Recently, tumor cells have been found to selectively accumulate certain n-3 fatty acids such as cis-4,7,10,13,16,19-docosahexenoic acid (DHA). DHA-paclitaxel, a conjugate of DHA and paclitaxel, has greatly increased therapeutic efficacy and reduced side effects in both the experimental animals and patients compared to free paclitaxel. We have synthesized over 100 novel CC-1065 analogues. These compounds are among the most potent anticancer agents found to date. We have uncovered important structural features that increase antitumor therapeutic efficacy and reduce toxicity. The objectives of this proposal are to synthesize and evaluate novel CC-1065 analogues that incorporate all of the newly discovered beneficial structural features. In addition, DHA will be conjugated to further increase the therapeutic efficacy and reduce toxicity. ? ?
