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Structure-Activity Study and Design of Multidrug-resistant Reversal Compounds by a Computer Automated Structure Evaluation Methodology

Chemistry Department, Case Western Reserve University, Cleveland, Ohio 44106 [G. K., S. S., I. K.], and Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada [R. F. E., N. A., R. M. E.]

We have studied the relation between the structure and the multidrug resistance-reversal activity of a set of diverse chemicals with the MULTICASE structure-activity program. A number of key structural features were identified as being related to multidrug resistance reversal activity. Using these key features, we identified seven new compounds predicted to have substantial activity. These were obtained and tested experimentally on a CHO/CH^RC5 cell line derived from the AB₁ Chinese hamster ovary line in the presence of vincristine and vinblastine. Of the seven compounds tested so far, four showed substantial reversal activity, the most potent of them exhibiting activity at par with verapamil.

Received 1/24/92. Accepted 5/12/92.

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