Integrating molecular networking and biological assays to target the isolation of a cytotoxic cyclic octapeptide, Samoamide A, from an American Samoan marine cyanobacterium

TitleIntegrating molecular networking and biological assays to target the isolation of a cytotoxic cyclic octapeptide, Samoamide A, from an American Samoan marine cyanobacterium
Publication TypeJournal Article
Year of Publication2017
AuthorsNaman C.B, Rattan R., Nikoulina S.E, Lee J., Miller B.W, Moss N.A, Armstrong L., Boudreau P.D, Debonsi H.M, Valeriote F.A, Dorrestein PC, Gerwick WH
JournalJournal of Natural Products
Volume80
Pagination625-633
Date Published2017/03
Type of ArticleArticle
ISBN Number0163-3864
Accession NumberWOS:000397695100007
Keywordsanalog; antineoplastic agents; chemistry; combinatorial; dipeptidyl-peptidase-iv; dolastatin 10; drugs; histone deacetylase inhibitor; natural-product discovery; potent; symploca sp
Abstract

Integrating LC-MS/MS molecular networking and bioassay-guided fractionation enabled the targeted isolation of a new and bioactive cyclic octapeptide, samoamide A (1), from a sample of cf. Symploca sp. collected in American Samoa. The structure of 1 was established by detailed 1D and 2D NMR experiments, HRESIMS data, and chemical degradation/chromatographic (e.g., Marfey's analysis) studies. Pure compound 1 was shown to have in vitro cytotoxic activity against several human cancer cell lines in both traditional cell culture and zone inhibition bioassays. Although there was no particular selectivity between the cell lines tested for samoamide A, the most potent activity was observed against H460 human non-small-cell lung cancer cells (IC50 = 1.1 mu M). Molecular modeling studies suggested that one possible mechanism of action for 1 is the inhibition of the enzyme dipeptidyl peptidase (CD26, DPP4) at a reported allosteric binding site, which could lead to many downstream pharmacological effects. However, this interaction was moderate when tested in vitro at up to 10 mu M and only resulted in about 16% peptidase inhibition. Combining bioassay screening with the cheminformatics strategy of LC-MS/MS molecular networking as a discovery tool expedited the targeted isolation of a natural product possessing both a novel chemical structure and a desired biological activity.

DOI10.1021/acsjnatprod.6600907
Short TitleJ. Nat. Prod.
Student Publication: 
Yes
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