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Mar. Drugs 2014, 12(4), 1788-1814; doi:10.3390/md12041788
Article

A Practical Strategy to Discover New Antitumor Compounds by Activating Silent Metabolite Production in Fungi by Diethyl Sulphate Mutagenesis

1,2,†
, 1,2,†
, 2
 and 1,2,*
Received: 13 December 2013; in revised form: 21 February 2014 / Accepted: 5 March 2014 / Published: 27 March 2014
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Abstract: Many fungal biosynthetic pathways are silent in standard culture conditions, and activation of the silent pathways may enable access to new metabolites with antitumor activities. The aim of the present study was to develop a practical strategy for microbial chemists to access silent metabolites in fungi. We demonstrated this strategy using a marine-derived fungus Penicillium purpurogenum G59 and a modified diethyl sulphate mutagenesis procedure. Using this strategy, we discovered four new antitumor compounds named penicimutanolone (1), penicimutanin A (2), penicimutanin B (3), and penicimutatin (4). Structures of the new compounds were elucidated by spectroscopic methods, especially extensive 2D NMR analysis. Antitumor activities were assayed by the MTT method using human cancer cell lines. Bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses were used to estimate the activated secondary metabolite production. Compounds 2 and 3 had novel structures, and 1 was a new compound belonging to a class of very rare natural products from which only four members are so far known. Compounds 13 inhibited several human cancer cell lines with IC50 values lower than 20 μM, and 4 inhibited the cell lines to some extent. These results demonstrated the effectiveness of this strategy to discover new compounds by activating silent fungal metabolic pathways. These discoveries provide rationale for the increased use of chemical mutagenesis strategies in silent fungal metabolite studies.
Keywords: natural products; alkaloids; structure elucidation; DES mutagenesis; silent fungal metabolite production natural products; alkaloids; structure elucidation; DES mutagenesis; silent fungal metabolite production
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Fang, S.-M.; Wu, C.-J.; Li, C.-W.; Cui, C.-B. A Practical Strategy to Discover New Antitumor Compounds by Activating Silent Metabolite Production in Fungi by Diethyl Sulphate Mutagenesis. Mar. Drugs 2014, 12, 1788-1814.

AMA Style

Fang S-M, Wu C-J, Li C-W, Cui C-B. A Practical Strategy to Discover New Antitumor Compounds by Activating Silent Metabolite Production in Fungi by Diethyl Sulphate Mutagenesis. Marine Drugs. 2014; 12(4):1788-1814.

Chicago/Turabian Style

Fang, Shi-Ming; Wu, Chang-Jing; Li, Chang-Wei; Cui, Cheng-Bin. 2014. "A Practical Strategy to Discover New Antitumor Compounds by Activating Silent Metabolite Production in Fungi by Diethyl Sulphate Mutagenesis." Mar. Drugs 12, no. 4: 1788-1814.


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