DEVELOPMENT OF ANTICANCER 1, 2-BIS(SULFONYL) HYDRAZINES

描述（由申请人提供）：烷基化剂是最常见的 有用且广泛使用的抗癌剂。因此，他们占据了一个中心 在癌症化疗中的地位。我们的实验室参与了 并合成了一类新的肿瘤抑制化合物， 双（磺酰基）肼，其通过活化反应生成 具有交联DNA能力的亲电结构。初步 研究表明，1，2-双（甲磺酰基）-1-（2-氯乙基）-2- 约（甲基氨基）Ca（在本申请中指定为10 μ M）是 在治疗上优于其它1，2-双（磺酰基）肼和1， 3-双（2-氯乙基）-1-亚硝基脲（BCNU），与10 1M一样，是生物活性的 氯乙基化剂，针对移植的鼠和人肿瘤。化合物 1O1M也能够容易地穿过血脑屏障，具有活性 当口服和胃肠外给药时，与 环磷酰胺、BCNU和美法仑，以及其活化的副产物， 异氰酸甲酯，能够抑制06-烷基鸟嘌呤-DNA 烷基转移酶活性（AGT），对化合物耐药的主要机制 其使DNA中鸟嘌呤的06位烷基化。因此，1O1M具有以下性质： 有足够的前景来保证临床评价，1O1M是 目前处于第一阶段试验。然而，101M的有限的水溶性， 在配制用于临床用途的该药剂时产生了困难， 在I期试验中使用的制剂增加了这种药物的毒性， 剂因此，本申请的具体目的不仅包括 1O1M作用机制的研究，但也（a）设计和 具有水溶性的10 1M的前药的合成，以及 其具有各种供电子和吸电子能力的类似物， 从而改变前药活化的速率（t1/2）， 增加治疗功效;（B）合成10 1 M的前药以靶向 BCNU耐药肿瘤细胞中富含GST μ前药，该药物靶向 低氧肿瘤细胞和101M类似物对骨髓的毒性降低， 肠粘膜;和（c）新的作用机制的比较 合成的前体药物与10 1M的前体药物相同，以确保新药物的优越性。 生成第二代代理。这些研究将包括测量 抗肿瘤功效、毒性、DNA活化和交联能力 以及抑制AGT的能力。

DESCRIPTION (provided by applicant): Alkylating agents are among the most useful and extensively used anticancer agents. Thus, they occupy a central position in cancer chemotherapy. Our laboratory has been involved in the design and synthesis of a new class of tumor inhibitory compounds, the 1, 2 bis(sulfonyl)hydrazines, which generate through activation reactive electrophilic structures with the capacity to cross-link DNA. Preliminary studies have demonstrated that 1, 2-bis (methylsulfonyl)- 1 -(2-chloroethyl)-2- about (methylamino) ca (designated 10 1M throughout this application) is therapeutically superior to other 1, 2-bis (sulfonyl) hydrazines and to 1, 3-bis(2-chloroethyl)- 1-nitrosourea (BCNU), which, like 1O1M, are biological chloroethylating agents, against transplanted murine and human tumors. Compound 1O1M also is capable of readily crossing the blood brain barrier, is active when administered both orally and parenterally, is not cross-resistant with cyclophosphamide, BCNU and melphalan, and a by-product of its activation, methyl isocyanate, is capable of inhibiting 06-alkylguanine-DNA alkyltransferase activity (AGT), a major mechanism of resistance to compounds which alkylate the 06 position of guanine in DNA. Thus, 1O1M has properties that are sufficiently promising to warrant clinical evaluation and 1O1M is currently in a phase I trial. The limited aqueous solubility of 1O1M, however, has created difficulties in formulating this agent for clinical usage and the formulation being used in the phase I trial increase the toxicity of this agent. Therefore, the specific aims of this application include not only studies on the mechanism of action of 1O1M but also (a) the design and synthesis of prodrugs of 1O1M with aqueous solubility, and the synthesis of analogs thereof with various electron donating and withdrawing abilities, thereby varying the rates (t1/2) of prodrug activation in an effort to further increase therapeutic efficacy; (b) the synthesis of a prodrug of 1O1M to target BCNU resistant tumor cells rich in GST mu prodrugs of this agent targeting hypoxic tumor cells and 1O1M analogs with decreased toxicity to bone marrow and intestinal mucosa; and (c) a comparison of the mechanism of action of newly synthesized prodrugs with that of 1O1M to ensure the superiority of newly generated second generation agents. These studies will include measurements of antitumor efficacy, toxicity, capacity for activation and cross-linking of DNA and capacity to inhibit AGT.