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 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.