SYNTHESIS AND IN-VITRO STUDY OF NOVEL (Z)-1-BENZHYDRYL-4-CINNAMYLPIPERAZINE DERIVATIVES AS POTENTIAL ANTICANCER AGENTS
Objective: The objective of this study was to synthesize Z- 1-benzhydryl-4-cinnamylpiperazines by novel stereo selective synthetic method and evaluation of their anticancer properties.
Methods: A series of novel (Z)-1-benzhydryl-4-cinnamylpiperazine derivatives (9a-j) were synthesized, starting from benzophenones in six steps. Wittig condensation of appropriate benzyltriphenyl phosphonium halides with various 1-benzhydryl- 4-(2-ethanal) piperazines (3a-j), and column purification over silica gel afforded pure Z- 1-benzhydryl-4-cinnamylpiperazines.
Results: The structures of newly synthesized compounds 9a-j were established by 1H & 13C NMR and mass spectral analysis. The anticancer potential (MTT assay) of synthesized compounds was tested against human cervical cancer (HeLa) and murine microglial (BV-2) cell lines. Results indicated that the most of the Z-derivatives exhibited moderate to good anticancer activity on both the cell lines over their E- antipodes.
Conclusion: Compound 9i (cis- flunarizine) exhibited exceptionally superior activity against both HeLa and BV-2 cell lines with IC50 value of 13.23Â±3.51 ÂµM and 23.1Â±4.12 ÂµM respectively. Hence, this compound may be considered to be a potential lead molecule for further development
2. Adjei AA. A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer. Br J Clin Pharmacol 1999;48:265-77.
3. Papamichael D. The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status. Stem Cells 2000;18:166-75.
4. Filosa R, Pedut A, Caprariis P, Saturnino C, Festa M, Petrella A, et al. Synthesis and antiproliferative properties of N3/8-disubstituted 3,8-diazabicyclo[3.2.1]octane analogues of 3,8-bis[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl-piperazine. Eur J Med Chem 2007;42:293-306.
5. Caballero J, Fernandez M. Artificial neural networks from MATLAB in medicinal chemistry. Bayesian-regularized genetic neural networks (BRGNN): application to the prediction of the antagonistic activity against human platelet thrombin receptor (PAR-1). Curr Top Med Chem 2008;8:1580-605.
6. Parmar VS, Sharma NK, Husain M, Watterson AC, Kumar J, Samuelson LA, et al. Synthesis, characterization and in vitro anti-invasive activity screening of polyphenolic and heterocyclic compounds. Bioorg Med Chem 2003;11:913-29.
7. Savikin K, Zdunic G, Jankovic T, Stanojkovic T, Juranic Z, Menkovic N. In vitro cytotoxic and antioxidative activity of Cornus mas and Cotinus coggygria. Nat Prod Res 2009;23:1731-9.
8. Berkheij M, van der SL, Sewing CJ, den Boer D, Terpstra JW, Hiemstra H, et al. Synthesis of 2-substituted piperazines via direct Î±-lithiation. Tetrahedron Lett 2005;46:2369â€“71.
9. Guo CC, Tong RB, Li KL. Chloroalkyl piperazine and nitrogen mustard porphyrins: synthesis and anticancer activity. Bioorg Med Chem 2004;12:2469â€“75.
10. Yi EY, Jeong EJ, Song HS, Lee MS, Kang DW, Joo JH, et al. Anti-angiogenic and anti-tumor apoptotic activities of SJ-8002, a new piperazine derivative. Int J Oncol 2004;25:365â€“72.
11. Naylor A, Judd DB, Lloyd JE, Scopes DI, Hayes AG, Birch PJ. A potent new class of. kappa.-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino) methyl] piperazines. J Med Chem 1993;36:2075-83.
12. Soukara S, Maier CA, Predoiu U, Ehret A, Jackisch R, WÃ¼nsch B. Methylated Analogues of Methyl (R)-4-(3, 4-Dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl) piperazine-1-carboxylate (GR-89,696) as Highly Potent Îº-Receptor Agonists: â€‰ Stereoselective Synthesis, Opioid-Receptor Affinity, Receptor Selectivity, and Functional Studies. J Med Chem 2001;44:2814-26.
13. Chern JH, Shia KS, Hsu TA, Tai CL, Lee CC, Lee YC, et al. Design, synthesis, and structure-activity relationship of pyrazolo [3,4-d] pyrimidines: a novel class of potent enterovirus inhibitors. Bioorg Med Chem Lett 2004;14:2519â€“25.
14. Amin EA, Welsh WJ. Three-dimensional quantitative structure-Activity relationship (3D-QSAR) models for a novel class of piperazine-based stromelysin-1 (MMP-3) inhibitors: applying a â€œdivide and conquerâ€ strategy. J Med Chem 2003;44:3849â€“55.
15. Gillet R, Jeannesson P, Sefraoui H, Arnould-GueArin M, Kirkiacharian LS, Jardillier JC, Pieri F. Piperazine derivatives of butyric acid as differentiating agents in human leukemic cells. Cancer Chemother Pharmacol 1998;41:252â€“5.
16. Braybrooke JP, Oâ€™Byrne KJ, Propper DJ, Blann A, Saunders M, Dobbs N, et al. A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis. Clin Cancer Res 2000;6:4697â€“704.
17. Sampson JJ, Donkor IO, Huang TL, Adunyah SE. Novel piperazine induces apoptosis in U937 cells. Int J Biochem Mol Biol 2011;2:78â€“88.
18. Narendra Sharath Chandra JN, Sadashiva CT, Kavitha CV, Rangappa KS. Synthesis and in vitro antimicrobial studies of medicinally important novel N-alkyl and N-sulfonyl derivatives of 1-[bis(4-fluorophenyl)-methyl]piperazine. Bioorg Med Chem 2006;14:6621â€“27.
19. Ananda Kumar CS, Nanjuda Swamy S, Thimmegowda NR, Benaka Prasad SB, Yip GW, Rangappa KS. Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of MDA-MB-231 human breast cancer cell proliferation. Med Chem Res 2007;16:179â€“87.
20. Ananda Kumar CS, Benaka Prasad SB, Viyana K, Chandrappa S, Thimmegowda R, Sunil Kumar YC, et al. Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines. Eur J Med Chem 2009;44:1223â€“9.
21. Ahn BZ, Sok DE. Michael acceptors as a tool for anticancer drug design. Curr Pharm Design 1996;2:247-62.
22. Zou HB, Dong SY, Zhou CX, Hu LH, Wu YH, Li HB, et al. Design, synthesis, and SAR analysis of cytotoxic sinapyl alcohol derivatives. Bioorg Med Chem 2006;14:2060-71.
23. Shivaprakash S, Reddy GC. Stereoselective synthesis of 1-benzhydryl-4-cinnamylpiperazine derivatives via the Wittig reaction. Synth Comm 2014;44:600-9.
24. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55-63.