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Amantelides A and B, Polyhydroxylated Macrolides with Differential Broad-Spectrum Cytotoxicity from a Guamanian Marine Cyanobacterium.

ABSTRACT: Cytotoxicity-guided fractionation of a Guamanian cyanobacterial collection yielded the new compounds amantelides A (1) and B (2). These polyketides are characterized by a 40-membered macrolactone ring consisting of a 1,3-diol and contiguous 1,5-diol units and a tert-butyl substituent. Amantelide A (1) displayed potent cytotoxicity with submicromolar IC?? against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cell lines. Acetylation of the hydroxy group at C-33 in 2 caused a close to 10-fold decrease in potency. Exhaustive acetylation of the hydroxy groups abrogated the antiproliferative activity of amantelide A (1) by 20-67-fold. Further bioactivity assessment of 1 against bacterial pathogens and marine fungi indicated a broad spectrum of bioactivity.

SUBMITTER: Salvador-Reyes LA

PROVIDER: S-EPMC4725301 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Amantelides A and B, Polyhydroxylated Macrolides with Differential Broad-Spectrum Cytotoxicity from a Guamanian Marine Cyanobacterium.

Salvador-Reyes Lilibeth A LA Sneed Jennifer J Paul Valerie J VJ Luesch Hendrik H

Journal of natural products 20150723 8

Cytotoxicity-guided fractionation of a Guamanian cyanobacterial collection yielded the new compounds amantelides A (1) and B (2). These polyketides are characterized by a 40-membered macrolactone ring consisting of a 1,3-diol and contiguous 1,5-diol units and a tert-butyl substituent. Amantelide A (1) displayed potent cytotoxicity with submicromolar IC₅₀ against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cell lines. Acetylation of the hydroxy group at C-33 in 2 caused a close to ...[more]

PMID: 26204500

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Project description:Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the continued development of broadly active antiviral compounds.

Dataset Information

Amantelides A and B, Polyhydroxylated Macrolides with Differential Broad-Spectrum Cytotoxicity from a Guamanian Marine Cyanobacterium.

Publications

Amantelides A and B, Polyhydroxylated Macrolides with Differential Broad-Spectrum Cytotoxicity from a Guamanian Marine Cyanobacterium.

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