SYNTHESIS OF ONCOGENE SPECIFIC LAVENDAMYCINS

性状：（主要研究者）拉文达霉素和链黑菌素， 生物合成相关的化合物是有效的抗肿瘤剂，但它们的 由于高毒性和不良反应， 溶解度 我们合成了33个不同取代的新的 熏衣草霉素和这些化合物中的几种已经显示出有希望的抗肿瘤活性， 活动 这些类似物中的一些似乎是高度ras K癌基因特异性的， 对ras K和刘易斯肺癌基因无细胞毒作用 转化或正常细胞。 这些结果表明， 相关衍生物可能是治疗肿瘤的非常有用的药物 其恶性表型由ras K癌基因维持，如人 胰腺癌 用三种针对K/1-NRK的类似物治疗 在裸鼠中的肿瘤导致高达90%的肿瘤减少。 在 此外，国家癌症研究所还对一组化合物进行了筛选， 这些化合物中有八种是在第二阶段， (in体外）或第三（体内）评估阶段。 尽管我们最近的工作使我们对 决定拉文霉素抗肿瘤活性的分子特征， 我们必须完成系统地阐明 结构活性关系， 具有更好治疗指数和更大溶解度的衍生物 可以被开发。 将通过以下方法制备约56种新的拉文达霉素： 所需的Picet-Spengler缩合 喹啉二酮-2-甲醛与色氨酸衍生物的反应， 短（5步）和实用的方法新开发的合成 拉文达霉素甲酯 这些化合物的生物活性将 根据ras K、ras H、ras N、3LL和亲本非转化（NRK）确定 细胞系以及NCI的60种人类肿瘤细胞系。 而且 这些类似物对CDC25A磷酸酶的抑制活性也将 被确定。 使用该测定法的初步研究表明， 类似物具有非常有前途的活性。 对于更有效的衍生物， 还将进行体内活性的评估。 因此，本项目的主要目标是完成我们的综合SAR 通过合成和筛选一系列的 类似物被各种基团取代，所述基团的大小、形状、电子性质 影响、氧化态、极性和水溶性。 本研究将 使我们能够清楚地确定最低有效药效团的 lavendamycin系统的作用，并确定父母的骨架和 单个取代基在分子的活性中起作用。 基于 这些发现，我们可以合理地设计类似物，提高效力， 选择性细胞毒性和溶解性作为潜在的抗肿瘤药物。

DESCRIPTION: (Principal Investigator's) Lavendamycin and streptonigrin, biosynthetically related compounds, are potent antitumor agents, but their clinical use has been precluded because of high toxicity and poor solubility. We have synthesized 33 variously substituted novel lavendamycins and several of these compounds have shown promising antitumor activity. Some of these analogs appear to be highly ras K oncogene specific (9-130 fold) and had no cytotoxicity against ras K and Lewis Lung oncogene transformed or normal cells. These results suggest that these and other related derivatives may be highly useful drugs for the treatment of tumors whose malignant phenotype is maintained by the ras K oncogene, such as human pancreatic cancer. Treatment with three of the analogs against the K/1-NRK tumor in nude mice resulted in up to 90 percent tumor reduction. In addition, the NCI has screened a number of these compounds against a panel of human tumor lines and eight of these compounds are either in their second (in vitro) or third (in vivo) stages of evaluation. Although our recent work has given us a general understanding of the molecular features which determine the lavendamycins' antitumor activity, it is imperative that we complete the systematic elucidation of the structure-activity relationship (SAR) of this important antibiotic system so that derivatives with better therapeutic indices and greater solubilities can be developed. Approximately 56 new lavendamycins will be prepared by the Picet-Spengler condensation of the desired quinolinedione-2-carbaldehydes with tryptophan derivatives according to our short (5-step) and practical method newly developed for the synthesis of lavendamycin methyl ester. The biological activity of these compounds will be determined on ras K, ras H, ras N, 3LL and parent nontransformed (NRK) cell lines as well as on the NCI's 60 human tumor lines. Furthermore, the inhibitory activity of these analogs toward the cdc25a phosphatase will also be determined. Preliminary studies using this assay have shown several of the analogs to have very promising activity. For more potent derivatives, an assessment of in vivo activity will also be performed. Thus, the main goal of this project is to complete our comprehensive SAR study of the lavendamycin system by synthesizing and screening a series of analogs substituted with various groups ranging in size, shape, electronic effects, oxidation state, polarity and water-solubility. This study will allow us to clearly identify the minimum potent pharmacophore of the lavendamycin system and to determine the role that the parent skeleton and individual substituents play in the activity of the molecule. Based on these findings, we can rationally design analogs which enhance potency, selective cytotoxicity and solubility as potential antitumor drugs.