Selective catalytic hydrogenation of the N-acyl and uridyl double bonds in the tunicamycin family of protein N-glycosylation inhibitors

Authors: Price, Neil; Jackson, Michael - Mike; Vermillion, Karl; Blackburn, Judith; LI, JIAKUN - Chinese Academy Of Sciences; YU, BIAO - Chinese Academy Of Sciences

Submitted to: Journal of Antibiotics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2017
Publication Date: 11/1/2017
Citation: Price, N.P.J., Jackson, M.A., Vermillion, K.E., Blackburn, J.A., Li, J., & Yu, B. 2017. Selective catalytic hydrogenation of the N-acyl and uridyl double bonds in the tunicamycin family of protein N-glycosylation inhibitors. Journal of Antibiotics. 70:1122-1128. doi: 10.1038/ja.2017.141.
DOI: https://doi.org/10.1038/ja.2017.141

Interpretive Summary: The tunicamycins are potent antibiotics isolated from soil bacteria, but cannot be used clinically because of their toxicity. The ARS scientists have previously reported that chemically-reducing the tunicamycins make them considerably less toxic. Importantly, these less toxic tunicamycins, called Tun R1 and Tun R2, maintain their potent antibacterial activities. The present paper describes new ways to produce Tun R1 and Tun R2 using catalytic hydrogenation. Selective catalysts have been found that can efficiently convert tunicamycin into either Tun R1 or Tun R2. The hydrogenations are a significant improvement on previously reported chemical reductions, and can be readily scaled up. This work is of value for animal and human novel treatments of bacterial infections.

Technical Abstract: Tunicamycin is a Streptomyces-derived inhibitor of eukaryotic protein N-glycosylation and bacterial cell wall biosynthesis, and is a potent and general toxin by these biological mechanisms. The antibacterial activity is dependent in part upon a p-p stacking interaction between the tunicamycin uridyl group and a specific Phe residue within MraY, a tunicamycin-binding protein in bacteria. We have previously shown that reducing the tunicamycin uridyl group to 5,6-dihydrouridyl (DHU) significantly lowers its eukaryotic toxicity, potentially by disrupting the p-stacking with the active site Phe. The present report compares the catalytic hydrogenation of tunicamycin and uridine with various precious metal catalysts, and describe optimum conditions for the selective production of N-acyl reduced tunicamycin or for tunicamycins reduced in both the N-acyl and uridyl double bonds. At room temperature, Pd-based catalysts are selective for the N-acyl reduction, whereas Rh-based catalysts favor the double reduction to provide access to fully reduced tunicamycin. The reduced DHU is highly base-sensitive, leading to amide ring opening under mild alkaline conditions.