AIDS-Antiviral Sulfolipids From Cyanobacteria (Blue-Green Algae)

Gustafson, Kirk R.; Cardellina, John H.; Fuller, Richard W.; Weislow, Owen S.; Kiser, Rebecca; Snader, Kenneth M.; Patterson, Gregory M. L.; Boyd, Michael R.

doi:10.1093/jnci/81.16.1254

Cited by 275 publications

(127 citation statements)

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“…11,14,15) One of them structurally coincided with a compound from a cyanobacterium reported as an AIDS anti-viral agent. 20,21) The sulfolipids potently inhibited the activities of mammalian pol. α and pol.…”

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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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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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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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“…Chemical investigations of combined F E' 5-F E' 8 fraction EtOAc extract led to the isolation of an unknown compound. The structure of the compound was elucidated by extensive analyses of NMR and ESITOF-MS spectral data, as well as by data comparison with previous reports 14 . The 1 H-NMR and 13 C-NMR spectra of the compound suggest that the compound has characteristic signals of glycolipid and sugar.…”

Section: Resultsmentioning

confidence: 95%

“…It is located in thylakoid membranes where it appears to be involved in maintaining a constant ratio of anionic lipids. Besides its role in the thylakoid membrane, SQDG is an attractive compound for development of new drugs because of its extensive biological activities which include inhibitory effects on DNA polymerase and HIV-reverse transcriptase, P-selectin receptors, the AIDS virus, telomerase, and inflammation/proliferation [11][12][13][14][15][16] . Cyanobacterium, Spirulina platensis, is a rich source of valuable compounds such as the antioxidant phycocyanin and polyunsaturated fatty acids (linoleic acid and gamma-linolenic acid) which have an important role in human metabolic pathways, particularly as a precursor of one kind of prostaglandin 17,18 .…”

Section: Introductionmentioning

confidence: 99%

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Chirasuwan¹,

Chaiklahan²,

Kittakoop³

et al. 2009

ScienceAsia

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Herpes simplex virus type 1 (HSV-1) causes a variety of infections in humans and can be found in many countries worldwide. Although the antiherpes drug, acyclovir, has been used very successfully, an acyclovir-resistant strain of HSV has recently been found in patients and drug toxicity has been reported with increasing use of it. As a potential alternative, it has been found that both a water soluble and a lipid extract of the microalga Spirulina platensis exhibit antiviral activity (HSV-1) in Vero cells. In this study, bioassay guided fractionation of a lipid extract from S. platensis led to the identification of sulphoquinovosyl diacylglycerol as the active antiviral agent. The chemical structure of this compound was confirmed by NMR and LC-mass spectroscopic analyses. Results from the study showed that the compound exhibited a remarkable activity against HSV-1 with an IC50 value of 6.8 µg/ml, which was comparable to that of acyclovir (1.5 µg/ml).

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“…В настоящее время ведется активный поиск источников сырья из цианобактерий, растений и водорослей (Kirk et al, 1989). В 2012 г. было установлено, что СХДГ ограничивает рост микобактерий туберкулеза в человеческих макро-фагах в результате видоспецифических взаимодействий (Gilmore et al, 2012), что может быть использовано при лечении туберкулеза.…”

Section: результаты и обсуждениеunclassified