UC San Diego

Thiopeptides are a versatile group of natural products with a wealth of therapeutic potential. To expand the methods of syntheses of these compounds and more closely study their in vitro activity, we report the total synthesis of micrococcin P1 enabled by robust thiazole forming reactions. Never before used in the synthesis of thiopeptides, we were able to access decagram quantities of several thiazole containing fragments through the condensation of nitriles and aminothiols. These thiazole forming reactions are robustly scalable and we were able to produce nearly 200 mg of the natural product. Micrococcin and other synthetic precursors were used to probe structure-activity relationships in in vivo anti-cancer assays where micrococcin was not found to have significant anti-cancer activity, though several smaller fragments were found to have low micromolar to high nanomolar potency. Previously, only series B thiopeptides and their complex central piperidine fragments were known to have this activity. This finding shows that not only series B thiopeptides like thiostrepton and siomycin A have anti-cancer activity. That fragments of micrococcin P1, a series D thiopeptide, show comparable activity indicates a broader scope of activity in the family. Importantly, we have established a minimum scaffold for activity, and these fragments are more easily accessible with our shorter, higher yielding synthesis than that of previous fragments from thiostrepton. Following these discoveries, medicinal chemistry efforts to increase pharmacokinetic properties and potency of these fragments can be explored.