Pharmacogenetics of Cyclophosphamide and Doxorubicin in Breast Cancer and Synthesis and Biological Evaluation of New Imidazole Based Putative Anticancer Agents

Abstract

Breast cancer is the second most prevalent cancer in women worldwide. It is newlinetreated by various strategies, including surgery, radiation therapy, hormonal newlinetherapy, targeted therapy and chemotherapy. Chemotherapeutic drugs like newlinecyclophosphamide, doxorubicin, paclitaxel and docetaxal are used to treat the newlinecancer either alone or in combination with other therapies, such as surgery, newlineradiation, or hormone therapy depending upon the stage and the location of newlinecancer cells. Cyclophosphamide and doxorubicin are also given in newlinecombination known as adjuvant chemotherapy (AC therapy). However, all the newlinepatients do not get benefited by this treatment. Inter-individual response in newlinepatients on AC therapy might be on account of variation in genes involved in newlinepharmacokinetics and pharmacodynamics of cyclophosphamide and newlinedoxorubicin. Therefore, a detailed pharmacogenomic study was performed newlineusing global screening array microchip that contains more than 700,000 upto- newlinedate markers, optimized for human genome-wide backbone for newlineunparalleled genomic coverage, including clinically relevant content and all newlinepharma GKB markers. Two gene variants CYP2C19*2 and ALDH1A1*2 newlineinvolved in the metabolism of cyclophosphamide were found to influence the newlineclinical outcome in breast cancer patients on AC therapy in Malwa region of newlinePunjab. However, none of the gene variants involved in pharmacokinetics newlinevi newlineand pharmacodynamics of doxorubicin were found to be involved in the interindividual newlineresponse. Therefore, patients should be screened for CYP2C19*2 newlineand ALDH1A1*2 gene variants before prescribing the AC therapy. Due to newlineseveral problems with the chemotherapeutic drugs the new therapeutic newlinestrategies have been introduced in the recent past that have led to the target newlinebased drug design. In an attempt to develop new drugs for targeting breast newlinecancer, imidazole based anti-cancer agents were computationally designed newlineand synthesized (Series 1 and Series 2). All the compounds were first newlineassessed for their anti-proliferative activity in T47D, MDA-MB-231, and MCF7 newlinebre