Structures of Nahuoic Acids B–E Produced in Culture by a Streptomyces sp. Isolated from a Marine Sediment and Evidence for the Inhibition of the Histone Methyl Transferase SETD8 in Human Cancer Cells by Nahuoic Acid A

• Published in: Journal of organic chemistry 2016-02, Vol.81 (4), p.1324-1332
• Main Authors: Williams, David E, Izard, Fanny, Arnould, Stéphanie, Dalisay, Doralyn S, Tantapakul, Cholpisut, Maneerat, Wisanu, Matainaho, Teatulohi, Julien, Eric, Andersen, Raymond J
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Cell Line; Cell Proliferation; Geologic Sediments; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - chemistry; Histones; Histones - chemistry; Human health and pathology; Humans; Life Sciences; Molecular Structure; Polyketides; Polyketides - chemistry; Polyketides - isolation & purification; Polyketides - pharmacology; Streptomyces; Streptomyces - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.5b02569

Nahuoic acids A–E (1–5) have been isolated from laboratory cultures of a Streptomyces sp. obtained from a tropical marine sediment. The structures of the new polyketides 2–5 were elucidated by analysis of spectroscopic data of the natural products and the chemical derivatives 6 and 7. Nahuoic acids 1–5 are in vitro inhibitors of the histone methyltransferase SETD8, and nahuoic acid A (1) and its pentaacetate derivative 8 inhibit the proliferation of several cancer cells lines in vitro with modest potency. At the IC50 for cancer cell proliferation, nahuoic acid A (1) showed selective inhibition of SETD8 in U2OS osteosarcoma cells that reflect its selectivity against a panel of pure histone methyl transferases. A cell cycle analysis revealed that the cellular toxicity of nahuoic acid A (1) is likely linked to its ability to inhibit SETD8 activity.