Objective

Cancer chemotherapy is majorly used to treat the disseminated tumors; however development of multidrug resistance has become an obstacle for cancer chemotherapy. The etiology of multidrug resistance is broad and overexpression of ATP binding cassette (ABC) transporters is one of the major reasons for chemotherapy failure. Among different ABC transporters, P-glycoprotein (P-gp) plays a major role in development of MDR by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. Large numbers of P-gp inhibitors were tested in the clinical trials; unfortunately, none were succeeded due to the toxicity issues. Therefore, phytochemicals have been in the focus to find the potent and safe P-gp inhibitors and already a large number of phytochemicals have been reported to inhibit the P-gp function. However, majority of P-gp inhibitors tested in the clinical trials have been reported to have the cross-reactivity with the CYP 450 drug metabolizing enzymes thus resulted in the unpredictable pharmacokinetics of drugs. Similarly, phytochemicals which were modulating the P-gp function were also reported to inhibit the CYP 450 enzymes. Therefore, potent and safe P-gp inhibitors with less cross-reactivity with CYP450 enzymes are still to be found. Therefore, known phytochemicals inhibiting the P-gp function could act as lead compounds to develop potent P-gp inhibitors with least cross-reactivity with CYP 450 enzymes.

Previously, we have reported two piperine based analogs Pip1 and Pip2 modulating the P-gp function. Pip1 was as potent as verapamil in reversing the drug resistance in P-gp over-expressing cancer cell lines. However, both piperine analogs (Pip1 and Pip2) inhibited CYP3A4 enzyme activity in in vitro more than that of piperine, suggesting that they may interfere with chemotherapeutic drug metabolism (major issue with previously developed P-gp inhibitors). Therefore, in this study two more piperine analogs (Pip1-1 and Pip1-2) were designed, synthesized and in vitro tested based on the lead Pip1. The in vitro results showed that both the analogs exerted similar drug resistant reversal activity as that of Pip1 and the activity increased with an increased in the concentrations of analogs in the drug resistant cancer cell lines. Both the analogs were found to be less toxic in the non-cancerous HEK293 cells compared to the Pip1 and exerted less in vitro CYP3A4 inhibitory activity compared to all other tested compounds. Furthermore, the Pgp-Glo assay suggests that these analogs could act as the competitive inhibitors of P-gp. Therefore, Pip1-2 could be a suitable agent for further pharmacological investigation to overcome MDR in cancer.