DEVELOPMENT OF MARINE MACROLIDES LATRUNCULINS AS ANGIOGENESIS MODULATORS

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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. 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.