ARCHIVES OF PHARMACAL RESEARCH
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2016
·Vol. 39
·期 6
·762-770
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IF 2.49
Wang Nan,Cui Cheng-Bin,Li Chang-Wei
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 Penicillium
purpurogenum 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 µg/mL, a similar inhibition intensity to that of the positive control 5-fluorouracil (IR % of 41.4 % at 100 µg/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.
研究领域:
微生物学
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药物化学
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肿瘤学
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DOI
PubMed
高影响因子
Marine Drugs
·
2015
·Vol. 13
·期 4
·2465-2487
·
IF 2.853
Chang-Jing Wu,Le Yi,Cheng-Bin Cui,Chang-Wei Li,Nan Wang,Xiao Han
Introduction of neomycin-resistance into a marine-derived, wild-typePenicillium purpurogenumG59 resulted in activation of silent biosynthetic pathways for the secondary metabolite production. Upon treatment of G59 spores with neomycin and dimethyl sulfoxide (DMSO), a total of 56 mutants were obtained by single colony isolation. The acquired resistance of mutants to neomycin was testified by the resistance test. In contrast to the G59 strain, the EtOAc extracts of 28 mutants inhibited the human cancer K562 cells, indicating that the 28 mutants have acquired the capability to produce bioactive metabolites. HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses further indicated that diverse secondary metabolites have been newly produced in the bioactive mutant extracts. Followed isolation and characterization demonstrated that five bioactive secondary metabolites, curvularin (1), citrinin (2), penicitrinone A (3),erythro-23-O-methylneocyclocitrinol (4) and 22E-7α-methoxy-5α,6α-epoxyergosta-8(14),22-dien-3β-ol (5), were newly produced by a mutant, 4-30, compared to the G59 strain. All1–5were also not yet found in the secondary metabolites of other wild typeP. purpurogenumstrains. Compounds1–5inhibited human cancer K562, HL-60, HeLa and BGC-823 cells to varying extents. Both present bioassays and chemical investigations demonstrated that the introduction of neomycin-resistance into the marine-derived fungal G59 strain could activate silent secondary metabolite production. The present work not only extended the previous DMSO-mediated method for introducing drug-resistance in fungi both in DMSO concentrations and antibiotics, but also additionally exemplified effectiveness of this method for activating silent fungal secondary metabolites. This method could be applied to other fungal isolates to elicit their metabolic potentials to investigate secondary metabolites from silent biosynthetic pathways.Keywords:Penicillium purpurogenumG59;marine-derived fungus;neomycin resistance;DMSO;antitumor activity;fungal metabolite production
研究领域:
微生物学
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药物化学
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分子生物学
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DOI
PubMed
高影响因子
Marine Drugs
·
2012
·Vol. 10
·期 6
·1266-1287
·
IF 3.854
Shi-Ming Fang,Cheng-Bin Cui,Chang-Wei Li,Chang-Jing Wu,Zhi-Jun Zhang,Li Li,Xiao-Jun Huang,Wen-Cai Ye
Two new drimenyl cyclohexenone derivatives, named purpurogemutantin (1) and purpurogemutantidin (2), and the known macrophorin A (3) were isolated from a bioactive mutant BD-1-6 obtained by random diethyl sulfate (DES) mutagenesis of a marine-derivedPenicillium purpurogenumG59. Structures and absolute configurations of1and2were determined by extensive spectroscopic methods, especially 2D NMR and electronic circular dichroism (ECD) analysis. Possible biosynthetic pathways for1–3were also proposed and discussed. Compounds1and2significantly inhibited human cancer K562, HL-60, HeLa, BGC-823 and MCF-7 cells, and compound3also inhibited the K562 and HL-60 cells. Both bioassay and chemical analysis (HPLC, LC-ESIMS) demonstrated that the parent strain G59 did not produce1–3, and that DES-induced mutation(s) in the mutant BD-1-6 activated some silent biosynthetic pathways in the parent strain G59, including one set for1–3production.Keywords:purpurogemutantin;purpurogemutantidin;sesquiterpene;meroterpenoid;structure determination;antitumor activity;Penicillium purpurogenum;marine-derived fungus;DES mutagenesis
研究领域:
药物化学
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微生物学
·
有机化学
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DOI
高影响因子
Marine Drugs
·
2014
·Vol. 12
·期 4
·1815-1838
·
IF 3.512
Chang-Jing Wu,Chang-Wei Li,Cheng-Bin Cui
AD-2-1 is an antitumor fungal mutant obtained by diethyl sulfate mutagenesis of a marine-derivedPenicillium purpurogenumG59. The G59 strain originally did not produce any metabolites with antitumor activities in MTT assays using K562 cells. Tracing newly produced metabolites under guidance of MTT assay and TLC analysis by direct comparison with control G59 extract, seven new (1–7) and two known (8–9) lipopeptides were isolated together with five known polyketides10–14from the extract of mutant AD-2-1. Structures of the seven new compounds including their absolute configurations were determined by spectroscopic and chemical evidences and named as penicimutalides A–G (1–7). Seven known compounds were identified as fellutamide B (8), fellutamide C (9), 1′-O-methylaverantin (10), averantin (11), averufin (12), nidurufin (13), and sterigmatocystin (14). In the MTT assay,1–14inhibited several human cancer cell lines to varying extents. All the bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses demonstrated that the production of1–14in the mutant AD-2-1 was caused by the activated production of silent metabolites in the original G59 fungal strain. Present results provided additional examples for effectiveness of the chemical mutagenesis strategy using diethyl sulphate mutagenesis to discover new compounds by activating silent metabolites in fungal isolates.Keywords:marine-derived fungus;lipopeptide;penicimutalide;Marfey analysis;polyketide;Penicillium purpurogenum;DES mutagenesis
研究领域:
微生物学
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药物化学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
Marine Drugs
·
2015
·Vol. 13
·期 8
·5219-5236
·
IF 2.853
Ming-Wen Xia,Cheng-Bin Cui,Chang-Wei Li,Chang-Jing Wu,Ji-Xing Peng,De-Hai Li
Three new and rare chromones, named epiremisporine B (2), epiremisporine B1 (3) and isoconiochaetone C (4), along with three known remisporine B (1), coniochaetone A (5) and methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (6) were isolated from a mutant from the diethyl sulfate (DES) mutagenesis of a marine-derivedPenicillium purpurogenumG59. The structures of2–4including the absolute configurations were determined by spectroscopic methods, especially by NMR analysis and electronic circular dichroism (ECD) experiments in conjunction with calculations. The absolute configuration of the known remisporine B (1) was determined for the first time. Compounds2and3have a rare feature that has only been reported in one example so far. The compounds1–6were evaluated for their cytotoxicity against several human cancer cell lines. The present work explored the great potential of our previous DES mutagenesis strategy for activating silent fungal pathways, which has accelerated the discovery of new bioactive compounds.Keywords:chromone derivatives;remisporine;epiremisporine;isoconiochaetone;ECD;marine-derived fungus;Penicillium purpurogenumG59;DES mutagenesis
研究领域:
微生物学
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药物化学
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生物合成
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DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2020
·Vol. 17
·期 7
·e2000241
·
IF 2.039
Nan Wang,Yuan Dong,Yu Yang,Rui Xu,Chang-Wei Li,Cheng-Bin Cui
Penicimutanin C, a new alkaloidal compound, was isolated from the neomycin-resistant mutant strain 3-f-31 of the marine-derived fungus, Penicillium purpurogenum G59, together with four known compounds. The structure of penicimutanin C, including the absolute configuration, was determined by spectroscopic and chemical methods. The absolute configuration of penicimutanin A was also re-confirmed by Marfey's and chiral HPLC analyses of the hydrolyzed products. Penicimutanins C and A inhibited the proliferation of five human cancer cell lines to some extent. Penicimutanin C is the third dimer of diketopiperazine and penicimutanolone, which are only produced by mutants of P. purpurogenum G59 isolated to date, and it showed cytotoxic activity against human cancer cell lines. The neomycin-resistant screening strategy has been previously successfully used to discover new compounds by activating silent metabolites in fungi, and the present results provide an additional example of the effectiveness of this method. Graphical
研究领域:
药理学
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微生物学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
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