MARINE NATURAL PRODUCTS AS ANTI-ANGIOGENIC AND ANTI-INVASIVE AGENTS

海洋天然产品作为抗血管生成和抗侵袭剂

• 批准号: 7609940
• 负责人: KHALID A EL SAYED
• 金额: $ 13.87万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609940
• 关键词: Actinobacteria class; Actinomyces; Callyspongia; Cause of Death; Class; Computer Retrieval of Information on Scientific Projects Database; Evaluation; Funding; Future; Genes; Goals; Grant; Hydantoins; Indoles; Institution; Invasive; Malignant Neoplasms; Marine Invertebrates; Marines; Mediating; Methods; Phenazines; Porifera; Reaction; Recombinant DNA; Red Sea; Research; Research Personnel; Resources; Ribosomal DNA; Source; Testing; United States National Institutes of Health; analog; anticancer activity; coral; design; diketopiperazine; indole; marine natural product; microorganism; novel; prototype; sarcophine; small molecule

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. Marine natural products are enormous resource of diverse, unique, and highly bioactive compounds. The ultimate goal of this study is to discover and optimize prototype antiproliferative, antimetastatic, anti-migratory, and antiinvasive leads of marine origin. Our research is focused on four different classes of readily available marine-derived secondary metabolites and their analogs. These compounds are common in the Red Sea marine sponges Negombata magnifica, Callyspongia siphonella, Hemimycale arabica, and the soft coral Sarcophyton glaucum. We hypothesized that effective prototypic anticancer latrunculins, sipholanes, hydantoins, and sarcophines can be generated and optimized using biocatalysis and rational semisynthetic approaches. Many bioactive compounds isolated from marine invertebrates are originating from symbiotic microorganisms. We also hypothesized that symbiotic microorganisms associated with the Red Sea sponges N. magnifica, and C. siphonella can be used as a source of novel anticancer entities. The specific aims of this study were: 1) optimization of latrunculins, sipholanes, hydantoins, and cembranoids using biocatalytic and rational semisynthetic reactions; 2) isolation and identification of symbiotic microorganisms associated with N. magnifica, and C. siphonella; 3) large-scale culturing of the isolated microorganisms and testing their extracts for novel secondary metabolites; and 4) evaluation of anticancer activities of the isolated compounds. Several new bioconversion and semisynthetic products of sarcophine, 2-epi-16-deoxysarcophine, latrunculins A and B, sipholenol A, and sipholenone A were generated and identified using spectral methods. More than 100 bacterial and actinomycete species were cultured and identified using 16S rDNA gene sequencing. Novel diketopiperazine, indole, and phenazine analogs were isolated from Kocuria, Pontibacillus, and Pelagiobacter species, respectively. Some of these compounds showed potent anticancer activities including antiinvasive, anti-migratory, anti-angiogenic, antiproliferative, HIF-1, and P-gp-mediated MDR inhibitory activities. Future efforts will be focused on the discovery and design of bioisosteric small molecules that can serve as prototype anticancer leads.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 癌症仍然是全球主要死亡原因之一。海洋天然产物是多样化、独特且高度生物活性化合物的巨大资源。这项研究的最终目标是发现和优化海洋来源的原型抗增殖、抗转移、抗迁移和抗侵袭引线。我们的研究重点是四种不同类别的容易获得的海洋来源的次生代谢物及其类似物。这些化合物常见于红海海绵 Negombata magnifica、Callyspongia siphonella、Hemimycale arabica 和软珊瑚 Sarcophyton glaucum 中。我们假设可以使用生物催化和合理的半合成方法来生成和优化有效的原型抗癌拉特伦库林、西弗兰、乙内酰脲和肌啡肽。从海洋无脊椎动物中分离出的许多生物活性化合物源自共生微生物。我们还假设与红海海绵 N. magnifica 和 C. siphonella 相关的共生微生物可以用作新型抗癌实体的来源。 本研究的具体目的是：1）利用生物催化和合理的半合成反应优化latrunculins、sipholanes、hydantoins和cembranoids； 2）与N. magnifica和C. siphonella相关的共生微生物的分离和鉴定； 3）大规模培养分离的微生物并测试其提取物中新的次生代谢产物； 4) 分离化合物的抗癌活性评价。 使用光谱方法生成并鉴定了几种新型生物转化和半合成产品：肉碱、2-epi-16-脱氧肉碱、latrunculins A 和 B、sipholenol A 和 sipholenone A。使用 16S rDNA 基因测序培养并鉴定了 100 多种细菌和放线菌物种。新型二酮哌嗪、吲哚和 吩嗪类似物分别从 Kocuria、Pontibacillus 和 Pelagiobacter 物种中分离出来。其中一些化合物表现出有效的抗癌活性，包括抗侵袭、抗迁移、抗血管生成、抗增殖、HIF-1 和 P-gp 介导的 MDR 抑制活性。未来的努力将集中于发现和设计可作为原型抗癌先导化合物的生物电子等排小分子。