SYNTHESIS OF ONCOGENE SPECIFIC LAVENDAMYCINS

描述：(主要研究人员)拉文达霉素和链球菌素， 生物合成相关化合物是有效的抗肿瘤药物，但它们的 由于其毒性大且质量差，临床应用被排除在外。 溶解度。我们已经合成了33种不同取代物的小说 莱旺霉素和其中几种化合物显示出了良好的抗肿瘤作用。 活动。其中一些类似物似乎是高度特异的ras K癌基因 (9-130倍)，对ras-K和Lewis肺癌基因无细胞毒作用 转化的或正常的细胞。这些结果表明，这些和其他 相关衍生物可能是治疗肿瘤的高度有用的药物 其恶性表型由ras K癌基因维持，如人类 胰腺癌。三种类似物对K/1-NRK的治疗 裸鼠体内的肿瘤导致高达90%的肿瘤减少。在……里面 此外，NCI已经针对一个小组筛选了一些这样的化合物 其中八种化合物要么是在它们的第二个 (体外)或第三(体内)评估阶段。 尽管我们最近的工作让我们对 决定拉旺霉素抗肿瘤活性的分子特征，它 当务之急是我们必须完成对 这一重要抗生素系统的构效关系(SAR) 具有更好的治疗指数和更大的溶解度的衍生物 可以被开发出来。大约56种新的莱旺霉素将在 期望的Picet-Spengler凝聚 根据我们的研究，带有色氨酸衍生物的喹啉二酮-2-甲醛 新开发的短(5步)实用的合成方法 拉旺大霉素甲酯。这些化合物的生物活性将 在ras K、ras H、ras N、3ll和亲本未转换(NRK)上确定 NCI的60个人类肿瘤细胞株也是如此。此外， 这些类似物对cdc25a磷酸酶的抑制活性也将 要下定决心。使用这种测试的初步研究表明，有几种 类似物具有非常有希望的活性。对于更强大的衍生品， 还将进行体内活动的评估。 因此，这个项目的主要目标是完成我们的综合特区 通过合成和筛选一系列拉旺霉素系统的研究 类似物被大小、形状、电子性质不同的基团取代 影响、氧化态、极性和水溶性。这项研究将 使我们能够清楚地确定最低有效的药效团 并确定了拉旺霉素系统和亲本骨架的作用 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来增强效力， 作为潜在的抗肿瘤药物的选择性细胞毒性和溶解性。

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.