Antiproliferative and antiplasmodial compounds from selected Streptomyces species

doi:10.1016/j.bmcl.2015.07.103

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 23, 1 December 2015, Pages 5646-5649

https://doi.org/10.1016/j.bmcl.2015.07.103 Get rights and content

Abstract

In continuation of our ongoing search for bioactive compounds from microbial extracts, we performed antiproliferative and/or antimalarial assays on extracts of 806 microbial species isolated from Madagascan marine organisms, on 1317 species isolated from Madagascan soil samples and on a Streptomyces species (S.4) from a marine sponge collected from the Florida Keys. This work identified active extracts from four Streptomyces isolates (S.1, S.2, S.3 and S.4). The extracts of Streptomyces S.1 and S.2 showed antiproliferative activity against the A2780 ovarian cancer cell line, while those of S.3 and S.4 displayed both antiproliferative and antimalarial activity. Bioassay-guided fractionation coupled with dereplication of the active extracts led to the identification and isolation of nonactin (1), monactin (2), dinactin (3), ±-nonactic acid (4), toyocamycin (5), piperafizine A (6) and a new dipeptide named xestostreptin (7). The structures of all isolated compounds 1–7 were elucidated by analyses of their NMR spectroscopic and mass spectrometric data, and were confirmed by comparison with the data reported in the literature. Compound 6 was crystallized and subjected to X-ray diffraction analysis to confirm its structure as piperafizine A (6). Compounds 1–3 displayed strong antiproliferative activity against A2780 ovarian cancer cells (IC₅₀ values of 0.1, 0.13 and 0.2 μM, respectively), A2058 melanoma cells (IC₅₀ values of 0.2, 0.02 and 0.02 μM, respectively), and H522-T1 non small-cell cancer lung cells (IC₅₀ values of 0.1, 0.01 and 0.01 μM, respectively), while compounds 4 and 7 exhibited weak antiplasmodial activity against the Dd2 strain of Plasmodium falciparum, with IC₅₀ values of 6.5 and 50 μM, respectively.

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Acknowledgements

This project was supported by the National Center for Complementary and Alternative Medicine under award 3U01TW000313-19S1 as a supplement to Cooperative Agreement U01 TW000313-19 from the Fogarty International Center, the National Cancer Institute, the National Science Foundation, the National Heart, Lung and Blood Institute, the National Institute of Mental Health, the Office of Dietary Supplements, and the Office of the Director of NIH, with the International Cooperative Biodiversity Groups.

References and notes (12)

D. Forner et al.
Anal. Chim. Acta
(2013)
B.M. Greenwood et al.
J. Clin. Invest.
(2008)
O. Miotto et al.
Nat. Genet.
(2015)
G.M. Cragg et al.
Phytochem. Rev.
(2009)
E.J. Crevelin et al.
J. Mass Spectrom.
(2014)
D.G.I. Kingston
J. Nat. Prod.
(2011)

There are more references available in the full text version of this article.

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Antiproliferative and antiplasmodial compounds from selected Streptomyces species

Abstract

Graphical abstract

Section snippets

Acknowledgements

Anal. Chim. Acta

J. Clin. Invest.

Nat. Genet.

Phytochem. Rev.

J. Mass Spectrom.

J. Nat. Prod.