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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 癌症仍然是全球主要的死亡原因之一。海洋天然产物是一种丰富多样、独特独特的高生物活性化合物资源。本研究的最终目标是发现和优化原型抗增殖，抗转移，抗迁移和抗侵入的海洋来源的铅。我们的研究重点是四种不同类型的现成的海洋衍生次级代谢产物及其类似物。这些化合物在红海海绵Negombata magnifica、Callysongia siphonella、Hemimycale arabica和软珊瑚Sarcophyton glaucum中很常见。我们假设，有效的原型抗癌latrunculins，sipholanes，乙内酰脲，和sarcophines可以产生和优化使用生物催化和合理的半合成方法。从海洋无脊椎动物中分离出的许多生物活性化合物来源于共生微生物。我们还假设与红海海绵N. magnifica和C.管胞菌可用作新抗癌实体的来源。 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，hetoins和cesbranoids; 2）分离和鉴定与N. magnifica和C.虹吸管; 3）大规模培养分离的微生物并测试其提取物的新次级代谢产物;和4）评价分离的化合物的抗癌活性。 利用光谱分析方法，合成并鉴定了几种新的sarcophine生物转化和半合成产物：2-epi-16-deoxysarcophine、latrunculins A和B、sipholenol A和sipholenone A。100多种细菌和放线菌的培养和鉴定使用16 S rDNA基因测序。新的二酮哌嗪，吲哚，和 吩嗪类似物分别从库克菌属（Kocuria）、庞蒂芽孢杆菌属（Pontibacillus）和Pelagiacillus物种中分离。这些化合物中的一些显示出有效的抗癌活性，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。未来的努力将集中在发现和设计生物电子等排小分子，可以作为原型抗癌线索。

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.