The diverse range of biological activity exhibited by cyclic guanidine-containing pharmacophores has piqued an interest in synthetic approaches for these class of molecules. Among these compounds is the natural product from Streptomyces sp. NA22598, NA22598A1, which displays inhibition of anchorage independent growth (AIG) of human colon-cancer DLD-1 cells. Matrix metalloproteinases (MMPs), which are endopeptidases required for extracellular matrix remodeling, have been linked to the ability of inhibiting growth in suspension cultures via a mechanism that has yet to be elucidated. Arresting the cell cycle progression at the G1 phase, NA22598A1 inhibits the MAPK-dependent expression of cyclin D1. The MAPK signaling cascade is hypothesized to be correlated with MMPs. The construction of NA22598A1 raises synthetic challenges but is approached by coupling three subunits with known stereochemistry - (1) carbamoyl guanidine, (2) aldonitrone, and (3) dipeptide. Current developments in the laboratory for this natural product have been focused on efficiently constructing these subunits. The synthetic effort towards NA22598A1 and other analogues offers a significant opportunity to overcome the limited availability of the natural product and further study their mechanisms of action, as well as other cancer-associated signaling pathways. New methodologies developed from this chemistry will allow for the application of such approaches to the synthesis of a number of natural products and other biologically relevant nitrogen rich heterocycles.

Synthetic efforts of natural product NA22598A<sub>1</sub> and the discussion of its biological effects

248th National Meeting (2014)

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Synthetic efforts of natural product NA22598A1 and the discussion of its biological effects

Synthetic efforts of natural product NA22598A₁ and the discussion of its biological effects