Synthesis and Biology of the Phorboxazoles

佛罗克斯唑的合成和生物学

• 批准号: 6697461
• 负责人: Craig J. Forsyth
• 金额: $ 26.43万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697461
• 关键词: Porifera; animal extract; antineoplastics; azoles; cell growth regulation; cell line; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation

DESCRIPTION (provided by applicant): Phorboxazoles are natural products isolated from the marine sponge Phorbas sp. The isolation, partial structure determination, and cytostatic activity towards the US National Cancer Institute's panel of 60 human cancer lines (mean GI50 values of less than 1.6 x 10-9 M; most cell lines were 100% inhibited at this lowest test concentration) were reported in August, 1995. The phorboxazoles represent an entirely new class of cytostatic agents, and are "among the most potent cytostatic agents yet discovered." The phorboxazoles' mechanism of action is not known, and additional material is unavailable from natural sources. The phorboxazoles have primary cellular targets and a mechanism of action that are distinct from those of known chemotherapeutic agents. Total synthesis represents an alternative source of the natural product and structural analogs. Synthetic phorboxazole A and several close synthetic analogs are cytotoxic in the pM concentration range and induce apoptotic cell death. The original synthetic entry has allowed some preliminary structure-activity relationship data to be obtained with respect to anticancer activity, and the existing synthesis may be modified to generate probes for the identification of the cellular targets. The overall goal of this proposal is to continue to develop the phorboxazole chemotype as a promising new class of anticancer therapeutic agents by innovating further synthetic organic chemistry to uniquely and rapidly access structural analogs of the phorboxazoles, identify their cellular targets, and determine the essential phorboxazole pharmacophore and likely mode of action. Identification of the phorboxazole receptor will be undertaken using affinity derivatives of synthetic phorboxazole A that will initially be screened against phage displayed libraries of human cDNA. This will be followed by classic affinity methods, as necessary. A novel fragment coupling approach to access the phorboxazole molecular architecture and in vitro screens will be used to test specific structure-activity hypotheses, map the natural product's essential pharmacophore and identify novel molecules that are significantly simpler in structure but maintain the anticancer activity of the parent compounds. The successful outcome of this project will provide unique, synthetically accessible phorboxazole-related anticancer agents. Identification of cellular targets of the phorboxazoles will provide direct insight into the mode of action and may provide a previously unexplored target for therapy.

描述（由申请人提供）： 佛罗克斯唑是从海绵 Phorbas sp. 中分离出来的天然产物。美国国家癌症研究所的 60 种人类癌细胞系（平均 GI50 值小于 1.6 x 10-9 M；大多数细胞系在此最低测试浓度下 100% 受到抑制）的分离、部分结构测定和细胞抑制活性如下： 1995 年 8 月报道。佛波唑类代表了一类全新的细胞抑制剂，并且是“迄今为止发现的最有效的细胞抑制剂之一”。佛波唑类的作用机制尚不清楚，并且无法从天然来源获得其他材料。佛波唑类具有与已知化疗药物不同的主要细胞靶点和作用机制。全合成代表了天然产物和结构类似物的替代来源。合成的佛波唑啉 A 和几种相近的合成类似物在 pM 浓度范围内具有细胞毒性，并诱导细胞凋亡。最初的合成条目已经获得了一些关于抗癌活性的初步结构-活性关系数据，并且可以修改现有的合成以生成用于识别细胞靶标的探针。该提案的总体目标是通过进一步创新合成有机化学来继续开发佛波唑化学型作为一种有前途的新型抗癌治疗剂，以独特且快速地获得佛波唑的结构类似物，识别其细胞靶标，并确定基本的佛波唑药效团和可能的作用方式。佛波唑受体的鉴定将使用合成佛波唑 A 的亲和衍生物进行，该衍生物最初将针对噬菌体展示的人类 cDNA 文库进行筛选。根据需要，随后将采用经典的亲和方法。一种新的片段偶联方法来获取佛波唑唑分子结构和体外筛选，将用于测试特定的结构活性假设，绘制天然产物的基本药效团，并鉴定结构明显简单但保持母体抗癌活性的新分子化合物。该项目的成功成果将提供独特的、可合成的佛波唑相关抗癌药物。佛波唑类细胞靶点的鉴定将提供对作用模式的直接了解，并可能提供以前未探索的治疗靶点。