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

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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 highly bioactive compounds. The ultimate goal of this study is to discover and optimize prototype anticancer leads of marine origin. Our research is focused on four different classes of readily available marine natural products. These compounds occur 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 cembranoids can be generated using biocatalysis and semisynthetic approaches. We also hypothesized symbiotic microorganisms associated with the Red Sea sponges N. magnifica and C. siphonella as novel biocatalysts appropriate to enhance the anticancer activity of natural product scaffolds. The specific aims of this study were: 1) optimization of latrunculins, sipholanes, hydantoins, and cembranoids using biocatalytic and rational semisynthetic approaches; 2) application of symbiotic microorganisms associated with N. magnifica, and C. siphonella as potential biocatalysts for bioactive scaffolds; 3) application of computational chemistry and molecular modeling for the design of active semisynthetic analogs; and 4) evaluation of anti-metastatic/anti-invasive activities of the isolated compounds. These compounds showed anti-invasive, anti-migratory, antiproliferative, and HIF-1 inhibitory activities. Future efforts will be focused on preclinical evaluation of few these compounds as potential anti-invasive leads.