Sulfo-quinovosyl-acyl-glycerol (SQAG), a eukaryotic DNA polymerase inhibitor and anti-cancer agent.
It was found that a class of sulfolipids known as sulfo-quinovosyl-acyl-glycerols (SQAGs) from ferns and algae are potent inhibitors of eukaryotic DNA polymerase alpha and beta and effective anti-neoplastic agents. In developing a procedure for the chemical synthesis of sulfolipids, many derivatives and stereoisomers of SQAGs have been obtained including sulfo-quinovosyl-monoacyl-glycerols (SQMGs) and sulfo-quinovosyl-diacyl-glycerols (SQDGs). This review describes studies on the structure-function relationship between synthetic SQAGs and DNA polymerase alpha and beta, and the relationship to cytotoxic activity. The major action was probably dependent on the fatty acid effect, which was reported previously, although each of the SQAGs was a much stronger inhibitor than just the fatty acid present in the SQAGs. The inhibitory effect could be influenced by the chain size of fatty acids in the SQAGs. The sulfonyl group in quinovose was also needed to inhibit the enzymes. Lineweaver-Burk plots of SQAGs indicated that DNA polymerase alpha was non-competitively inhibited, but the SQAGs were effective as antagonists of both the template-primer DNA-binding and the nucleotide substrate-binding of DNA polymerase beta. Based on these results, the molecular actions of SQAGs and drug design strategies for developing new anti-neoplastic agents were discussed.
Mizushina
Yoshiyuki
Y
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp
Kasai
Nobuyuki
N
Iijima
Hiroshi
H
Sugawara
Fumio
F
Yoshida
Hiromi
H
Sakaguchi
Kengo
K
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006017:Glycolipids; D008958:Models, Molecular; D015394:Molecular Structure; D009005:Monosaccharides / Q000737:chemistry / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006017:Glycolipids; D009005:Monosaccharides; D019384:Nucleic Acid Synthesis Inhibitors; C496611:sulfoquinovosylacylglycerol; D005990:Glycerol