Synthesis and structure revision of tyroscherin, a growth inhibitor of IGF-1-dependent tumor cells

Synthesis of the alkaloid tyroscherin by an aldol/Curtius strategy

“…According to the 1 H NMR the synthetic material corresponds to the natural compound. However, we could not obtain the sharp resolution as reported by Watanabe et al 3,4 The same was the case for the trifluoroacetate salt. We made this salt because it has been reported that with an alkaloid this can lead to better resolved spectra.…”

“…In 2008, total synthesis studies led to the conclusion that the original published stereostructure needed revision. 3,4,5 Thus, the syn-amino alcohol stereochemistry actually has anti-configuration and the C8,C10-stereochemistry is opposite to the originally proposed configurations. The molecule was reported to inhibit the growth of cancer cells that depend on the insulin-like growth factor (IGF).…”

“…In particular derivatives thereof might allow for identification of the cellular target. The approach followed by Watanabe et al 3,4 uses the Weinreb amide of N-Boc-N-methyl tyrosine for chain extension. The section containing the two methyl groups was later attached via a Julia olefination.…”

Unexpected stereochemical tolerance for the biological activity of tyroscherin

“…Thus, the syntheses and biological characterization of all possible tyroscherin diastereomers revealed an unexpected and expansive stereochemical tolerance for the observed cytotoxic activity. While there were occasional minor differences in relative potency of inhibition between serum and IGF-driven proliferation, none of them were of the magnitude reported in the original isolation or recent structural revision report 11,12…”

Scedosporium and Pseudallescheria low molecular weight metabolites revealed by database search

“…This small metabolite being extracted by 50% aqueous methanol was putatively ascribed by mMass as tyroscherin, a growth inhibitor of IGF-1dependent cancer cells produced by Pseudallescheria sp. 10 The isotopic pattern fit to C 21 H 36 NO 2 (Fig. 2, inset).…”