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

描述(申请人提供)：烷基化剂是最重要的 用途广泛的抗癌剂。因此，他们占据了中央 癌症化疗方面的职位。我们的实验室参与了这项设计 并合成了一类新的肿瘤抑制化合物1，2 活化反应生成的双(磺酰基)肼 具有使DNA交联的能力的亲电结构。初步 研究表明，1，2-二(甲磺酰基)-1-(2-氯乙基)-2- 关于(甲氨基)钙(在本申请中标示为10 1M)是 在治疗方面优于其他1，2-双(磺酰基)肼和1，2-二(磺酰)肼， 3-二(2-氯乙基)-1-亚硝脲(BCNU)，和101M一样，是生物的 氯乙基化试剂，抗移植的小鼠和人类肿瘤。化合物 101M还能够轻易地穿越血脑屏障，是活跃的 当口服和非肠道给药时，与 环磷酰胺、BCNU和马法兰及其活化的副产物， 甲基异氰酸酯，能够抑制06-烷基鸟嘌呤-DNA 烷基转移酶活性(AGT)，化合物耐药的主要机制 它使DNA中鸟嘌呤的06位烷基化。因此，101M具有以下性质 有足够的希望进行临床评估，而101M是 目前正处于I期试验阶段。然而，101M的有限水溶解度， 在配制这种用于临床的药物方面造成了困难，而且 在第一阶段试验中使用的配方增加了这种药物的毒性 探员。因此，这项申请的具体目标不仅包括 101M作用机理的研究以及(A)设计和 水溶性101M前体药的合成及其合成 具有各种供电子和引出能力的类似物， 从而改变前药物激活率(t1/2)以努力进一步 提高治疗效果；(B)合成101M靶向前药 BCNU耐药肿瘤细胞富含GST-Mu前体药物的靶向性研究 低氧肿瘤细胞和101M类似物，对骨髓和 肠粘膜；(C)新生的作用机制的比较 用101M合成前药确保新药的优势 生成了第二代代理。这些研究将包括测量 DNA的抗肿瘤效果、毒性、活化能力和交联度 和抑制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.