Total Synthesis of Plocamium Polyhalogenated Monoterpenes, Analogues, and Biologi

Plocamium 多卤单萜、类似物和 Biologi 的全合成

• 批准号: 8734233
• 负责人: Carl Vogel
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-23 至 2016-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734233
• 关键词: 6-bromo-3-(bromomethyl)-7-methyl-2,3,7-trichloro-1-octene; Alkenes; Antifungal Agents; Antineoplastic Agents; Attention; Biological; Biological Availability; Biological Factors; Biological Models; Biological Testing; Brain; California; Cancer cell line; Carbon; Cells; Characteristics; Chlorine; Collaborations; Colon; Complex; Development; Etoposide; Family; Goals; Halogens; Institution; Kidney; Marines; Medical center; Methodology; Minor; Modification; Monoterpenes; Oceanography; Pharmaceutical Preparations; Plants; Plocamium; Procedures; Red Algae; Reporting; Solid Neoplasm; Source; System; Testing; Therapeutic; Topotecan; Universities; analog; base; cancer cell; cytotoxic; cytotoxicity; docetaxel; in vivo; interest; member; pre-clinical; public health relevance; tumor

DESCRIPTION (provided by applicant): Plocamium polyhalogenated monoterpenes are metabolites first isolated from the red algae Plocamium cartilagineum, featuring several units of unsaturation, as well as multiple halogens, including two contiguous stereogenic chlorine-bearing carbons. These molecules possess a wide range of biological activity, but most notably show cytotoxicity against a range of solid-tumor cancer cell lines. This promising activity has caught the attention of William Gerwick (Scripps Institution of Oceanography) and Dr. Fred Valeriote (Henry Ford Medical Center). The testing of several members of the Plocamium polyhalogenated monoterpene family suggests only moderate cytotoxicity levels, initial results indicate that these compounds are selective for solid tumors, while remaining nontoxic to healthy cells. However, due to the low abundance from natural sources, these compounds were only isolated in small quantities, and in vivo studies could not be conducted. The Vanderwal group at the University of California Irvine aims to develop the first synthesis of members of the Plocamium polyhalogenated monoterpenes, The proposed synthesis is concise and modular, allowing for multiple members of the class to be synthesized, as well as a host of unnatural analogues, with only minor modifications to the procedure. Initial results on the synthesis of simplified model systems are promising, and once completed, the Plocamium polyhalogenated monoterpene natural products will be synthesized. Through collaboration with Gerwick and Dr. Valeriote, the synthesized compounds will be tested for biological activity, and in the case of known bioactive members, continue in vivo studies.

描述(由申请人提供)：多卤代单萜是首先从红藻软骨藻中分离出来的代谢物，具有几个单位的不饱和性，以及多个卤素，包括两个连续的立体生成含氯碳。这些分子具有广泛的生物活性，但最显著的是对一系列实体瘤癌细胞株具有细胞毒性。这一有希望的活动引起了斯克里普斯海洋研究所的威廉·格维克和亨利·福特医学中心的弗雷德·瓦莱里奥特博士的注意。对PLocamium多卤化单萜家族的几个成员的测试表明，只有中等的细胞毒性水平，初步结果表明，这些化合物对实体瘤具有选择性，同时对健康细胞保持无毒。然而，由于天然来源的丰度较低，这些化合物只能分离出少量的化合物，无法进行体内研究。加州大学欧文分校的Vanderwal小组的目标是开发首次合成多卤代单萜的PLocamium成员，拟议的合成是简洁和模块化的，允许合成该类别的多个成员，以及许多非天然类似物，只需对程序进行微小的修改。简化模型体系合成的初步结果是有希望的，一旦完成，将合成多卤代单萜天然产物。通过与Gerwick和Valeriote博士的合作，合成的化合物将进行生物活性测试，如果是已知的生物活性成员，将继续进行体内研究。