5-arylidene(thio)hydantoin derivatives as modulators of cancer efflux pump.

Multidrug resistance has become a factor seriously limiting treatment of various diseases, including bacterial (1ñ3) and fungal (4) infections and cancer (5ñ7). The major mechanism of multidrug resistance (MDR) in cancer is the over-expression of ATP-dependent drug-efflux pumps (drug transporters), which reduces the accumulation of agents. One of the most important mechanisms of MDR in cancer is the over-expression of ABC multidrug transporters, e.g., P-glycoprotein (P-gp, ABCB1). Various chemical groups possessing efflux pump inhibitor (EPI) properties in P-gp have been described (7ñ9), including three generations of P-gp modulators, but none of them has passed the phase of clinical trials because of the undesirable side effects (5). Consequently, it is a big challenge to search for new successful P-gp inhibitors which are active during chemotherapy and produce minimal side effects. In this context, our interest has been focused on potential EPI activity of arylidene(thio)hydantoin derivatives. Particularly, as recent lines of evidence distinctly identified and described a presence of benzyl-hydantoin binding site in protein transporters (10, 11). Recently, there is an increasing interest in hydantoin derivatives as potential anticancer agents (12ñ14). It has been shown that hydantoin derivatives inhibit autophosphorylation and proliferation of some human cancer cells that over-express EGFR (12, 13). Furthermore, phenylmethylene-hydantoins with anti-metastatic activity were described as well (14). Derivatives of (thio)hydantoin are one of our main interests for more than twenty years. Our previous works described a number of aromatic hydantoin derivatives which demonstrated various pharmacological properties as antimicrobial (15ñ17), hypotensive, antiarrhythmicor/and GPCR-agents 5-ARYLIDENE(THIO)HYDANTOIN DERIVATIVES AS MODULATORS OF CANCER EFFLUX PUMP*