title: Integrating Molecular Networking and Biological Assays To Target the Isolation of a Cytotoxic Cyclic Octapeptide, Samoamide A, from an American Samoan Marine Cyanobacterium.
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 μM). 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 μM 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.
authors.forename: C Benjamin
authors.initials: CB
authors.lastname: Naman
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
authors.forename: Svetlana E
authors.initials: SE
authors.lastname: Nikoulina
authors.forename: John
authors.initials: J
authors.lastname: Lee
authors.forename: Bailey W
authors.initials: BW
authors.lastname: Miller
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Moss
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo , Avenida Do Café, s/n, Campus Universitario, CEP 14040-903, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Lorene
authors.initials: L
authors.lastname: Armstrong
authors.forename: Paul D
authors.initials: PD
authors.lastname: Boudreau
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo , Avenida Do Café, s/n, Campus Universitario, CEP 14040-903, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Hosana M
authors.initials: HM
authors.lastname: Debonsi
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Valeriote
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Dorrestein
authors.forename: William H
authors.identifier: 0000-0003-1403-4458
authors.initials: WH
authors.lastname: Gerwick
mesh_terms: D018948:American Samoa; D002289:Carcinoma, Non-Small-Cell Lung; D000458:Cyanobacteria / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms; D008386:Marine Biology; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D010456:Peptides, Cyclic; C000621256:samoamide A