Merging Marine-Derived Cytotoxic Natural Products With Experimental Therapeutics

将海洋来源的细胞毒性天然产品与实验疗法相结合

• 批准号: 9038079
• 负责人: Phil Crews
• 金额: $ 6.35万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038079
• 关键词: Address; Alkaloids; Antineoplastic Agents; Bacteria; Biological Assay; Biological Factors; Breast; California; Cancer Center; Chemistry; Clinical; Collaborations; Colorectal; Developmental Therapeutics Program; Diffusion; Evaluation; Foundations; Fractionation; Goals; Gram-Negative Bacteria; Grant; Growth; Health; In Vitro; Libraries; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of ovary; Marines; Methodology; Mining; Oxygen; Pancreas; Pathway interactions; Pharmacology; Porifera; Relative (related person); Research; Science; Solid; Solid Neoplasm; Source; Structure; System; Therapeutic; Universities; Water; Work; cytotoxic; cytotoxicity; follow-up; fungus; in vivo; interest; marine natural product; microorganism; novel; repository; small molecule; therapeutic evaluation; tumor

DESCRIPTION (provided by applicant): Our long-term objective is to discover and develop leads for new anticancer agents. This research utilizes a collaboration between the Marine Bioorganic Chemistry group at U. of California Santa Cruz (UCSC) led by Prof. P. Crews and the Developmental Therapeutics Program at the Josephine Ford Cancer Center (JFCC) led by Dr. F. A. Valeriote. The hypothesis is that small molecule natural products (<2000 amu), can be identified and used, to selectively inhibit the growth of solid cancer tumors. The aims outlined below will provide a foundation to discover and explore new biomolecules that will be of broad interest while also addressing general hypotheses guiding this research. Our focus is on tumors with relative insensitivity to most of the standard anticancer drugs. Thus, the overall aim is to obtain new compounds with effective activity against solid tumors, especially pancreatic, colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. The general aims for the next grant period are: 1. To mine our repository of unstudied sponges either to continue or to begin new studies on both known and new bioactive, small biomolecules. 2. To use marine-derived fungi cultured in various media as a source for new active small biomolecules. 3. To use and refine our sponge-inspired hypothesis as the rationale for pursuing culture of Gram-positive and Gram-negative bacteria as a source of new active small biomolecules. 4. To utilize the in vitro cytotoxicity disk diffusion assay network to identify extracts obtained from Aims 1, 2, and 3 with solid tumor selectivity for follow-up fractionation and SAR expansion in Aim 6. 5. To make use of promising analytical methodologies, especially DART MS and DANS NMR, to guide further work on marine extracts, fractions, and library pure compounds obtained from Aims 1, 2, and 3. 6. To efficiently isolate, characterize and/or dereplicate compounds by focusing on the priority hits identified in Aims 4 and 5. 7. To continue capstone studies of solid tumor selective compounds through pharmacology evaluations and therapeutic assessment.

描述（由申请人提供）：我们的长期目标是发现和开发新的抗癌药物的先导化合物。这项研究利用了 P. Crews 教授领导的加州大学圣克鲁斯分校 (UCSC) 海洋生物有机化学小组与 F. A. Valeriote 博士领导的约瑟芬·福特癌症中心 (JFCC) 发展治疗项目之间的合作。假设可以鉴定和使用小分子天然产物（<2000 amu）来选择性抑制实体癌肿瘤的生长。下面概述的目标将为发现和探索引起广泛兴趣的新生物分子奠定基础，同时也解决指导这项研究的一般假设。我们的重点是对大多数标准抗癌药物相对不敏感的肿瘤。因此，总体目标是获得对实体瘤，特别是胰腺癌、结肠直肠癌、乳腺癌、前列腺癌、脑癌、卵巢癌和肺癌具有有效活性的新化合物。 下一个资助期的总体目标是： 1. 挖掘我们未研究的海绵资源库，以继续或开始对已知和新的生物活性、小生物分子的新研究。 2. 利用在各种培养基中培养的海洋真菌作为新的活性小生物分子的来源。 3. 使用和完善我们的海绵启发假设，作为追求革兰氏阳性和革兰氏阴性细菌培养作为新的活性小生物分子来源的基本原理。 4. 利用体外细胞毒性纸片扩散测定网络来鉴定从目标 1、2 和 3 获得的提取物，其具有实体瘤选择性，用于目标 6 中的后续分级分离和 SAR 扩展。 5. 利用有前景的分析方法，特别是 DART MS 和 DANS NMR，指导对从目标 1、2 和 3 获得的海洋提取物、馏分和库纯化合物的进一步工作。 6. 有效分离、表征和/或通过关注目标 4 和 5 中确定的优先命中来消除化合物的重复。 7. 通过药理学评价和治疗评估继续实体瘤选择性化合物的顶点研究。