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）：phorboxazoles是从海洋海绵phorbas sp中分离出来的天然产物。 1995年8月，报道了对美国国家癌症研究所的60种人类癌症系的小组（平均GI50值小于1.6 x 10-9 m；平均GI50值小于1.6 x 10-9 m；大多数细胞系在最低的测试浓度下被抑制100％）。凤梨唑是凤尾唑唑代表了全新的细胞固定剂，并且在最新的细胞稳定剂中又是“最多的”，并且是“最多的”，并且是“最多的”。苯辅唑的作用机理尚不清楚，并且自然来源不可用。苯辅唑具有主要的细胞靶标和一种与已知化学治疗剂不同的作用机理。总合成代表了天然产物和结构类似物的替代来源。合成phorboxazole a和几个紧密的合成类似物在PM浓度范围内具有细胞毒性，并诱导凋亡细胞死亡。原始的合成条目允许获得一些初步的结构 - 活性关系数据，并且可以对抗癌活性获得，并且可以修改现有的合成以生成探针以鉴定细胞靶标。该提案的总体目的是通过通过创新进一步的合成有机化学，以独特而快速访问phorboxazoles的结构类似物，确定其细胞靶标并确定基本的Phorboxazole Pharmacophore和可能的动作模式，从而继续开发phorboxazole化学型作为一种有希望的新型抗癌治疗剂。将使用合成phorboxazole A的亲和力衍生物来鉴定phorboxazole受体，该衍生物最初将在显示的人类cDNA的噬菌体库中进行筛选。必要时将是经典的亲和力方法。一种新的碎片耦合方法，用于访问phorboxazole分子结构和体外筛选，将用于测试特定的结构活性假设，绘制天然产物的必需药效团并识别结构中明显更简单但保持父母化合物的抗癌活性的新颖分子。该项目的成功结果将提供独特的，合成的phorboxazole相关抗癌剂。苯辅唑的细胞靶标识别将直接洞悉作用方式，并可能提供先前未开发的治疗靶标。