Conglobatins B-E: cytotoxic analogues of the C2-symmetric macrodiolide conglobatin

  • J Antibiot (Tokyo). 2020 Nov;73(11):756-765. doi: 10.1038/s41429-020-0332-3.
Heather J Lacey  1  2 ,  Thomas J Booth  3 ,  Daniel Vuong  4 ,  Peter J Rutledge  5 ,  Ernest Lacey  4  6 ,  Yit-Heng Chooi  3 ,  Andrew M Piggott  6
Affiliations
  • 1. Microbial Screening Technologies, Smithfield, Sydney, NSW, 2164, Australia. [email protected].
  • 2. School of Chemistry, The University of Sydney, Camperdown, Sydney, NSW, 2006, Australia. [email protected].
  • 3. School of Molecular Sciences, The University of Western Australia, Crawley, Perth, WA, 6009, Australia.
  • 4. Microbial Screening Technologies, Smithfield, Sydney, NSW, 2164, Australia.
  • 5. School of Chemistry, The University of Sydney, Camperdown, Sydney, NSW, 2006, Australia.
  • 6. Department of Molecular Sciences, Macquarie University, North Ryde, Sydney, NSW, 2109, Australia.
PMID: 32555501 DOI: 10.1038/s41429-020-0332-3
Abstract

Chemical investigation of a previously unreported indigenous Australian Streptomyces strain MST-91080 has identified six novel analogues related to the oxazole-pendanted macrodiolide, conglobatin. Phylogenetic analysis of the 16S rRNA gene sequence identified MST-91080 as a species of Streptomyces, distinct from reported conglobatin producer, Streptomyces conglobatus ATCC 31005. Conglobatins B-E diverge from conglobatin through differing patterns of methylation on the macrodiolide skeleton. The altered methyl positions suggest a deviation from the published biosynthetic pathway, which proposed three successive methylmalonyl-CoA extender unit additions to the conglobatin monomer. Conglobatins B1, C1 and C2 exhibited more potent cytotoxic activity selectively against the NS-1 myeloma cell line (IC50 0.084, 1.05 and 0.45 µg ml-1, respectively) compared with conglobatin (IC50 1.39 µg ml-1).

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