Development of Anticancer 1,2-Bis(sulfonyl)hydrazines

抗癌1,2-双(磺酰)肼的研制

• 批准号: 7101262
• 负责人: ALAN CLAYTON SARTORELLI
• 金额: $ 30.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101262
• 关键词: CHO cells; antineoplastics; athymic mouse; bioassay; brain neoplasms; colon neoplasms; drug design /synthesis /production; drug interactions; drug screening /evaluation; high performance liquid chromatography; hydrazines; leukemia; lung neoplasms; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; pharmacokinetics; prodrugs; prostate neoplasms; sulfites

DESCRIPTION (provided by applicant): Alkylating agents are among the most useful and extensively used anticancer agents; they occupy a central position in cancer chemotherapy. Our laboratory has designed and synthesized a new class of tumor inhibitory prodrugs, the 1,2-bis(sulfonyl) hydrazines, which generate through activation reactive electrophilic structures that cross-link DNA. Preclinical studies have shown that 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)- 2-[(methylamino)carbonyl]hydrazine, designated Cloretazine, is therapeutically superior to other 1,2- bis(sulfonyl) hydrazines and to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), which like Cloretazine are biological chloroethylating agents, against a variety of transplanted murine and human tumors. Cloretazine also readily crosses the blood brain barrier, is active both orally and parenterally, is not cross-resistant with cyclophosphamide, BCNU, or melphalan, and a by-product of its activation, methyl isocyanate, has synergistic cytotoxic activity with the generated chloroethylating species. Methyl isocyanate functions in part by inhibiting O6-alkylguanine-DNA alkyltransferase activity (AGT), a major mechanism of resistance to agents such as Cloretazine, which alkylate the O-6 position of guanine in DNA. Methyl isocyanate also enhances the cytotoxicity of the chloroethylating species generated from Cloretazine in cell lines devoid of AGT indicating that methyl isocyanate produces other metabolic lesions. Cloretazine has shown significant antileukemic activity against adult AML in Phase I and II clinical trials; it is presently in a Phase III trial in combination with AraC in adult AML and in Phase II trials in adult and pediatric glioblastoma. A second 1,2-bis(sulfonyl)hydrazine, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1- (4-nitrophenyl) ethoxy] carbonyl]hydrazine, designated KS119, with selective activation by and kill of hypoxic cells of solid tumors, is in preclinical development. The Specific Aims of this application include continued studies on the mechanism(s) of action of Cloretazine and KS119 and also (a) the synthesis of analogs of Cloretazine designed to circumvent the resistance afforded by AGT, and analogs designed to release increased quantities of the methyl isocyanate to enhance the chloroethylating properties of Cloretazine; (b) the synthesis of analogs of KS119 and water-soluble derivatives thereof that not only release an alkylating species but also of methyl isocyanate upon activation; and (c) a comparison of the mechanism(s) of action of newly synthesized 1,2-bis(sulfonyl)hydrazines to ensure preclinical superiority of newly developed second generation agents. These studies will include measurements of antitumor efficacy against a broad spectrum of transplanted tumors, of toxicity, pharmacological disposition, cross-linking and repair of DNA, and the capacity to inhibit AGT. These investigations should lead to optimization of the anticancer potential of the 1,2-bis(sulfonyl)hydrazine prodrugs.

描述（由申请人提供）：烷基化剂是最有用，最广泛使用的抗癌剂之一；它们在癌症化疗中占据了中心位置。我们的实验室设计并合成了一类新的肿瘤抑制作用，即1,2-双（磺酰基）肼，通过激活反应性电电结构可以通过交联DNA来产生。临床前研究表明，1,2-双（甲基磺酰基）-1-（2-氯乙基）-2 - [（甲基氨基）羰基]氢嗪（指定的氯酸苯嗪）在治疗上优于其他1,2-双（sulfonyl）（sulfonyl）的水氮和1,3-二氯）（2-氯） - 氯）-1-a（2-氯）-1-a（bc） - 氯吡替嗪是针对多种移植鼠和人类肿瘤的生物氯乙基剂。氯吡替嗪还很容易跨越血脑屏障，口服和肠胃均具有活性，与环磷酰胺，BCNU或Melphalan均不交叉抗性，其激活的甲基异氰酸酯的副产品，具有协同的细胞毒性活性，具有生成的氯乙基溶质性。异氰酸甲酯部分通过抑制O6-烷基鸟嘌呤-DNA烷基转移酶活性（AGT）的作用，这是对氯替嗪等耐药性的主要机制，氯甲嗪在DNA中的O-6位置烷基化的O-6位置。异氰酸甲酯还增强了在没有AGT的细胞系中由氯地嗪产生的氯乙基物质的细胞毒性，表明异氰酸甲酯会产生其他代谢病变。在I和II期临床试验中，氯地嗪对成人AML表现出显着的抗白血病活性。目前，它是在成人AML中与ARAC结合使用的III期试验以及成人和小儿胶质母细胞瘤的II期试验。第二个1,2-双（磺酰基）肼，1,2-双（甲基磺酰基）-1-（2-氯乙基）-2-- [[1-（4-硝基苯基）乙氧氧基]碳氧基]氢嗪，指定为KS119，指定为KS119，并通过固体象征性的选择性细胞的选择性激活，并杀死了固体象征性的细胞，均为固体象征性的开发。该应用的具体目的包括持续研究氯吡嗪和KS119的作用机制，以及（a）旨在绕过AGT抗药性的类似物的类似物的合成，以及旨在释放增加甲基异糖含量增加的甲基氯甲基甲基甲基甲基化特性的类似物； （b）KS119和其水溶性衍生物的类似物的合成不仅释放烷基化物质，而且在激活时也释放异氰酸甲基酸性； （c）比较新合成的1,2-双（磺酰基）肼的作用机制，以确保新开发的第二代药物的临床前优势。这些研究将包括测量针对广泛移植肿瘤，毒性，药理学性格，DNA的交联和修复以及抑制AGT的能力的抗肿瘤功效。这些研究应导致优化1,2-双（磺酰基）肼前药的抗癌潜力。