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

描述（由申请人提供）：烷化剂是最有用和最广泛使用的抗癌药物之一;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的肿瘤抑制前药，1，2-双（磺酰基）肼，其通过活化产生交联DNA的反应性亲电结构。临床前研究表明，1，2-双（甲磺酰基）-1-（2-氯乙基）-2-[（甲氨基）羰基]肼（命名为Cloretazine）在治疗上优于其他1，2-双（磺酰基）肼和1，3-双（2-氯乙基）-1-亚硝基脲（BCNU），后者与Cloretazine一样，是生物氯乙基化剂，对各种移植的鼠和人肿瘤具有治疗上级效果。氯雷他嗪也容易穿过血脑屏障，口服和胃肠外都有活性，与环磷酰胺、BCNU或美法仑没有交叉耐药性，其活化的副产物异氰酸甲酯与产生的氯乙基化物质具有协同细胞毒性活性。异氰酸甲酯通过抑制O 6-烷基鸟嘌呤-DNA烷基转移酶活性（AGT）发挥部分作用，AGT是对Cloretazine等试剂产生抗性的主要机制，Cloretazine可使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，表明异氰酸甲酯产生其他代谢病变。Cloretazine在I期和II期临床试验中显示出对成人AML的显着抗白血病活性;目前正在成人AML中与AraC联合进行III期试验，并在成人和儿童胶质母细胞瘤中进行II期试验。第二种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，命名为KS 119，具有选择性激活和杀死实体瘤的缺氧细胞的作用，正在临床前开发中。本申请的具体目的包括继续研究Cloretazine和KS 119的作用机制，以及（a）合成设计用于规避AGT提供的抗性的Cloretazine类似物，以及设计用于释放增加量的异氰酸甲酯以增强Cloretazine的氯乙基化性质的类似物;（B）合成KS 119的类似物及其水溶性衍生物，其在活化时不仅释放烷基化物质而且释放异氰酸甲酯;和（c）新合成的1，2-双（磺酰基）肼的作用机制的比较，以确保新开发的第二代药剂的临床前优越性。这些研究将包括对广谱移植肿瘤的抗肿瘤疗效、毒性、药理学处置、DNA交联和修复以及抑制AGT的能力的测量。这些调查应导致优化的抗癌潜力的1，2-双（磺酰基）肼前药。

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.