Synthesis & Evaluation of Lavendamycin Antitumor Agents

尽管抗生素拉旺霉素是一种有效的抗肿瘤药物，但由于其高毒性，其临床应用被排除在外。我们已经合成了大量取代的拉旺霉素类似物，并对其中相当数量的化合物进行了各种体内外抗肿瘤筛选。这些测试表明，相当数量的拉旺霉素对多种人类癌症都有很高的活性。 台词。我们发现，与其简单的喹啉二酮类似物相比，拉旺霉素对动物的毒性要小得多，并显示出高度的选择性毒性。看来，该分子的FI-Caroline(CDE环)部分在赋予这种选择性毒性中起着重要作用。我们的数据也表明了C-7氨基和C-2‘酰胺或酯在提高分子活性方面的重要性。NCI开发治疗计划选择了几个莱旺霉素类似物，用于体内中空纤维和异种小鼠模型的测试。这些化合物已被证明具有高的最大耐受量，在中空纤维检测中具有很强的活性，并已在动物身上对一些癌症进行了评估。然而，这些化合物的低水溶性一直是体内抗肿瘤研究的一个严重限制。因此，这项建议的主要目标是合成一些新型的带有酸性侧臂的水溶性类似物，以增加水的溶解性，同时保留那些对生物活性至关重要的官能团。我们的初步研究表明，这些可溶性类似物确实可能比相应的不溶性类似物具有更强的抗肿瘤活性。此外，还没有评估还原潜力在拉旺霉素抗肿瘤活性中的作用。因此，待合成的新型莱旺霉素还将包括五环骨架上具有零、一、二、三或四个取代基的类似物，代表具有广泛还原潜力的分子。研究的第二个目标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：针对H60肿瘤细胞系的活性的NCI；用于克隆生存分析和DNA损伤评估的R.Abraham的小组；以及用于NQO1还原酶分析的H.Bealars小组。将对这些生物的生物活性进行评估 化合物与它们的还原电位有关，就像对较简单的对苯二酚所观察到的那样。最后两组进行的检测旨在阐明莱旺霉素的作用机制(S)。希望这些研究不仅能阐明结构和水溶性在确定药物抗肿瘤活性中所起的作用，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.