Novel Multidrug Resistance Reversal Agents

A series of 59 α-aryl-α-thioether-alkyl, -alkanenitrile, and -alkanecarboxylic acid methyl ester tetrahydroisoquinoline and isoindoline derivatives (15a−48) were synthesized and evaluated as multidrug resistance (MDR) reversal agents. The compounds were tested on S1-B1-20 human colon carcinoma cells selected for resistance to bisantrene. Both the cytotoxicity of the reversal agents and their ability to resensitize the cells to bisantrene were determined. All but two of these compounds (15q, 40) were more effective MDR reversal agents in vitro than verapamil (VRP), a calcium channel antagonist which also has been shown to possess MDR modulating activity. Several showed good activity in this assay (IC50's < 0.5 μM), the most potent being isoindolines 44 (IC50 0.26 μM) and 46 (IC50 0.26 μM) and tetrahydroisoquinolines 47 (IC50 0.29 μM) and 15m (IC50 0.30 μM). A number of compounds were evaluated in vivo against vincristine (VCR)-resistant murine P388 leukemia, as well as against human epidermoid carcinoma KB...