KMID : 0043320160390060762
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Archives of Pharmacal Research 2016 Volume.39 No. 6 p.762 ~ p.770
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A new cyclic dipeptide penicimutide: the activated production of cyclic dipeptides by introduction of neomycin-resistance in the marine-derived fungus Penicilliumpurpurogenum G59
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Wang Nan
Cui Cheng Bin Li Chang Wei
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Abstract
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A novel cyclic dipeptide, named penicimutide (1), and four known cyclic dipeptides, cyclo(l-Val-l-Pro) (2), cyclo(l-Ile-l-Pro) (3), cyclo(l-Leu-l-Pro) (4) and cyclo(l-Phe-l-Pro) (5), were isolated from a neomycin-resistant mutant of the marine-derived fungus Penicilliumpurpurogenum G59. The structure of 1, including the absolute configuration, was determined by spectroscopic and chemical methods, especially NMR and Marfey¡¯s analysis. An unusual amino acid in 1, 4,5-didehydro-l-leucine, was found for the first time occurring in nature. HPLC?ESI?MS analysis evidenced that 1?3 were produced only in the mutant strain, but 4 and 5 were produced in both the mutant and parental strains, indicating that the introduction of neomycin-resistance in the mutant activated pathways of 1?3 biosynthesis that were silent in the parental strain. Compound 1 selectively inhibited HeLa cells (among five tested human cancer cell lines) with an inhibition rate (IR %) of 39.4 % at 100 ¥ìg/mL, a similar inhibition intensity to that of the positive control 5-fluorouracil (IR % of 41.4 % at 100 ¥ìg/mL against HeLa cells). The present work exemplifies the effectiveness of our previous DMSO-mediated method for introducing drug-resistance in fungi to activate silent biosynthetic pathways to obtain new bioactive compounds.
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KEYWORD
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Cyclic dipeptide, Penicimutide, Structure determination, Fungal metabolite, Marine-derived Penicillium purpurogenum, Neomycin-resistant mutant
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