Semisynthesis of Mycothiazole Analogs having Distinct Bioactivity

Semisynthetic modification of mycothiazole (1) with Meerwein’s salt to generate a more stable and/or potent analog than 8-O-acetylmycothiazole (2) unexpectedly yielded diastereomers devoid of the diene. Analysis of NMR, HR-LCMS, and optical rotation confirmed the structures as (−)-4,4-hydroxy-methyl-(5Z)-(8S)-(14Z)-mycothiazole (5a, 5b: dr 1:1.1). Both compounds demonstrated reduced stability versus 1 or 2. Cytotoxicity evaluation of 5a versus 5b indicated 5-fold differences in potency against pancreatic (IC50 = 7.81, 1.34 μM; PANC-1) and glioblastoma (IC50 = 8.53, 1.63 μM; U251N) cancer cells, respectively. In vivo evaluation of 5a and 5b, using Caenorhabditis elegans in aging studies, indicated 5b not 5a inhibited mitochondrial function, while neither affected lifespan compared to 1. These results demonstrate the diene of 1 may be required for its picomolar cytotoxic potency to cancer cells or effects on lifespan in C. elegans, and minor variations in the stereochemistry of this chemotype merit further investigation to modulate its bioactivity.