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

抗癌剂1, 2-双(磺酰)肼的研制

• 批准号: 6869547
• 负责人: ALAN CLAYTON SARTORELLI
• 金额: $ 32.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869547
• 关键词: CHO cells; antineoplastics; athymic mouse; bioassay; brain neoplasms; colon neoplasms; drug design /synthesis /production; drug interactions; drug screening /evaluation; high performance liquid chromatography; hydrazines; leukemia; lung neoplasms; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; pharmacokinetics; prodrugs; prostate neoplasms; sulfites

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.

描述（由申请人提供）： 烷基化剂是最常用的烷基化剂之一。 有用且广泛使用的抗癌剂。因此，他们占据了中心位置 在癌症化疗中的地位。我司实验室已参与设计 和合成一类新的肿瘤抑制化合物，1, 2 双(磺酰)肼，通过活化反应生成 具有交联 DNA 能力的亲电结构。初步的 研究表明 1, 2-双(甲磺酰基)- 1 -(2-氯乙基)-2- 大约(甲基氨基)ca(在本申请中指定为10 1M)是 治疗效果优于其他 1, 2-双（磺酰）肼和 1, 3-双(2-氯乙基)- 1-亚硝基脲 (BCNU)，与 1O1M 一样，是生物性的 氯乙基化剂，针对移植的小鼠和人类肿瘤。化合物 1O1M 也能够轻易穿过血脑屏障，具有活性 当口服和肠胃外给药时，不会与以下药物产生交叉耐药性： 环磷酰胺、BCNU和美法仑及其活化的副产物， 异氰酸甲酯，能够抑制 06-烷基鸟嘌呤-DNA 烷基转移酶活性（AGT），化合物耐药性的主要机制 其将 DNA 中鸟嘌呤的 06 位烷基化。因此，1O1M 具有以下性质 足够有希望进行临床评估，并且 1O1M 是 目前正处于第一阶段试验。然而1O1M的水溶性有限， 为临床使用配制该药物造成了困难， I 期试验中使用的制剂增加了该药物的毒性 代理人。因此，本申请的具体目标不仅包括 研究 1O1M 的作用机制，还 (a) 设计和 1O1M水溶性前药的合成，以及 具有各种给电子和吸电子能力的其类似物， 从而改变前药激活的速率（t1/2），以进一步 提高治疗效果； (b) 1O1M靶向前药的合成 BCNU耐药肿瘤细胞富含GST mu该药剂靶向的前药 缺氧肿瘤细胞和 1O1M 类似物，对骨髓和毒性降低 肠粘膜； (c) 新药物作用机制的比较 与1O1M合成前药，确保新药的优越性 产生了第二代代理。这些研究将包括测量 抗肿瘤功效、毒性、DNA 激活和交联能力 和抑制 AGT 的能力。