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

描述（申请人提供）：烷基化剂是最有用和应用最广泛的抗癌剂之一；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的肿瘤抑制前药，1,2-双（磺酰基）肼，它通过激活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-[（甲氨基）羰基]肼，即氯噻嗪，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），后者与氯噻嗪一样是生物氯乙基化剂，可治疗多种移植小鼠和人类肿瘤。氯噻嗪也很容易穿过血脑屏障，口服和肠外均有活性，与环磷酰胺、BCNU或melphalan无交叉耐药，其激活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抑制o6 -烷基鸟嘌呤-DNA烷基转移酶活性（AGT），这是对氯噻嗪等药物耐药的主要机制，氯噻嗪使鸟嘌呤在DNA中的O-6位置烷基化。在缺乏AGT的细胞系中，异氰酸甲酯也增强了氯噻嗪产生的氯乙基化物质的细胞毒性，这表明异氰酸甲酯会产生其他代谢损伤。氯噻嗪在I期和II期临床试验中显示出显著的抗白血病活性；目前，该药物正在与AraC联合进行成人AML的III期临床试验，以及成人和儿童胶质母细胞瘤的II期临床试验。另一种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）乙氧基]羰基]肼，命名为KS119，具有选择性激活和杀死实体肿瘤缺氧细胞的作用，目前正处于临床前研究阶段。本申请的具体目的包括继续研究氯噻嗪和KS119的作用机制，以及(a)氯噻嗪的类似物的合成，以绕过AGT的抗性，以及设计类似物释放更多的异氰酸甲酯，以增强氯噻嗪的氯乙基化性能；(b) KS119的类似物及其水溶性衍生物的合成，不仅释放烷基化物质，而且在激活后释放异氰酸甲酯；(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。这些研究将包括对广泛的移植肿瘤的抗肿瘤功效、毒性、药理学处置、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.