Synthesis Characterization and In silico Anticancer Activity of D-ring Substituted Steroidal Pyrazolecarboxamides

PDF

Published: 2023-07-09

DOI: 10.56557/upjoz/2023/v44i133546

Page: 70-91


D. Abilasha

Department of Chemistry, Pioneer Kumaraswamy College, Nagercoil-629003, Tamil Nadu, India.

C. Jeysiha

Department of Chemistry, Pioneer Kumaraswamy College, Nagercoil-629003, Tamil Nadu, India.

P. Palanisamy *

Department of Chemistry, Pioneer Kumaraswamy College, Nagercoil-629003, Tamil Nadu, India.

S. Kumaresan

School of Basic Engineering and Science, PSN College of Engineering and Technology, Melathediyoor, Tirunelveli-627152, Tamil Nadu, India.

*Author to whom correspondence should be addressed.


Abstract

In the present study, a few D ring substituted pyrazolecarboxamide derivatives were synthesized from the key intermediate 2,3-dihydrothiopyrano[3,2-c]thiochromen-4(5H)-one(2). In order to determine the structure-activity relationships, the pyrazolecarboxamide derivatives (7 a-m) were analyzed for anticancer activity and molecular docking studies were carried out   against two cancer cell lines (HeLa and HCT116). The structures of all these compounds have treating been elucidated on the basis of their spectral data. We performed docking studies with the selective inhibitor proteins 4J96 (HeLa) and 5FGK (HCT 116). The binding energy of compound 7k (-9.6 Kcal/mol-HeLa and -10.1 Kcal/mol-HCT116) was found to be lower than that of all other pyrazole derivatives as well as standard doxorubicin. Furthermore, compound 7k was also found to be a promising anticancer agent against 4J96 and 5FGK cells, given its significant inhibitory effect [IC50=20.56μM (HeLa) and 18.19μM (HCT116)] compared to doxorubicin [IC50=21.32 μM (HeLa) and 19.58 μM (HCT116)]. Hence it is understood that, the pyrazole carboxamide derivatives (7k) has selectivity for inhibitor proteins having anticancer activity against HeLa and HCT116 compared with doxorubicin.

Keywords: Pyrazole carboxamide, D-Ring Steroid, docking study, HeLa cell, HCT116 cell, anticancer activity


How to Cite

Abilasha , D., Jeysiha, C., Palanisamy, P., & Kumaresan , S. (2023). Synthesis Characterization and In silico Anticancer Activity of D-ring Substituted Steroidal Pyrazolecarboxamides. UTTAR PRADESH JOURNAL OF ZOOLOGY, 44(13), 70–91. https://doi.org/10.56557/upjoz/2023/v44i133546

Downloads

Download data is not yet available.

References

Morand PF, Lyall JM. Steroidal estrogens. Chem Rev. 1968;68:85-124.

Natalija M, Krstic NM, Mira S, Bjelakovic MS, Vladimir D, Pavlovic VD. New androst-4-en-17-spiro-1,3,2-oxathiaphospholanes. Synthesis, assignment of absolute configuration and In vitro cytotoxic and antimicrobial activities. Steroids. 2012; 77:558-565.

Banday AH, Mir BP, Lone IH, Suri KA, Kumar HM. Studies on novel D-ring substituted steroidal pyrazolines as potential anticancer agents. Steroids. 2010;75: 805-809.

Clinton RO, Manson AJ, Stonner FW, Neumann HC, Christiansen RG, Clarke RL, Ackerman JH, Page DF, Dean JW, Dickinson WB, Carabateas C. Steroidal[3,2-c]pyrazoles. II.1 Androstanes, 19-Norandrostanes and their Unsaturated Analogs. J Am Chem Soc. 1961;83:1478-1491.

Gupta R, Pathak D, Jindal DP. Synthesis and biological activity of azasteroidal [3,2-c]- and [17,16-c]pyrazoles. Eur J Med Chem. 1996;31:241-247.

Camoutsis C. Steroidal oxazoles, oxazolines, and oxazolidines. J Heterocycl Chem. 1996;33: 539-557.

Green B, Sheu K. Synthesis of steroidal D-ring fused pyrazolines: study of regiochemistry of addition. Steroids. 1994; 59: 479-484.

Manson AJ, Stonner FW, Neumann HC, Christiansen RG, Clarke RL, Ackerman JH, Page D F, Dean JW, Phillips DK, Potts GO, Arnold A, Beyler AL, Clinton RO. Steroidal heterocycles. vii. androstano(2,3-d)isoxazoles and related compounds. J Med Chem, 1963; 6: 1-9.

Clinton RO, Clarke RL, Stonner FW, Manson AJ, Jennings KF, Phillips DK. J Org Chem, 1962; 27:2800.

Hirschmann R, Steinberg N, Buschacher P, Fried JH, Kent GJ, Tishler M. J Am Chem Soc. 1963; 85:120.

Combs Zumbar Chandanshive, J. Z; González, B. G; Tiznado, W; Bonini, B. F., Tetrahedron. 2012, 68, 3319.

Bekhit AA, Aziem TA. Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents. Bioorg Med Chem. 2004; 12: 1935-1945.

Combs AP, Saubern S, Rafalski M, Lam PYS. Solid supported arylheteroaryl CN cross-coupling reactions. Tetrahedron Lett. 1999;40:1623-1626.

John WL, Patera RM, Plummer MJ, Halling BP, Yuhas DA. Synthesis, mechanism of action, and QSAR of herbicidal 3-substituted-2-aryl-4,5,6,7-tetrahydroindazoles. Pest Sci. 1994; 42: 29-36.

Genin MJ, Biles C, Keiser BJ, Poppe SM, Swaney SM, Tarpley WG, Yagi Y,Romero DL. Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives. J Med Chem.2000; 43: 1034-1040.

Li X, Lu X, Xing M, Yang XH, Zhao TT, Gong HB, Zhu HL. Synthesis, biological evaluation, and molecular docking studies of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives as anticancer agents. Bioorg Med Chem Lett. 2012; 22:3589-3593.

Schenone S, Bruno O, Bondavalli F, Ranise A, Mosti L, Menozzi G, Fossa P, Donnini S, Santoro A, Ziche M, Manetti F, Botta M. Antiproliferative activity of new 1-aryl-4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives toward the human epidermoid carcinoma A431 cell line. Eur J Med Chem. 2004; 39:939.

Gupta S, Rodrigues LM, Esteves AP, Oliveira-Campos AM, Nascimento MS, Nazareth N, Cidade H, Neves MP, Fernandes E, Pinto M, Cerqueira NM, Bras N. Synthesis of N-aryl-5-amino-4-cyanopyrazole derivatives as potent xanthine oxidase inhibitors Eur J Med Chem. 2008;43:771.

Menozzi G, Fossa P, Cichero E, Spallarossa A, Ranise A, Mosti L. Rational design, synthesis and biological evaluation of new 1,5-diarylpyrazole derivatives as CB1 receptor antagonists, structurally related to rimonabant. Eur J Med Chem. 2008; 43: 2627-2638.

Silvestri R, Cascio MG, Regina GL, Piscitelli F, Lavecchia A, Brizzi A, Pasquini S, Botta M, Novellino E, Marzo VD, Corelli F. Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted1-Aryl-5-(1H -pyrrol-1-yl)-1H-pyrazole-3-carboxamides. J Med Chem. 2008; 51: 1560-1576.

Ding XL, Zhang HY, Qi L, Zhao BX, Lian S, Shui H, Miao JY. Synthesis of novel pyrazole carboxamide derivatives and discovery of modulators for apoptosis or autophagy in A549 lung cancer cells. Bioorg Med Chem Lett. 2009; 19:5325-5328.

Villar R, Encio I, Migliaccio M, Gil MJ, Merino VM. Synthesis and Cytotoxic Activity of Lipophilic Sulphonamide Derivatives of the Benzo[b]thiophene-1,1-dioxide. Bioorg Med Chem. 2004;12: 963-968.

Alonso MM, Asumendi A, Villar J, Gil MJ, Merino VM, Encio I, Migliaccio M. New benzo(b)thiophenesulphonamide 1,1-dioxide derivatives induce a reactive oxygen species-mediated process of apoptosis in tumor cells. Oncogene. 2003; 22: 3759-3769.

Alonso MM, Encio I, Merino VM, Gil M, Migliaccio M. New cytotoxic benzo(b)thiophenilsulfonamide 1,1-dioxide derivatives inhibit a NADH oxidase located in plasma membranes of tumor cells. Br J Cancer. 2001; 85:1400-1402.

Sagardoy AA, Gil MJ, Villar R, Viñas MJ, Encío I, Merino VM. Bioorg Med Chem. 2010;18: 5701.

Palanisamy P, Kumaresan S. Analogues of N,1-diphenyl-4,5-dihydro-1H-[1]benzothiepino[5,4-c]pyrazole-3-carboxamide and N,1-diphenyl-4,5-dihydro-1H-[1]benzothiepino[5,4-c]pyrazole-3-carboxamide-6,6-dioxide: syntheses, characterization, antimicrobial, antituberculosis, and antitumor activity. RSC Advances. 2013;3:4704-4715.

Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55-63.

Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Wolff AV. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst. 1991; 83: 757-766.

Trott O, Olson AJ. AutoDockVina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem. 2010; 31: 455–461.

Afriza D, Suriya, WH, Ichwan SJA. In silico analysis of molecular interactions between the antiapoptotic protein survivin and dentatin, nordentatin, and quercetin. J Phys Conf Ser. 2018; 1073: 032001.

Kumaresan S, Palanisamy P. Syntheses, Characterization, Antimicrobial-, Antituberculosis and anticancer activity of N,1-Diphenyl-1,4-dihydrothiocromeno[4,3-c]pyrazolecarboxamide analogues. Int J Adv Phar Res. 2013; 4: 1402-1412.

Kumaresan S, Ramadas SR. New Steroidal Heterocycles: Total synthesis of 2,6-bisthiabenz-[3,4]estra-3,5(10),8,14-tetraen-17-one and its D-homo analogue and 2,6,16-tristhiabenz[3,4]-D-homoestra-5(10),8,14-tetraen-17a-one. Sulfur Letters. 1984;2: 31.

Kumaresan S, Ramadass SR. Phosphorus and Sulfur lett. 1984;2:131.

Vaarla K, Kresharwani KR, Santosh K, Rao R, Kotamraju S, Toopurani MK. Synthesis, biological activity evaluation and molecular docking studies of novel coumarin substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes. Bioorg Med Chem Lett. 2015; 25: 5797- 5803.

Pace CN, Fu H, Fryar KL, Landua J, Trevino SR, Shirley BA, Hendricks MM, Limura S, Gajiwala K, Scholtz JM, Grimsley GR. Contribution of hydrophobic interactions to protein stability. J Mol Biol. 2011; 408: 514–528.

Sergeev YV, Dolinska MB, Wingfield PT. Thermodynamic analysis of weak protein interactions using sedimentation equilibrium. Curr Protoc Protein Sci. 2014; 77: 20.

DOI:13.1 -20.13.15.

Du X, Li Y, Xia YL, Ai SM, Liang J, Sang P, Ji XL, Liu SQ. Insights into protein–ligand interactions: mechanisms, models, and methods. Int J Mol Sci. 2016; 17: 144.

Hariono M, Abdullah N, Damodaran KV, Kamarulzaman EE, Mohamed N, Hassan SS, Shamsuddin S, Wahab HA. Potential new H1N1 neuraminidase inhibitors from ferulic acid and vanillin: molecular modelling, synthesis and in vitro assay. Sci Rep. 2016; 6: 38692.

Azab EIH, El-Sheshtawy HS, Bakr RB, Elkanzi NAA. New 1,2,3-Triazole-Containing Hybrids as Antitumor Candidates: Design, Click Reaction Synthesis, DFT Calculations, and Molecular Docking Study. Molecules. 2021;26:1-16.