Design and synthesis of 4-[1,3-diaryl-1H-pyrazole-4-yl]-2,6-dimethyl-1,4-dihydropyridine compounds and evaluation as anti-proliferative and multi-drug resistance reversal agents

Abstract

1,4-Dihydropyridines are well known for their use as calcium channel blockers and are extensively used in treatment of hypertension. Dihydropyridine derivatives such as nifedipine have been shown to have the potential to overcome Pgp-mediated multidrug resistance thus can function as both L-type calcium channel blockers and multi-drug resistance (MDR) reversal agents. In this thesis, the design and synthesis of a number of novel structure modifications of initially identified lead 4-(1,3-diaryl- 1H-pyrazole-4-yl)-1 ,4-dihydropyrdines and evaluation of their anti-proliferative properties on MCF-7 (ER positive) and MDA-MB-231 (ER negative) breast cancer cell lines is described. These compounds were shown to have negligible effects on activation or inhibition of calcium transporters in MCF-7 cells. This investigation revealed that the anti¬proliferative effect of this scaffold compound is independent of effects on the calcium channel in MCF-7 cell. Moreover, flow cytometric analysis and viability assay suggest that the novel dihydropyridines were effective modulators of Pgp mediated paclitaxel resistance and induced G1 phase cell accumulation and cell death both at μM range level. Initial synthesis work focused on the modified aryl rings at N-1 and C-3 of the pyrazole structure including a comprehensive panel of substituted heterocyclic rings, together with the optimised study of N-substitution on the DHP. Synthesis of corresponding products lacking the DHP methyl substituents via novel synthetic route has also been carried out. A number of these scaffold derivatives were screened against a comprehensive NCI60 cell line panel and showed broad spectrum antiproliferative activity against various tumour cell lines and presented activity comparable to or exceeding that of tamoxifen.