Total Synthesis and Antimycobacterial Activity of Ohmyungsamycin A,Deoxyecumicin, and Ecumicin |
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| Authors: | Paige M E Hawkins Wendy Tran Dr Gayathri Nagalingam Chen-Yi Cheung Dr Andrew M Giltrap Prof Gregory M Cook Prof Warwick J Britton Prof Richard J Payne |
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| Institution: | 1. School of Chemistry, The University of Sydney, Sydney, NSW, 2006 Australia;2. Centenary Institute, The University of Sydney, Sydney, NSW, 2006 Australia;3. Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, PO Box 56, 9016 Dunedin, New Zealand;4. Centenary Institute, The University of Sydney, Sydney, NSW, 2006 Australia
Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006 Australia |
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| Abstract: | The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid-phase strategy to assemble the linear peptide precursor, involving a key on-resin esterification and an optional on-resin dimethylation step, before a final solution-phase macrolactamization between the non-proteinogenic N-methyl-4-methoxy-l -tryptophan amino acid and a bulky N-methyl-l -valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC90’s ranging from 110–360 nm and retained activity against Mtb in Mtb-infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing against Mtb, sterilizing cultures after 21 days. |
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| Keywords: | natural products peptides solid-phase synthesis total synthesis tuberculosis |
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