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

说明(申请人提供)：烷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有中心地位。本实验室设计并合成了一类新的肿瘤抑制前药1，2-双磺酰肼，它通过活化产生与DNA交联的反应性亲电结构。临床前研究表明，1，2-二(甲磺酰基)-1-(2-氯乙基)-2-[(甲氨基)羰基]肼，命名为氯雷他津，对多种移植的小鼠和人类肿瘤的治疗效果优于其他1，2-二(2-氯乙基)肼和1，3-二(2-氯乙基)-1-亚硝脲(BCNU)。氯雷他津也很容易通过血脑屏障，具有口服和肠外活性，与环磷酰胺、BCNU或马法兰没有交叉耐药性，其激活的副产物甲基异氰酸酯与生成的氯乙基化物种具有协同细胞毒活性。甲基异氰酸酯的部分作用是通过抑制O6-烷基鸟嘌呤-DNA烷基转移酶活性(AGT)来发挥作用，AGT是抗药性的主要机制，可使DNA中鸟嘌呤的O-6位烷基化。异氰酸甲酯还可增强氯乙基化产生的氯乙基化物种在缺乏AGT的细胞系中的细胞毒性，表明异氰酸甲酯会产生其他代谢损伤。在I期和II期临床试验中，氯雷他津对成人AML显示出显著的抗白血病活性；目前，它正处于与AraC联合治疗成人AML的第三阶段试验，以及成人和儿童胶质母细胞瘤的第二阶段试验。第二个1，2-双(磺酰基)肼，1，2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-硝基苯基)乙氧基]羰基]肼，命名为KS119，可选择性激活和杀伤实体瘤的缺氧细胞，处于临床前开发阶段。本申请的具体目的包括继续研究氯氮肼和KS119的作用机理(S)，以及(A)合成旨在规避AGT耐药性的氯氮肼类似物，以及旨在释放更多异氰酸甲酯以增强氯乙基化性能的类似物；(B)KS119的类似物及其在活化时不仅释放烷基化物种而且还释放异氰酸甲酯的水溶性衍生物的合成；(C)新合成的1，2-双磺酰肼的作用机理(S)的比较，以确保新开发的第二代药物的临床前优势。这些研究将包括对广泛移植肿瘤的抗肿瘤效果、毒性、药理作用、DNA的交联和修复以及抑制AGT的能力的测量。这些研究将有助于优化1，2-双(磺酰基)肼前药的抗癌潜力。

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.