Conference Grant: "DNA Alkylation: From Natural Products to Chemotherapy"

描述（由申请人提供）：本提案是对为期半天的题为“DNA烷基化：从天然产物到化疗”的研讨会的财务支持的请求，该研讨会将于2006年9月10日至14日在弗朗西斯科，加州举行的第232届美国化学学会全国会议上举行。 研讨会将由化学毒理学部主办，药物化学部协办。 该活动的目的是作为一个论坛，讨论目前的思想有关的化学和生物学机制，其中DNA烷基化剂获得其药用特性。 DNA-烷基化剂是在20世纪40年代成功用于治疗人类癌症的第一批化学治疗剂之一。 从那时起，已经开发了大量的DNA烷基化抗癌药物，这些化合物由于其治疗各种癌症的功效而在癌症化疗中发挥着核心作用。 即使癌症化疗的新方法被开发出来，DNA烷基化药物也可能继续被广泛使用。这类药物将继续得到广泛使用，因为它们在治疗某些癌症方面取得了公认的成功，而且还因为许多对抗癌症的新方法，包括抑制血管生成、免疫疗法和调节细胞周期，当与细胞毒性药物（例如DNA烷基化剂）联合使用时最有效。 因此，持续需要了解临床使用的DNA-烷基化药物的化学和生物学，并且需要开发化学上新颖的DNA-烷基化剂以潜在地用作新的化疗剂。 研讨会将集中在三个领域，持有有效的DNA烷基化抗癌药物的发展前景。 (1)新型DNA烷基化天然产物的表征。从历史上看，天然产物已被证明是抗癌药物的丰富来源。在这次研讨会上，将讨论几种结构新颖的具有非常有效活性的天然产物的化学和生物学，包括倍癌霉素，azinomycin，丝裂霉素C，隐球菌素和莱那霉素。 (2)检查DNA烷基化加合物的化学结构如何与它所引起的生物反应相关。这一主题将被认为是所有的代理商，但特别是丝裂霉素C，其中各种各样的结构不同的加合物已被证明诱导非常不同的生物反应。清楚地了解加合物结构与细胞毒性的关系对于抗癌药物的开发非常有用。(3)最后，酶介导的过程，如DNA修复，对细胞杀伤烷化剂的影响将被检查。在这种情况下，将讨论选择性杀死癌细胞的DNA烷基化剂的合理设计。

DESCRIPTION (provided by applicant): This proposal is a request for financial support of a half-day symposium entitled: "DNA Alkylation: From Natural Products to Chemotherapy" to take place at the 232nd National Meeting of the American Chemical Society on September 10-14, 2006 in San Francisco, California. The symposium will be sponsored by the Division of Chemical Toxicology and co-sponsored by the Division of Medicinal Chemistry. The event is designed as a forum for discussion of current thinking regarding the chemical and biological mechanisms by which DNA-alkylating agents derive their medicinally useful properties. DNA-alkylating agents were among the first chemotherapeutic agents successfully employed for the treatment of cancer in humans in the 1940s. Since that time, a large number of DNA-alkylating anticancer drugs have been developed and these compounds now play a central role in cancer chemotherapy due to their efficacy in treating various cancers. Even as fundamentally new approaches to cancer chemotherapy are developed, it is likely that DNA-alkylating drugs will remain widely used. This class of drugs will continue to see widespread use because of their well-established success in treating certain cancers and also because many of the new approaches for fighting cancer, including inhibition of angiogenesis, immunotherapies, and modulation of the cell cycle, are most effective when used in combination with cytotoxic agents such as the DNA alkylators. Thus, there is an ongoing need to understand the chemistry and biology of clinically-used DNA-alkylating drugs and for the development of chemically novel DNA-alkylating agents for potential use as new chemotherapeutic agents. The symposium will focus on three areas that hold promise for the development of effective DNA-alkylating anticancer drugs. (1) Characterization of novel DNA alkylating natural products. Historically, natural products have proven a rich source of anticancer drugs. In this symposium, the chemistry and biology of several structurally novel natural products with very potent activity will be discussed including duocarmycin, azinomycin, mitomycin C, the illudins, and leinamycin. (2) Examination of how the chemical structure of a DNA alkylation adduct relates to the biological response that it elicits. This topic will be considered for all agents, but especially for mitomycin C, where a variety of structurally diverse adducts have been shown to induce very different biological responses. A clear understanding of how adduct structure relates to cytotoxicity would be very useful in anticancer drug development. (3) Finally, the influences of enzyme-mediated processes, such as DNA repair, on cell killing by alkylating agents will be examined. In this vein, the rational design of DNA-alkylating agents that selectively kill cancer cells will be discussed.