Total Synthesis and Complete Structural Assignment of Thiocillin I

The total synthesis of the thiopeptide antibiotic, thiocillin I, is described. This work unequivocally defines the full structure (constitution and configuration) of the natural product as <b>1</b>

Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β‑<i>N</i>-acetylhexosaminidase Activity

In order to identify structural features of pyri­meth­amine (5-(4-chloro­phenyl)-6-ethyl­pyrimidine-2,4-diamine) that contribute to its inhibitory activity (IC₅₀ value) and chaperoning efficacy toward β-<i>N</i>-acetyl­hexos­aminidase, derivatives of the compound were synthesized that differ at the positions bearing the amino, ethyl, and chloro groups. Whereas the amino groups proved to be critical to its inhibitory activity, a variety of substitutions at the chloro position only increased its IC₅₀ by 2–3-fold. Replacing the ethyl group at the 6-position with butyl or methyl groups increased IC₅₀ more than 10-fold. Surprisingly, despite its higher IC₅₀, a derivative lacking the chlorine atom in the <i>para</i>-position was found to enhance enzyme activity in live patient cells a further 25% at concentrations >100 μM, while showing less toxicity. These findings demonstrate the importance of the phenyl group in modulating the chaperoning efficacy and toxicity profile of the derivatives