SYNTHESIS OF INDOLOCARBAZOLES AS TOPOISOMERASE I POISONS

描述（改编自申请）：该II期项目的目标是合成和评价吲哚并咔唑类似物作为人类拓扑异构酶I（Topo I）的毒药，拓扑异构酶I是一种代表抗肿瘤药物开发的有吸引力的靶标的酶。I期研究涉及艾德-110（一种半合成Topo I毒物）的所有四种“对称”区域异构体的合成。该研究鉴定了一种区域异构体，当与艾德-11 O直接比较时，其对Topo I的效力约为10倍。此外，相对于艾德-110，该化合物对HT 29结肠癌、OVCAR-3卵巢癌和DU-145前列腺癌细胞系显示出增强的体外抗肿瘤活性。在该第二阶段项目的过程中，将优化用于合成我们的先导化合物的合成方法。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的抗肿瘤活性的化合物。将开发固相合成方法，以允许快速生成吲哚并咔唑类似物的库。将评价所有新合成化合物对人Topo I活性的抑制作用。将筛选对Topo I有活性的类似物的体外抗肿瘤活性，并评估其对其他靶酶（包括拓扑异构酶II、蛋白激酶C和蛋白激酶A）的活性。最后，将选择有前途的类似物进行急性毒性、药代动力学和体内抗肿瘤活性的评价。拟定商业应用：目前只有两种临床抗癌剂通过拓扑异构酶I的中毒起作用，Camptosar和Hycamtin。这两种药物均基于相同的母体化合物喜树碱。具有抗癌活性和适当毒性的吲哚咔唑类似物将具有巨大的市场潜力。这种药剂可以单独使用或与现有的抗肿瘤剂联合使用，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.