Structure-function relationship of synthetic sulfoquinovosyl-acylglycerols as mammalian DNA polymerase inhibitors.
We reported previously that sulfo-glycolipids such as sulfoquinovosyl-diacylglycerol (SQDG) and sulfoquinovosyl-monoacylglycerol (SQMG) are potent inhibitors of DNA polymerase alpha and beta and antineoplastic agents. Then, we succeeded in synthesizing SQDG and SQMG chemically, including their stereoisomers, glucopyranosyl-diacylglycerol (GDG) and glucopyranosyl-monoacylglycerol (GMG). In this study, we demonstrated the structure-function relationship of the synthetic sulfo-glycolipids to DNA polymerase alpha and beta and their relationship to the cytotoxic activity. Both SQDG and SQMG inhibited the activity of mammalian DNA polymerase alpha with IC(50) values of 3-5 microM, but GMG only moderately inhibited it. GDG, diacylglycerol (DG), and monoacylglycerol (MG) did not influence any of the DNA polymerase activities. The sulfate moiety in the quinovose was important in inhibiting the enzyme activity. The one-fatty-acid-sulfo-glycolipids, SQMG, GMG, and MG, prevented the growth of NUGC-3 human gastric cancer cells and induced apoptotic cell death, but the two-fatty-acid-sulfo-glycolipids, SQDG, GDG, and DG, did not. SQMG and GMG could halt the cell cycle at the G1 phase, but the cell cycle was not changed by MG. The relationship between the DNA polymerase inhibition and the cell growth effect by these compounds are discussed.
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, 651-2180, Hyogo, Japan
Chikako
C
Murakami
Takayuki
T
Yamazaki
Shinya
S
Hanashima
Shunya
S
Takahashi
Keisuke
K
Ohta
Hiromi
H
Yoshida
Fumio
F
Sugawara
Kengo
K
Sakaguchi
Yoshiyuki
Y
Mizushina
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006017:Glycolipids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008322:Mammals; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006017:Glycolipids; C013694:sulfoquinovosyl diglyceride; D004256:DNA Polymerase I; D019951:DNA Polymerase beta