Natural products and their synthetic derivatives constitute a significant fraction of the drugs approved for use by regulatory bodies such as the U.S. FDA, and this is particularly true for cancer chemotherapeutic agents. One example is dolastatin 10, a potently cytotoxic cyanobacterial natural product that was originally purified from the sea hare <i>Dolabella auricularia </i>and later determined to originate from several species of <i>Symploca</i>. Many cytotoxic analogues of dolastatin 10 have also since been discovered and reported. Although dolastatin 10 failed in initial drug clinical trials, it served as the lead molecule for the development of monomethyl auristatin E (MMAE) that has been incorporated into the antibody-drug conjugate brentuximab vedotin. We have utilized the untargeted metabolomics tool Global Natural Products Social molecular networking (GNPS) to interrogate and prioritize cyanobacterial extracts for isolation studies. This data analysis allowed for the dereplication of dolastatin 10 and suggested the presence of several new analogues of this compound. These molecules were targeted using LC-MS, isolated chromatographically, and characterized structurally using MS/MS fragmentation patterns and NMR spectroscopic methods. The structure and biological activity of these new compounds will be presented.

Targeted isolation and simplified structure elucidation of new analogues of dolastatin 10 from marine cyanobacteria using MS/MS molecular networking

253rd National Meeting (2017)

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