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

抗癌1,2-双(磺酰)肼的研制

• 批准号: 7475212
• 负责人: ALAN CLAYTON SARTORELLI
• 金额: $ 29.46万
• 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/7475212
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adult; Adult Acute Myeloblastic Leukemia; Alkylating Agents; Antineoplastic Agents; Biological; Blood - brain barrier anatomy; Carmustine; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Childhood; Class; Clinical Trials; Cyclophosphamide; DNA; DNA Repair; Development; Ensure; Generations; Glioblastoma; Guanine; Human; Hydrazine; Hydrazines; Hypoxia; Investigation; Laboratories; Lead; Lesion; Measurement; Melphalan; Metabolic; Mus; Neoplasm Transplantation; Nitrosourea Compounds; O(6)-Methylguanine-DNA Methyltransferase; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Positioning Attribute; Prodrugs; Property; Refractory; Relapse; Resistance; Solid Neoplasm; Structure; Toxic effect; Transplantation; Water; analog; crosslink; cytotoxic; cytotoxicity; design; killings; methyl isocyanate; pre-clinical; preclinical study; resistance mechanism; tumor

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）：烷基化剂是最有用和最广泛使用的抗癌剂之一；它们在癌症化疗中占据中心地位。我们的实验室设计并合成了一类新型肿瘤抑制前药，即1,2-双(磺酰)肼，它通过活化反应性亲电结构产生交联DNA。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]肼（称为氯雷他嗪）在治疗上优于其他 1,2-双（磺酰基）肼。 1,3-双(2-氯乙基)-1-亚硝基脲 (BCNU)，与氯雷他嗪一样，都是生物氯乙基化剂，可对抗多种移植的小鼠和人类肿瘤。氯雷他嗪也很容易穿过血脑屏障，口服和肠胃外均具有活性，与环磷酰胺、BCNU或美法仑不具有交叉耐药性，其活化的副产物异氰酸甲酯与生成的氯乙基化物质具有协同细胞毒活性。异氰酸甲酯的部分功能是通过抑制 O6-烷基鸟嘌呤-DNA 烷基转移酶活性 (AGT)，这是对氯雷他嗪等药物产生耐药性的主要机制，氯雷他嗪会将 DNA 中鸟嘌呤的 O-6 位烷基化。异氰酸甲酯还增强了氯雷他嗪在缺乏 AGT 的细胞系中产生的氯乙基化物质的细胞毒性，表明异氰酸甲酯会产生其他代谢损伤。氯雷他嗪在 I 期和 II 期临床试验中显示出显着的针对成人 AML 的抗白血病活性；目前，该药物正处于与 AraC 联合治疗成人 AML 的 III 期试验以及成人和儿童胶质母细胞瘤的 II 期试验中。第二个1,2-双(磺酰基)肼，1,2-双(甲磺酰基)-1-(2-氯乙基)-2-[[1-(4-硝基苯基)乙氧基]羰基]肼，指定为KS119，其中通过选择性激活和杀死实体瘤的缺氧细胞，目前正处于临床前开发阶段。本申请的具体目标包括继续研究氯雷他嗪和 KS119 的作用机制，以及 (a) 旨在规避 AGT 产生的耐药性的氯雷他嗪类似物的合成，以及旨在释放更多量的氯雷他嗪类似物。异氰酸甲酯可增强氯雷他嗪的氯乙基化特性； (b) KS119类似物及其水溶性衍生物的合成，其在活化时不仅释放烷基化物质而且释放异氰酸甲酯； (c) 比较新合成的 1,2-双（磺酰）肼的作用机制，以确保新开发的第二代药物的临床前优越性。这些研究将包括测量针对广泛的移植肿瘤的抗肿瘤功效、毒性、药理分布、DNA 交联和修复以及抑制 AGT 的能力。这些研究应该能够优化 1,2-双（磺酰基）肼前药的抗癌潜力。