SYNTHESIS AND STUDY OF RAS K SPECIFIC ANTITUMOR DRUGS

链黑菌素（20 a）和链黑菌素（20 a）的潜在临床应用 拉文达霉素（5）因其毒性而被排除。 本建议的长期目标是确定 控制这两个相关系统的生物活性， 设计和开发选择性药物的合理方法可以 追求。 先前的构效关系（SAR）研究结果 对拉文达霉素和链黑菌素的部分结构的研究尚无定论 与用母体分子获得的结果相比。 这 表明完整的分子结构可能有一定的影响， 在活动上。 因此，本建议的直接目标是合成和执行SAR 研究了一系列新的拉文达霉素衍生物， 完整的母环结构。 衍生品的范围将从 未取代的五环环至单、二和三取代的衍生物， 包括那些在C-7上具有吸电子和释放电子基团的化合物 位置 这项研究将使我们能够清楚地确定最低有效 拉文达霉素系统的药效团，并确定作用， 母体骨架、喹啉二酮还原潜力和每个个体 取代基在分子的整体活性中起作用。 Pictet-Spengler总共将制备19种化合物 所需喹啉二酮-2-甲醛与色胺的缩合 或根据我们的新的和有效的路线使用的 拉文达霉素甲酯合成 这些化合物的生物活性 化合物将在rasK、rasH、3LL和亲本非转化型上测定 （NRKE）细胞系。 对于更有效的选择性衍生物， 还将进行体内活性。

The potential clinical use of the potent antitumor streptonigrin (20a) and lavendamycin (5) has been precluded because of their toxicity. The long-term objective of this proposal is to determine the factors which control the biological activity of these two related systems so that rational approaches to the design and development of selective drugs can be pursued. Results of previous structure-activity relationship (SAR) studies on partial structures of lavendamycin and streptonigrin are inconclusive compared with the results obtained with the parent molecules. This indicates that the complete molecular structures may have a definite effect on the activity. Thus, the immediate goal of this proposal is to synthesize and perform SAR studies on a series of novel lavendamycin derivatives all possessing the complete parent ring structure. The derivatives will range from the unsubstituted pentacyclic ring to mono, di and trisubstituted derivatives, including those with electron withdrawing and releasing groups at the C-7 position. 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, the quinolinedione reduction potential and each individual substituent plays in the overall activity of the molecule. A total of 19 compounds will be prepared by the Pictet-Spengler condensation of the desired quinolinedione-2-carbaldehydes with tryptamine or tryptophans according to our new and efficient route used in the synthesis of lavendamycin methyl ester. The biological activity of these compounds will be determined on rasK, rasH, 3LL and parent nontransformed (NRKE) cell lines. For more potent selective derivatives an assessment of in vivo activity will also be performed.