NOVEL A RING AND E RING MODIFIED CAMPTOTHECIN ANALOGS

拓扑异构酶I（topo I）抑制剂是目前最有前途的新型抗肿瘤药物之一。1996年，两种喜树碱（CPT）类似物获得监管批准用于实体恶性肿瘤患者：拓扑替康用于先前治疗的晚期卵巢癌患者，CPT-11（伊立替康）用于晚期结肠直肠癌患者。迄今为止，拓扑异构酶I抑制剂对某些形式的癌症无效，尽管生化证据表明拓扑异构酶I是这些肿瘤类型的良好靶点。所需要的是“第三代”拓扑异构酶I抑制剂，其继承第二代试剂CPT-11和TPT的活性，正如这些试剂继承CPT一样。我们建议开发和评估新的拓扑异构酶I抑制剂，具有双重活性的（i）有效的，可逆的拓扑异构酶I抑制剂，和（ii）拓扑异构酶I介导的DNA烷化剂。我们有以下具体目标：1.为了表征7-烷基-10，11-亚甲二氧基compatothecin类似物与DNA和拓扑异构酶I产生稳定的可切割复合物的能力。这些包括用于水溶性和内酯环稳定性的20（S）-甘氨酸酯。2.开发7-取代-10，11-亚甲二氧基喜树碱类似物，通过拓扑异构酶I介导的机制与拓扑异构酶I-DNA复合物共价结合。3.开发具有稳定内酯环的喜树碱类似物，从而防止药物的pH依赖性开环和失活。4.评价新的喜树碱类似物对体外和体内癌细胞的作用，特别强调对目前可用的喜树碱类似物临床反应较差的肿瘤类型，如前列腺癌。

Topoisomerase I (topo I) inhibitors are among the most promising new anti-neoplastic agents available. In 1996, two campothecin (CPT) analogs received regulatory approval for use in patients with solid malignancies: topotecan for previous treated patients with advanced ovarian cancer, and CPT-11 (Irinotecan) for patients with advanced colorectal carcinoma. To date, topo I inhibitors have not been effective against certain forms of cancer, despite the biochemical evidence that suggests topo I is good target in these tumor types. What is needed is a "third generation" of topo I inhibitors, that succeed the activity of 2nd generation agents CPT-11 and TPT just as these agents succeeded CPT. We propose to develop and evaluate novel topo I inhibitors that have dual activity as both (i) potent, reversible topo I inhibitors, and (ii) topo I-mediated DNA alkylating agents. We have the following specific aims: 1. To characterize 7-alkyl-10,11-methylenedioxycompatothecin analogs with respect to their ability to produce stable cleavable complex with DNA and topoisomerase I. These include the 20(S)-glycinate esters for water solubility and stability of the lactone ring. 2. To develop 7-substituted-10,11-methylenedioxycamptothecin analogs that bind covalently to topoisomerase I-DNA complexes by a topoisomerase I-mediated mechanism. 3. To develop camptothecin analogs that have stabilized lactone rings, thereby preventing pH-dependent ring opening and deactivation of the drugs. 4. To evaluate the new camptothecin analogs against in vitro and in vivo cancer cells, with particular emphasis in tumor types such as prostate cancer that respond poorly clinically to currently available camptothecin analogs.