Novel multidrug resistance reversal agents.

Abstract

A series of 59 alpha-aryl-alpha-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 microM), the most potent being isoindolines 44 (IC50 0.26 microM) and 46 (IC50 0.26 microM) and tetrahydroisoquinolines 47 (IC50 0.29 microM) and 15m (IC50 0.30 microM). A number of compounds were evaluated in vivo against vincristine (VCR)-resistant murine P388 leukemia, as well as against human epidermoid carcinoma KB/8.5 implanted sc in athymic mice. The reversal agents which consistently showed the highest activity, together with low toxicity, were alpha-aryl-alpha-thiotolylalkanenitrile tetrahydroisoquinoline derivatives with electron-rich alkoxy substituents on the aromatic rings. Of the tested compounds, the most effective reversal agents for both tumor lines were 15h (33% increased life span at 12.5 mg/kg, 0.2 mg/kg VCR versus VCR alone in the VCR-resistant P388 leukemia model and 59% relative tumor growth at 50 mg/kg, 8 mg/kg doxorubicin versus doxorubicin alone in the KB/8.5 model) and 39a (48% increased life span at 50 mg/kg, 0.2 mg/kg VCR versus VCR alone in the VCR-resistant P388 leukemia model and 46% relative tumor growth at 25 mg/kg, 8 mg/kg doxorubicin versus doxorubicin alone in the KB/8.5 model). The mechanism of action of these compounds is believed to involve blocking the drug efflux pump, P-glycoprotein.