Dihydropyridine Derivatives to Overcome Atypical Multidrug Resistance: Design, Synthesis, QSAR Studies, and Evaluation of Their Cytotoxic and Pharmacological Activities

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Abstract
Multidrug resistance (MDR) is defined as resistance of tumor cells to the cytotoxic action of multiple structurally dissimilar and functionally divergent drugs commonly used in chemotherapy. Until now, there is no evidence for the effect of 1,4‐dihydropyridines (DHPs) on atypical MDR, although there are some indications about the effect of DHPs on p‐glycoprotein‐mediated MDR. However, it was reported that a DHP derivative (Dexniguldipine) inhibited human DNA topoisomerase I through a non‐competitive mechanism. Therefore, some derivatives of DHP were synthesized and their effect in reversing atypical MDR was evaluated. The results showed that two compounds were the potent reversals of atypical MDR. In addition, the intrinsic cytotoxicity of compounds was determined on four different cell lines. Furthermore, their Ca2+ channel blocking activity was evaluated and showed a clear structure‐activity relationship (SAR) trend according to the moieties in C‐4 position which confirmed the importance of C‐4 moiety on Ca2+ channel blocking.

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