Integrating Molecular Networking and Biological Assays
To Target the Isolation of a Cytotoxic Cyclic Octapeptide, Samoamide
A, from an American Samoan Marine Cyanobacterium
posted on 2017-01-05, 20:05authored byC. Benjamin Naman, Ramandeep Rattan, Svetlana E. Nikoulina, John Lee, Bailey W. Miller, Nathan A. Moss, Lorene Armstrong, Paul D. Boudreau, Hosana M. Debonsi, Frederick A. Valeriote, Pieter C. Dorrestein, William H. Gerwick
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.