Download (4Mb) - Etheses - Saurashtra University

Part-IIIAdvances Dihydropyridines and …When the acetyl group of G series was replaced with the benzoyl group (3, 5-dibenzoyl-1,4-DHPs) for GB series and test for their antibacterial effect along with Erythromycin,the MIC values are reduced against clinical isolates of E.coli Gy-1/A res Er res. Compound79 was the most effective in enhancing the activity of erythromycin. 106 Fifteen 4-phenyl-3,5-dibenzoyl-1,4-dihydropyridines substituted at the 4-phenyl ring were synthesized andcompared for their cytotoxic activity and MDR reversing activity in in vitro assaysystems. Among them, 2-CF 3 , 2-Cl and 3-Cl derivatives showed the highest cytotoxicactivity against human oral squamous carcinoma (HSC-2) cells. The activity of Pgpresponse for MDR in tumor cells was reduced by some of new derivatives, verapamil andnifedipine. These data suggest that 3,5-dibenzoyl-4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine 79 can be recommended as a new drug candidate for MDR cancertreatment. 107Further, it was found that 4-(2'trifluoromethylphenyl)-80 and 4-(3'chlorophenyl)-3,5-dibenzoyl-2,6-dimethyl-1,4-dihydropyridine 79 showed not only MDR reversal activity,but also markedly higher cytotoxicity against two human oral tumor cell lines than onenormal cell (human gingival fibroblast). In this report, tumor-specificity of 80 and 79 wasfirst confirmed using a total of seven human cells, including four tumor cell lines(squamous cell carcinoma HSC-2, HSC-3, submandibular carcinoma HSG,promyelocytic leukemia HL-60) and three normal cells (gingival fibroblast HGF, pulpcells HPC and periodontal ligament fibroblast HPLF). Compound 80 and 79 were alsocapable to induce apoptotic cell death in HL-60 and HSC-2 cells, monitored by usingseveral apoptosis associated markers, such as internucleosomal DNA fragmentation,activation of caspases -3, -8 and -9 and expression of pro-apoptotic proteins and an antiapoptoticprotein (Bcl-2). It was proposed that cell death was induced by 80 and 79 viaradical-mediated reaction. 108ClOOOCF 3OH 3 C NHCH 379H 3 C NHCH 380Figure-12. Structures of active GB DHPs418