Manish S. Bhatia 1*, Santosh S. Kumbhar 1, Vikram S. Kawade 1, Prafulla B. Choudhari 1, Neela M. Bhatia 1, Sandip B. Patil 2, Pradip B. Patil 3
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Near Chitranagari, Kolhapur - 416 013, Maharashtra, India
- Department of Pharmacology, Appasaheb Birnale College of Pharmacy, Sangli, Maharashtra, India
- Department of Chemistry, Shivaji University, Vidyanagar, Kolhapur, Maharashtra, India
Abstract
Purpose : The Spiropyranopyrazole derivatives are used as cytotoxic agents and nitrogen containing heterocyclic analogs targeting CDK7 inhibition shows better cytotoxic activity.Methodology: A new series of compounds were synthesized using various substituted isatin derivatives and then characterized and analyzed for biological activity by in-silico and using MTT assay targeting CDK7. All the synthesized compounds were analyzed for their biological activity for this purpose breast cancer cell lines (MCF7) were used and analyzed by MTT assay. Docking studies into ATP binding site of CDK7 were performed to predict their binding affinity scores and possible interactions with receptor to evaluate bioactivity in-silico using VLife MDS 4.3.Findings : A novel series of Spiropyranopyrazole derivatives were successfully synthesized via Multicomponent reaction (MCR). From experimental data indicated that compounds 2c and 3c showed most promising results as their inhibitory activity with 23.20% and 26.50% respectively at 10?M and these were selected for further preclinical studies.Social Implications : If the present findings of spiropyranopyrazole derivatives passes preclinical studies and we develop drug like candidate then it is a massive achievement in anticancer therapy that could save many lives.Original : Successfully develop a novel series of spiropyranopyrazole having CDK7 inhibitor activity. This could be helpful for development of a drug like candidate having significant cytotoxic activity.
References
- Sun J, Lv X, Qiu H, Wang Y, Du Q, Li D, Yang Y, Zhu H. Synthesis, biological evaluation and molecular docking studies of pyrazole derivatives coupling with a thiourea moiety as novel CDKs inhibitors. Eur J Med Chem. 2013; 68:1-9.
- Diallo A, Prigent C. The serine/threonine kinases that control cell cycle progression as therapeutic targets. Bull Cancer.2011;98:1335�1345.
- Doonan JH, Kitsios G. Functional evolution of cyclin dependent kinases.Mol Biotechnol.2009;42:14�29.
- Pines J. Cyclins and cyclin-dependent kinases: Take your partners.Trends Biochem Sci.1993;18:195�197.
- Malumbres M. Therapeutic opportunities to control tumor cell cycles.Clin Transl Oncol.2007;8:399�408.
- Cicenas J, Valius M.The CDK inhibitors in cancer research and therapy. J Cancer Res Clin. Oncol. 2011; 137:1409�1418.
- Fisher RP. Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci. 2005; 118: 5171�5180.
- Gullick WJ. Prevalence of aberrant expression of the epidermal growth factor receptors in human cancers. Br Med Bull.1991;47(1):87�98.
- Lapenna S, Giordano A. Review: Cell cycle kinases as therapeutic targets for cancer.Nat Rev Drug Discov. 2009; 8:547-566.
- Sausville EA. Review: Complexities in the development of cyclin-dependent kinase inhibitor drugs.Trends Mol. Med. 2002;8(4):532-537.
- Yardern Y, Ullrich A. Growth factor receptor tyrosine kinases.Annu Rev Biochem.1988;57:443-478.
- Pore DM, Patil PB, Gaikwad DS, Hegade PG, Patil JD, Undale KA. Green access to novel spiropyranopyrazole derivatives.Tetrahedron Lett.2013;54:5876-5878.
- Yu J, Zhou Y, Shen T, Mao W, Chen K, Song Q. Novel and efficient one-pot synthesis of spiro [indoline-3,4'- pyrano [2,3-c]pyrazole] derivatives catalysed by L-proline in aqueous medium.J Chem Research.2013;37:365-368.
- www.vlifesciences.com
- Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB. Evaluation of a tetrazolium-based semi automated colorimetrie assay: assessment of radio sensitivity. Cancer Res.1987;47:943-946.
- Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.J Immunol Methods.1983;65:55-63.
- Zhao Y, Abraham MH, Lee J, Hersey A, Luscombe NC, Beck G, Sherborne B, Cooper I. Rate-limited steps of human oral absorption and QSAR studies, Pharm. Res. 2002;19:1446-1457.
- Molinspiration Cheminformatics, Bratislava, Slovak Republic. Available from: http://www.molinspiration.com/ services/properties.html
- Tripathi L, Kumar P, Singh R, Stables J, Design, synthesis and anticonvulsant evaluation of novel N-(4-substituted phenyl)-2-[4-(substituted) benzylidene]-hydrazinecarbothio amides.Eur J of Med Chem.2012;47:153-166.
