Y. The platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are major players in oncogenesis, drug resistance, and attractive oncologic targets in cancer. Growth Factors 2016; 34(1-2): 64-71. http://dx.doi.org/10.1080/08977194.2016.1180293
Fthenou E, Zafiropoulos A, Katonis P, Tsatsakis A, Karamanos NK, Tzanakakis GN. Chondroitin sulfate prevents platelet derived growth factor-mediated phosphorylation ofPDGF-Rβ in normal human fibroblasts severely impairing mitogenic responses. J Cell Biochem 2008; 103(6): 1866- 1876. http://dx.doi.org/10.1002/jcb.21570
Ho CY, Ludovici DW, Maharoof USM, Mei J, Sechler JL, Tuman RW, et al. (6,7-Dimethoxy-2,4-dihydroindeno[1,2- c]pyrazol-3-yl)phenylamines: Platelet-derived growth factor receptor tyrosine kinase inhibitors with broad antiproliferative activity against tumor cells. J Med Chem 2005; 48(26): 8163- 8173. http://dx.doi.org/10.1021/jm050680m
Cicenas J, Valius M. The CDK inhibitors in cancer research and therapy. J Cancer Res Clin Oncol 2011; 137(10): 1409- 1418. http://dx.doi.org/10.1007/s00432-011-1039-4
Nugiel DA, Etzkorn AM, Vidwans A, Benfield PA, Boisclair M, Burton CR, et al. Indenopyrazoles as novel cyclin dependent kinase (CDK) inhibitors [1]. J Med Chem 2001; 44(9): 1334- 1336. http://dx.doi.org/10.1021/jm0100032
Nugiel DA, Vidwans A, Etzkorn AM, Rossi KA, Benfield PA, Burton CR, et al. Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 2. Probing the indeno ring substituent pattern. J Med Chem 2002; 45(24): 5224-5232. http://dx.doi.org/10.1021/jm020171+
Yue EW, Higley CA, DiMeo SV, Carini DJ, Nugiel DA, Benware C, Benfield PA, et al. Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3. J Med Chem 2002; 45(24): 5233-5248. http://dx.doi.org/10.1021/jm0201722
de Bruijn P, Moghaddam-Helmantel IM, de Jonge MJ, Meyer T, Lam MH, Verweij J, et al. Validated bioanalytical method for the quantification of RGB-286638, a novel multi-targeted protein kinase inhibitor, in human plasma and urine by liquid chromatography/tandem triple-quadrupole mass spectrometry. J Pharm Biomed Anal 2009; 50(5): 977-982. http://dx.doi.org/10.1016/j.jpba.2009.06.048
Cirstea D, Hideshima T, Santo L, Eda H, Mishima Y, Nemani N, et al. Small-molecule multi-targeted kinase inhibitor RGB286638 triggers P53-dependent and -independent antimultiple myeloma activity through inhibition of transcriptional CDKs. Leukemia 2013; 27(12): 2366-2375. http://dx.doi.org/10.1038/leu.2013.194
Vindya NG, Sharma N, Yadav M, Ethiraj KR. Tubulins - the target for anticancer therapy. Curr Top Med Chem 2015; 15(1): 73-82. http://dx.doi.org/10.2174/1568026615666150112115805
Barbier P, Tsvetkov PO, Breuzard G, Devred F. Deciphering the molecular mechanisms of anti-tubulin plant derived drugs. Phytochem Rev 2013; 13(1): 157-169. http://dx.doi.org/10.1007/s11101-013-9302-8
Ji Y-T, Liu Y-N, Liu Z-P. Tubulin colchicine binding site inhibitors as vascular disrupting agents in clinical developments. Curr Med Chem 2015; 22(11): 1348-1360. http://dx.doi.org/10.2174/0929867322666150114163732
Minegishi H, Futamura Y, Fukashiro S, Muroi M, Kawatani M, Osada H, Nakamura H. Methyl 3-((6-methoxy-1,4- dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate (GN39482) as a tubulin polymerization inhibitor identified by MorphoBase and ChemProteoBase profiling methods. J Med Chem 2015; 58(10): 4230-4241. http://dx.doi.org/10.1021/acs.jmedchem.5b00035
Liu Y-N, Wang J-J, Ji Y-T, Zhao G-D, Tang L-Q, Zhang C-M, et al. Design, synthesis, and biological evaluation of 1- methyl-1,4-dihydroindeno[1,2-c]pyrazole analogues as potential anticancer agents targeting tubulin colchicine binding site. J Med Chem 2016; 59(11): 5341-5355. http://dx.doi.org/10.1021/acs.jmedchem.6b00071
Charpentier T, Hammami A, Stager S. Hypoxia inducible factor 1α: A critical factor for the immune response to pathogens and Leishmania. Cell Immunol 2016; in press. http://dx.doi.org/10.1016/j.cellimm.2016.06.002
Unwith S, Zhao H, Hennah L, Ma D. The potential role of HIF on tumour progression and dissemination. Int J Cancer 2015; 136(11): 2491-2503. http://dx.doi.org/10.1002/ijc.28889
Minegishi H, Fukashiro S, Ban HS, Nakamura H. Discovery of indenopyrazolesas a new class of hypoxia inducible factor (HIF)-1 inhibitors. ACS Med Chem Lett 2013; 4(2): 297-301. http://dx.doi.org/10.1021/ml3004632
Hegazi B, Abdel-Gawad H, Mohamed HA, Badria FA, Farag AM. Synthesis of new indeno[1,2-c]pyrazole-based heterocycles and evaluation of their protective effect against DNA damage induced by Bleomycin-Iron. J Heterocycl Chem 2013; 50(2): 355-360. http://dx.doi.org/10.1002/jhet.1566
Rostom SA. Synthesis and in vitro antitumor evaluation of some indeno[1,2-c]pyrazol(in)es substituted with sulfonamide, sulfonylurea(-thiourea) pharmacophores, and some derived thiazole ring systems. Bioorg Med Chem 2006; 14(19): 6475-6485. http://dx.doi.org/10.1016/j.bmc.2006.06.020