SYNTHESIS OF INDOLOCARBAZOLES AS TOPOISOMERASE I POISONS

描述（改编自申请）：本二期项目的目标是合成和评价吲哚咔唑类似物作为人类拓扑异构酶I （Topo I）的毒物，这种酶代表了抗肿瘤药物开发的一个有吸引力的目标。第一阶段的研究涉及ED-110的所有四种“对称”区域异构体的合成，ED-110是一种半合成的Topo I毒药。该研究发现了一个区域异构体，与ed - 110相比，它对Topo I的效力大约是ed - 110的10倍。此外，与ED-110相比，该化合物对HT29结肠癌、OVCAR-3卵巢癌和DU-145前列腺癌细胞的体外抗肿瘤活性增强。在这个二期项目的过程中，我们将优化我们先导化合物的合成方法。几个系列的类似物将被合成，以确定相对于先导化合物具有增强抗肿瘤活性的化合物。将开发一种固相合成方法，以允许快速生成吲哚咔唑类似物库。所有新合成的化合物将被评估对人类Topo I活性的抑制作用。对Topo I有活性的类似物将被筛选体外抗肿瘤活性，并评估对其他靶酶的活性，包括拓扑异构酶II、蛋白激酶C和蛋白激酶a。最后，有希望的类似物将被选择用于评估急性毒性、药代动力学和体内抗肿瘤活性。拟议的商业应用：目前只有两种临床抗癌药物通过拓扑异构酶I中毒起作用，Camptosar和Hycamtin。这两种药物都是基于相同的母体化合物喜树碱。一种具有抗癌活性且具有适当毒性的吲哚咔唑类似物将具有巨大的市场潜力。这种药物可以单独使用，也可以与现有的抗肿瘤药物联合使用，特别是对现有药物产生耐药性的患者。

DESCRIPTION (Adapted from the application): The goal of this Phase II project is the synthesis and evaluation of indolocarbazole analogues as poisons of human topoisomerase I (Topo I), an enzyme which represents an attractive target for development of antitumor agents. The Phase I study involved synthesis of all four "symmetrical" regioisomers of ED-110, a semi-synthetic Topo I poison. That study identified a regioisomer, which was approximately l0-fold more potent against Topo I, when directly compared to ED-11O. Additionally, the compound showed enhanced in vitro antitumor activity against HT29 colon, OVCAR-3 ovarian, and DU-145 prostate cancer cell lines relative to ED-110. During the course of this Phase II project, the synthetic methodology used to synthesize our lead compound will be optimized. Several series of analogues will be synthesized in an effort to identify compounds having enhanced antitumor activity relative to the lead compound. A solid phase synthetic method will be developed to allow rapid generation of a library of indolocarbazole analogues. All new synthetic compounds will be evaluated for inhibition of human Topo I activity. Analogues active against Topo I will be screened for in vitro antitumor activity, as well as assessed for activity against other target enzymes, including topoisomerase II, protein kinase C, and protein kinase A. Finally, promising analogues will be selected for evaluation of acute toxicity, pharmacokinetics, and in vivo antitumor activity. PROPOSED COMMERCIAL APPLICATION: There are currently only two clinical anticancer agents that operate via poisoning of topoisomerase I, Camptosar and Hycamtin. Both of these agents are based upon the same parent compound camptothecin. An indolocarbazole analogue that possessed anticancer activity with the appropriate toxicity profile would have enormous market potential. Such as agent could be used alone or in combination with existing antitumor agents, especially in patients who develop resistance to existing medications.