Synthesis & Evaluation of Lavendamycin Antitumor Agents

尽管抗生素拉文霉素是一种有效的抗肿瘤剂，但由于其高毒性而被排除在临床使用之外。我们已经合成了大量的取代拉文达霉素类似物和各种体外和体内抗肿瘤筛选已进行了大量的这些化合物。这些试验表明，大量的拉文达霉素对广泛的人类癌症具有高度活性 线我们已经发现，与其简单的喹啉二酮类似物相比，拉文霉素对动物的毒性小得多，并显示出高度的选择性毒性。似乎分子的f-咔啉（CDE环）部分在赋予这种选择性毒性中起重要作用。我们的数据还表明C-7氨基和C-2'酰胺或酯在增强分子活性方面的重要性。NCI Developmental Therapeutics Program选择了几种拉文达霉素类似物用于体内中空纤维和异种移植小鼠模型试验。这些化合物已被证明具有高的最大耐受剂量，在中空纤维测定中具有强活性，并已被评估为针对动物中的许多癌症。然而，这些化合物的体内抗肿瘤研究的严重限制是它们的低水溶性。因此，该提议的主要目的是合成许多具有酸侧臂的新型水溶性类似物，以增加水溶性，同时保留对生物活性至关重要的那些官能团。我们的初步研究表明，这些可溶性类似物可能确实是更有效的抗肿瘤剂比其相应的不溶性类似物。此外，尚未评估还原电位在拉文霉素抗肿瘤活性中的作用。因此，待合成的新型拉文霉素的列表还将包括在五环骨架上具有零个、一个、两个、三个或四个取代基的类似物，代表具有宽范围还原电位的分子。研究的第二个目的是确定这些新化合物的生物活性。新的类似物以及一些可用的未经测试的类似物将提交给三个独立的合作小组：NCI对H 60肿瘤细胞系的活性; R.Abraham的克隆存活测定和DNA损伤评估小组和H.Bealrs的NQO 1还原酶测定小组。将评估这些化合物的生物活性是否 化合物与它们的还原电位相关，如对于较简单的醌所观察到的。最后两组进行的试验旨在阐明拉文霉素的作用机制。希望这些研究不仅能阐明结构和水溶性在决定Lavendamycins抗肿瘤活性中的作用，而且还能阐明这些潜在有用的治疗性抗癌药物的作用机制。

Although the antibiotic lavendamycin is a potent antitumor agent, its clinical use has been precluded because of high toxicity. We have synthesized a large number of substituted lavendamycin analogs and various in vitro and in vivo antitumor screenings have been performed on a substantial number of these compounds. These tests have shown that a significant number of lavendamycins are highly active against a wide range of human cancer lines. We have found that compared to their simple quinolinedione analogs, the lavendamycins are much less toxic to animals and show a high degree of selective toxicity. It appears that the fi-carboline (CDE ring) moiety of the molecule plays an important role in conferring this selective toxicity. Our data also indicate the importance of the C-7 amino and the C-2' amides or esters in enhancing the molecular activity. Several of the lavendamycin analogs were selected by the NCI Developmental Therapeutics Program for the in vivo hollow fiber and xenograft mouse models assays. These compounds have been shown to have high maximum tolerated doses, strong activity in the hollow fiber assays and have been evaluated against a number of cancers in animals. A serious limitation for the in vivo antitumor studies of these compounds, however, has been their low water solubility. Thus, the major objective of this proposal is to synthesize a number of novel water soluble analogs with acid side arms to increase water solubility while retaining those functional groups critical for biologic activity. Our preliminary studies indicate that these soluble analogs may indeed be more potent antitumor agents than their corresponding insoluble analogs. In addition, the role of the reduction potential in the antitumor activity of the lavendamycins has not been assessed. Thus, the list of novel lavendamycins to be synthesized will also include analogs with zero, one, two, three or four substituents on the pentacyclic skeleton representing molecules with a wide range of reduction potentials. The second objective of the research is to determine the biological activity of these novel compounds. The new analogs as well as some available untested analogs will be submitted to three independent collaborating groups: the NCI for the activity against H 60 tumor cell lines; R.Abraham's group for clonogenic survival assays and DNA damage assessment and H.Bealrs group for the NQO1 reductase assays. Assessments will be made as to whether the biological activity of these compounds correlates with their reduction potentials as has been observed for the simpler quinones. The assays perfomed by the last two groups are designed to elucidate the mechanism(s) of action of the lavendamycins. Hopefully, these studies will clarify not only the roles that the structure and water solubility play in determining the antitumor activity of the lavendamycins, but also the mechnism of action of these potentially useful therapeutic anticancer agents.