Novel dithiane analogues of tiapamil with high activity to overcome multidrug resistance in vitro.

Dithiane analogues of tiapamil are highly active as modifiers of P-glycoprotein mediated multidrug resistance (MDR) in vitro. In an assay using the P-glycoprotein over-expressing cell line KB-8-5, the most active analogues for decreasing vincristine resistance were the racemate Ro 11-5160 and its two enantiomers, Ro 44-5911 (R) and Ro 44-5912 (S). In the KB-8-5 assay, the resistance modification index (RMI) of Ro 11-5160 was approximately 12-fold higher than those of the most active reference compounds tested, dipyridamole, cepharanthine, reserpine and cyclosporin A, when compared at concentrations equal to one-tenth of the IC50 of each compound (RMI0.1). The enantiomers have similar resistance modifying activities, but the (S) enantiomer Ro 44-5912 is somewhat more active, fully reverting the vincristine sensitivity of KB-8-5 cells to the level of the parental KB-3-1 cells at a concentration of 2 microM. The (R) enantiomer attained this level of modification at a concentration of 3.5 microM. These concentrations are both well below their IC50 values for KB-8-5 cells (150 microM). The enantiomers appear to interact with P-glycoprotein because they inhibited [3H]azidopine and [3H]-vinblastine binding to plasma membrane fractions prepared from resistant K562/ADR cells. However, in addition to their resistance modifying activities with KB-8-5 cells, these compounds also decreased the IC50 values of vincristine and doxorubicin with KB-3-1 cells that do not express detectable levels of P-glycoprotein. Ro 44-5911 overcame doxorubicin and vincristine resistance in three colorectal cancer cell lines (DLD-1, WiDr and COLO 201) that express P-glycoprotein. No effect was seen with the 3 colorectal cell lines on the IC50 values of three drugs not related to the MDR phenotype, 5-fluorouracil, 5'-deoxy-5-fluorouridine and cis-diaminodichloroplatinum (II). The in vitro vasodilatory activity of these dithianes, measured with strips of rat aorta contracted with KCl, was about 5% of that of verapamil. These results suggest that diathianes could be useful agents for MDR modification in vivo.