Lucidenic acid O and lactone, new terpene inhibitors of eukaryotic DNA polymerases from a basidiomycete, ganoderma lucidum

Mizushina, Yoshiyuki; Takahashi, Naoko; Hanashima, Linda; Koshino, Hiroyuki; Esumi, Yasuaki; Uzawa, Jun; Sugawara, Fumio; Sakaguchi, Kengo

doi:10.1016/s0968-0896(99)00121-2

Cited by 90 publications

(51 citation statements)

References 24 publications

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“…β protein, probably around the template-binding site. 6,8) The sulfolipids may bind more tightly to the pol. α protein in a different manner.…”

Section: Resultsmentioning

confidence: 99%

“…1) In screening studies, we found many inhibitors of mammalian DNA polymerases. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] At present, we are engaged in analyzing the structure and function of the DNA polymerases using these inhibitors from two different viewpoints; to understand the precise role of each polymerase in vivo, and to develop a drug design strategy for cancer chemotherapy agents. Since DNA polymerases are essential enzymes for DNA replication and repair, and thus for cell division, inhibition of the enzymes will lead to killing of cells, especially under conditions of proliferation.…”

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confidence: 99%

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Structure‐Activity Relationship of a Novel Group of Mammalian DNA Polymerase Inhibitors, Synthetic Sulfoquinovosylacylglycerols

Hanashima

Mizushina

Ohta

et al. 2000

Japanese Journal of Cancer Research

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We reported previously that sulfolipids in the sulfoquinovosylacylglycerol class from a fern and an alga are potent inhibitors of DNA polymerase α α α α and β β β β and potent anti-neoplastic agents. In developing a procedure for chemical synthesis of sulfolipids, we synthesized many derivatives and stereoisomers of sulfoquinovosylmonoacylglycerol (SQMG)/sulfoquinovosyldiacylglycerol (SQDG). Some of these molecules were stronger inhibitors than the SQMG/SQDG originally reported as natural compounds. In this study, we examined the structure-inhibitory function relationship of synthetic SQMG/SQDG and its relationship to cytotoxic activity. The inhibitory effect is probably mainly dependent on the fatty acid effect, which we reported previously, although each of the SQMG/SQDG was a much stronger inhibitor than the fatty acid alone that was present in the SQMG/SQDG. The inhibitory effect could be influenced by the chain size of fatty acids in the SQMG/SQDG. The sulfate moiety in the quinovose was also important for the inhibition. Lineweaver-Burk plots of SQMG/SQDG indicated that DNA polymerase α α α α was non-competitively inhibited, but the SQMG/SQDG were effective as antagonists of both template-primer DNA-binding and nucleotide substrate-binding of DNA polymerase β β β β. The SQMG had an cytotoxic effect, but the SQDG tested did not. The SQDG might not be able to penetrate into cells. Based on these results, we discuss the molecular action of SQMG/SQDG and propose drug design strategies for developing new anti-neoplastic agents.Key words: Sulfoquinovosylmonoacylglycerol (SQMG) -Sulfoquinovosyldiacylglycerol (SQDG) -DNA polymerase -Enzyme inhibitor -Anti-neoplastic agentsAt least seven classes of DNA polymerases (pol. α, β, γ, δ, ε, ζ and η) have been identified in mammalian cells.1-3) Moreover, pol. θ may also be expressed in mammals. Recent studies have revealed the biochemical and structural properties of these polymerases, and some of their genes have been cloned. The in vivo functions of some of these polymerases, especially pol. β, δ, ε, ζ and η, appear to be related to DNA repair and/or recombination. On the other hand, pol. α, γ, δ and ε are mainly involved in nuclear or mitochondrial DNA replication. Our recent studies of the polymerases have focused on understanding the structure and function of these polymerases, especially pol. α and β types, and identifying the factors controlling their activities. For these studies, potent and selective inhibitors are required.1) In screening studies, we found many inhibitors of mammalian DNA polymerases. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] At present, we are engaged in analyzing the structure and function of the DNA polymerases using these inhibitors from two different viewpoints; to understand the precise role of each polymerase in vivo, and to develop a drug design strategy for cancer chemotherapy agents. Since DNA polymerases are essential enzymes for DNA replication and repair, and thus for cell division, inhibition of the enzymes will le...

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“…β protein, probably around the template-binding site. 6,8) The sulfolipids may bind more tightly to the pol. α protein in a different manner.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Structure‐Activity Relationship of a Novel Group of Mammalian DNA Polymerase Inhibitors, Synthetic Sulfoquinovosylacylglycerols

Hanashima

Mizushina

Ohta

et al. 2000

Japanese Journal of Cancer Research

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“…Over 130 triterpenoids have been isolated from the fruiting bodies, cultured mycelia, and spores during the past two decades [8,9]. Some of the triterpenoids showed antiandrogenic [10], antihepatitis B [11], antioxidant [12,17], antitumor [13,15], anticomplement [14], antimicrobial [16], anti-HIV-1 [18], selectively inhibit eukaryotic DNA polymerase [19], and angiotensin converting enzyme-inhibitory activities [20]. Thus, a valuable and convincing method for characterization of triterpenoids of G. lucidum is necessary for quality control of the herbal medicine.…”

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confidence: 99%

Analysis of triterpenoids in Ganoderma lucidum using liquid chromatography coupled with electrospray ionization mass spectrometry

Yang

Wang

Guan

et al. 2007

J. Am. Soc. Mass Spectrom.

136

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Triterpenoids extracted from Ganoderma lucidum (Leyss. ex Fr.) Karst were separated and characterized using optimized reversed-phase liquid chromatography with diode array detection and electrospray ion trap tandem mass spectrometry (HPLC-DAD-ESI-MS n ). They could be classified into five types depending on the fragmentation behavior. second alcohol at C-15 were oxidized to ketone, the prominent cleavage would occur at C-ring and produce a group of ions of a; if C-7 were oxidized to ketone, transference of two hydrogen atoms would occur during the cleavage of rings and a list of ions about a ϩ 2 and/or b ϩ 2 would appear instead. The above fragmentations and regularities in fragmentation pathways were reported for the first time, and were implemented for the analysis of triterpenoids in G. lucidum. The chloroform extract was separated on a Zorbax SB-C 18 column, eluting with an acetonitrile-0.2% acetic acid gradient. A total of 32 triterpenoids, including six new ones, were identified or tentatively characterized based on the tandem mass spectra of the HPLC peaks. (J Am Soc Mass Spectrom 2007, 18, 927-939)

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“…Other ganoderic acid derivatives were also isolated from the fruiting bodies of G. lucidum, and results showed the presence of ganoderiol F, ganodermanontriol, ganoderic acid B, ganoderiol B, ganoderic acid C1, ganoderic acid α, ganoderic acid H and ganoderiol A [13]. Later, other terpenoids have been isolated and their chemical structure elucidated among them lucidenic acid O, lucidenic lactone and cerevisterol [38]. With the development of modern analytical techniques, especially the GC and LC coupled to mass spectrometry (GC-MS and LC-MS), Yang et al [39] investigated the terpenoids profile of G. lucidum and this investigation led to the characterisation of 32 different structures of triterpenoids among them six new ones.…”

Section: Ganoderic Acid Typesmentioning

confidence: 99%

Ganoderma lucidum Polysaccharides and Terpenoids: Profile and Health Benefits

Benkeblia¹

2016

J Food Nutri Diete

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Recent studies have shown that mushrooms are recognized as a promising source of functional and nutraceutical compounds. The species Ganoderma lucidum (also called Reishi or Lingzhi) is a mushroom used in medicine because Chinese attributes to this fungus better health and longevity. Among the numerous bioactive compounds identified in G. lucidum are polysaccharides mostly β-glucans, heteropolysaccharides or glycoproteins, terpenoids mostly ganoderic acids and derivatives, as well as many other bioactive proteinases that contribute to health and diseases prevention. The aim of this review is to report on the profile of the most bioactive compounds, particularly polysaccharides and terpenoids of G. lucidum.

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Lucidenic acid O and lactone, new terpene inhibitors of eukaryotic DNA polymerases from a basidiomycete, ganoderma lucidum

Cited by 90 publications

References 24 publications

Structure‐Activity Relationship of a Novel Group of Mammalian DNA Polymerase Inhibitors, Synthetic Sulfoquinovosylacylglycerols

Structure‐Activity Relationship of a Novel Group of Mammalian DNA Polymerase Inhibitors, Synthetic Sulfoquinovosylacylglycerols

Analysis of triterpenoids in Ganoderma lucidum using liquid chromatography coupled with electrospray ionization mass spectrometry

Ganoderma lucidum Polysaccharides and Terpenoids: Profile and Health Benefits

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