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Merocyclophanes A and B, antiproliferative cyclophanes from the cultured terrestrial Cyanobacterium Nostoc sp.

ABSTRACT: The cell extract of a cultured terrestrial Nostoc sp. (UIC 10062), obtained from a sample collected at Grand Mere State Park in Michigan, displayed antiproliferative activity against the HT-29 human colon cancer cell line. Bioactivity-guided fractionation of the cell extract, combined with LC-MS analysis, led to the isolation of two cyclophanes, named merocyclophanes A and B (1 and 2). Their structures were determined by various spectroscopic techniques including HRESIMS, and 1D and 2D NMR analyses. The stereoconfiguration was assigned on the basis of X-ray crystallographic and CD analyses. The structures of merocyclophanes A and B (1 and 2) established a hitherto unknown [7.7]paracyclophane skeleton in nature, as characterized by ?-branched methyls at C-1/14. Merocyclophanes A and B (1 and 2) displayed antiproliferative activity against the HT-29 human colon cancer cell line with IC?? values of 3.3 and 1.7 ?M, respectively.

SUBMITTER: Kang HS

PROVIDER: S-EPMC3374012 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Merocyclophanes A and B, antiproliferative cyclophanes from the cultured terrestrial Cyanobacterium Nostoc sp.

Kang Hahk-Soo HS Santarsiero Bernard D BD Kim Hyunjung H Krunic Aleksej A Shen Qi Q Swanson Steven M SM Chai Heebyung H Kinghorn A Douglas AD Orjala Jimmy J

Phytochemistry 20120507

The cell extract of a cultured terrestrial Nostoc sp. (UIC 10062), obtained from a sample collected at Grand Mere State Park in Michigan, displayed antiproliferative activity against the HT-29 human colon cancer cell line. Bioactivity-guided fractionation of the cell extract, combined with LC-MS analysis, led to the isolation of two cyclophanes, named merocyclophanes A and B (1 and 2). Their structures were determined by various spectroscopic techniques including HRESIMS, and 1D and 2D NMR analy ...[more]

PMID: 22571940

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Project description:Swinholides are 42-carbon ring polyketides with a 2-fold axis of symmetry. They are potent cytotoxins that disrupt the actin cytoskeleton. Swinholides were discovered from the marine sponge Theonella sp. and were long suspected to be produced by symbiotic bacteria. Misakinolide, a structural variant of swinholide, was recently demonstrated to be the product of a symbiotic heterotrophic proteobacterium. Here, we report the production of swinholide A by an axenic strain of the terrestrial cyanobacterium Nostoc sp. strain UHCC 0450. We located the 85-kb trans-AT polyketide synthase (PKS) swinholide biosynthesis gene cluster from a draft genome of Nostoc sp. UHCC 0450. The swinholide and misakinolide biosynthesis gene clusters share an almost identical order of catalytic domains, with 85% nucleotide sequence identity, and they group together in phylogenetic analysis. Our results resolve speculation around the true producer of swinholides and demonstrate that bacteria belonging to two distantly related phyla both produce structural variants of the same natural product. In addition, we described a biosynthesis cluster from Anabaena sp. strain UHCC 0451 for the synthesis of the cytotoxic and antifungal scytophycin. All of these biosynthesis gene clusters were closely related to each other and created a group of cytotoxic macrolide compounds produced by trans-AT PKSs of cyanobacteria and proteobacteria.IMPORTANCE Many of the drugs in use today originate from natural products. New candidate compounds for drug development are needed due to increased drug resistance. An increased knowledge of the biosynthesis of bioactive compounds can be used to aid chemical synthesis to produce novel drugs. Here, we show that a terrestrial axenic culture of Nostoc cyanobacterium produces swinholides, which have been previously found only from marine sponge or samples related to them. Swinholides are polyketides with a 2-fold axis of symmetry, and they are potent cytotoxins that disrupt the actin cytoskeleton. We describe the biosynthesis gene clusters of swinholide from Nostoc cyanobacteria, as well as the related cytotoxic and antifungal scytophycin from Anabaena cyanobacteria, and we study the evolution of their trans-AT polyketide synthases. Interestingly, swinholide is closely related to misakinolide produced by a symbiotic heterotrophic proteobacterium, demonstrating that bacteria belonging to two distantly related phyla and different habitats can produce similar natural products.

Dataset Information

Merocyclophanes A and B, antiproliferative cyclophanes from the cultured terrestrial Cyanobacterium Nostoc sp.

Publications

Merocyclophanes A and B, antiproliferative cyclophanes from the cultured terrestrial Cyanobacterium Nostoc sp.

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