DEVELOPMENT OF MARINE MACROLIDES LATRUNCULINS AS ANGIOGENESIS MODULATORS

作为血管生成调节剂的海洋大环内酯 Latrunculins 的开发

• 批准号: 7381335
• 负责人: KHALID A EL SAYED
• 金额: $ 11.84万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381335
• 关键词: DEVELOPMENT; MARINE; MACROLIDES; LATRUNCULINS; ANGIOGENESIS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer remains one of the major global causes of death. Tumor metastasis is one of the main causes of cancer mortality. Cancer progression, especially solid tumors, invasion, and angiogenesis have become potential targets for anticancer drug development.1 Bevacizumab (Avastin) is the first anti-angiogenic drug approved by the FDA this year.1 Bevacizumab induced 5-months prolonged survival in metastatic colorectal cancer patients. Avastin approval opened the horizon to discover more effective prototype anti-angiogenic and anti-invasive entities. The chemical and biological diversity of marine natural products make them an enormous resource of unique and highly bioactive compounds. The anti-angiogenic marine natural products squalamine and AE-941 (Neovastat) are advancing into clinical trials phases II/III.1 Hence, the objective of this proposal is to discover prototype anti-angiogenic and anti-invasive leads of marine origin with improved potency compared to bevacizumab. Three different classes of readily available marine-derived secondary metabolites and their analogs are the focus of this project. Our hypothesis is: effective and non-toxic prototype lead anti-angiogenic/anti-invasive latrunculins, sipholanes, and sarcophines can be generated and optimized using biocatalysis, combinatorial biocatalysis, and sulfation reactions. The targeted marine derived compounds are the non-toxic semisynthetic latrunculin analogs 15-O-methyl latrunculin B 1) 2 and 15-O-methyllatrunculin A; 2) the sipholane triterpenes sipholenone A; 3) and sipholenol A; 4) and the cembranolide diterpenes sarcophine; and 5) 16-deoxysarcophine. This proposal targets achieving the following specific aims: Aim 1: Collection of the three common source animals from the Red Sea and isolation of gram amounts of latrunculins, sipholanes, and sarcophines. Aim 2: Bioconversion and combinatorial bioconversion studies of latrunculins, sipholanes, and sarcophines. Aim 3: To Culture and investigate symbiotic microbial species associated with the sponges Negombata magnifica and Siphonochalina siphonella, and the soft coral Sarcophyton glaucum and explore their ability to produce latrunculins, sipholanes, and sarcophines. Aim 4: To subject the latrunculins, sipholanes, sarcophines and their major bioconversion products to various sulfation reactions to improve or enhance their anticancer activity. Aim 5: To evaluate of the anti-invasive and anti-angiogenic effects of the resulting compounds.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。癌症仍然是全球主要的死亡原因之一。 肿瘤转移是癌症死亡的主要原因之一。癌症进展，特别是实体瘤、侵袭和血管生成已成为抗癌药物开发的潜在靶点。1贝伐单抗（Avastin）是FDA今年批准的第一种抗血管生成药物。1贝伐单抗可延长转移性结直肠癌患者的生存期5个月。阿瓦斯丁的批准打开了发现更有效的原型抗血管生成和抗侵入实体的视野。 海洋天然产品的化学和生物多样性使其成为独特和高度生物活性化合物的巨大资源。抗血管生成的海洋天然产物角鲨胺和AE-941（Neovastat）正在进入II/III期临床试验阶段。1因此，本提案的目的是发现海洋来源的原型抗血管生成和抗侵入先导物，与贝伐单抗相比具有更高的效力。三个不同类别的容易获得的海洋衍生的次级代谢产物及其类似物是这个项目的重点。我们的假设是：可以使用生物催化、组合生物催化和硫酸化反应来产生和优化有效和无毒原型先导抗血管生成/抗侵入的latrunculins、sipholanes和sarcophines。目标海洋衍生化合物是无毒的半合成latrunculin类似物15-O-甲基latrunculin B 1）2和15-O-甲基latrunculin A; 2）sipholane三萜sipholenone A; 3）和sipholenol A; 4）和cembranetine二萜sarcophine;和5）16-deoxysarcophine。该提案旨在实现以下具体目标：目标1：从红海收集三种常见来源动物，并分离克量的latrunculins，sipholanes和sarcophines。 目的2：研究latrunculins，sipholanes和sarcophines的生物转化和组合生物转化。 目标3：培养和调查与海绵Negombata magnifica和Siphonochalina siphonella以及软珊瑚Sarcophyton glaucum相关的共生微生物物种，并探索它们产生latrunculins，sipholanes和sarcophines的能力。 目标4：对latrunculins、sipholanes、sarcophines及其主要生物转化产物进行各种硫酸化反应，以改善或增强其抗癌活性。 目的5：评价所得化合物的抗侵袭和抗血管生成作用。