Synthesis and Evaluation of Novel Antitumor Agents

描述（由申请人提供）：最近，已经发现肿瘤细胞选择性地积累某些n-3脂肪酸，例如顺式-4，7，10，13，16，19-二十二碳六烯酸（DHA）。DHA-紫杉醇是DHA和紫杉醇的结合物，与游离紫杉醇相比，在实验动物和患者中具有显著增加的治疗功效和降低的副作用。我们已经合成了100多种新型CC-1065类似物。这些化合物是迄今为止发现的最有效的抗癌剂之一。我们已经发现了重要的结构特征，增加抗肿瘤治疗效果和降低毒性。该提案的目的是合成和评估新的CC-1065类似物，其包含所有新发现的有益结构特征。此外，DHA将被结合以进一步增加治疗功效并降低毒性。

DESCRIPTION (provided by applicant): 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.