Synthesis of a bromotyrosine-derived natural product inhibitor of mycothiol-S-conjugate amidase.
Recently we described the structures of two new bromotyrosine-derived alkaloids that inhibit the detoxification enzyme mycothiol-S-conjugate amidase (MCA) from Mycobacterium tuberculosis. Here we describe a concise total synthesis of bromotyrosine oxime 1. The six-step synthesis of 1 utilized a trifluoromethyloxazole intermediate, whose hydrolysis product underwent alkylation and coupling to agmatine to give the inhibitor in approximately 40% overall yield. Oxime 1 inhibited MCA and its homolog AcGI deacetylase with IC(50) values of 30 and 150 microM, respectively.
Fetterolf
Brandon
B
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0820, USA.
Bewley
Carole A
CA
D000478:Alkylation; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010080:Oxazoles / Q000737:chemistry; D010091:Oximes / Q000737:chemistry; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D006845:Hydrocarbons, Fluorinated; D010080:Oxazoles; D010091:Oximes; C475724:bromotyrosine; D014443:Tyrosine; D000581:Amidohydrolases; C417275:N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase; C413523:mycothiol S-conjugate amidase