SYNTHESIS OF INDOLOCARBAZOLES AS TOPOISOMERASE I POISONS

描述：该二期项目的目标是合成和评估吲哚咔唑类似物作为人类拓扑异构酶I(TOPO I)的毒药，TOPO I是一种代表抗肿瘤药物开发的有吸引力的靶标。第一阶段的研究包括合成ED-110的所有四个“对称”区域异构体，ED-110是一种半合成的TOPO I毒药。这项研究确定了一种区域异构体，与ED-110相比，它对Topo I的效力约为10倍。此外，与ED-110相比，该化合物在体外对HT29结肠癌细胞、OVCAR-3卵巢癌细胞和DU-145前列腺癌显示出更强的抗肿瘤活性。在这个二期项目的过程中，用于合成我们的先导化合物的合成方法将得到优化。将合成几个系列的类似物，以努力鉴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的库。将评估所有新的合成化合物对人类TOPO I活性的抑制作用。对Topo I具有活性的类似物将被筛选出体外抗肿瘤活性，以及对其他目标酶的活性进行评估，包括拓扑异构酶II、蛋白激酶C和蛋白激酶A。最后，将选择有前景的类似物用于急性毒性、药代动力学和体内抗肿瘤活性的评估。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。这两种药物都基于相同的母体化合物喜树碱。具有适当毒性的吲哚咔唑类似物具有抗癌活性，将具有巨大的市场潜力。这类药物可以单独使用，也可以与现有的抗肿瘤药物联合使用，特别是在对现有药物产生耐药性的患者中。

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.