Merging Marine-Derived Cytotoxic Natural Products With Experimental Therapeutics

描述(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线索。这项研究利用了加州大学圣克鲁斯分校(UCSC)的海洋生物有机化学小组(由P.Crews教授领导)和约瑟芬·福特癌症中心(JFCC)的开发治疗计划(由F.A.Valeriote博士领导)之间的合作。假设小分子天然产物(&lt；2000Amu)可以被识别和使用，选择性地抑制实体癌肿瘤的生长。下面概述的目标将为发现和探索新的生物分子提供基础，这些生物分子将引起广泛的兴趣，同时也解决了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，我们的总体目标是获得对实体肿瘤，特别是胰腺癌、结直肠癌、乳腺癌、前列腺癌、脑癌、卵巢癌和肺癌有效的化合物。下一批赠款的总体目标是：1.挖掘我们未研究的海绵库，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.利用在不同介质中培养的海洋真菌作为新的活性生物小分子的来源。3.使用和完善我们的海绵启发假说，作为寻求培养革兰氏阳性和革兰氏阴性细菌作为新的活性小生物分子来源的理论基础。4.利用体外细胞毒性纸片扩散分析网络鉴定AIMS 1、2和3中具有实体肿瘤选择性的提取物，用于AIM 6.5中的后续分离和SAR扩展。利用有前途的分析方法，特别是DART MS和DANS核磁共振，指导从AIMS 1、2和3.6获得的海洋提取物、组分和文库纯化合物的进一步工作。通过重点关注AIMS 4和5.7中确定的优先命中，有效地分离、表征和/或去复制化合物。通过药理学评价和疗效评估，继续实体瘤选择性化合物的关键研究。

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.