Murakami Chikako, Yamazaki Takayuki, Hanashima Shinya, Takahashi Shunya, Ohta Keisuke, Yoshida Hiromi, Sugawara Fumio, Sakaguchi Kengo, Mizushina Yoshiyuki
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, 651-2180, Hyogo, Japan
Arch Biochem Biophys. 2002 Jul 15;403(2):229-36. doi: 10.1016/s0003-9861(02)00219-9.
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.
我们之前报道过，磺基糖脂如磺基喹啉二酰基甘油（SQDG）和磺基喹啉单酰基甘油（SQMG）是DNA聚合酶α和β的有效抑制剂以及抗肿瘤药物。然后，我们成功地化学合成了SQDG和SQMG，包括它们的立体异构体吡喃葡萄糖基二酰基甘油（GDG）和吡喃葡萄糖基单酰基甘油（GMG）。在本研究中，我们证明了合成磺基糖脂与DNA聚合酶α和β之间的结构 - 功能关系以及它们与细胞毒性活性的关系。SQDG和SQMG均以3 - 5 microM的IC（50）值抑制哺乳动物DNA聚合酶α的活性，但GMG仅适度抑制该活性。GDG、二酰基甘油（DG）和单酰基甘油（MG）对任何DNA聚合酶活性均无影响。喹诺糖中的硫酸根部分对抑制酶活性很重要。单脂肪酸磺基糖脂SQMG、GMG和MG可抑制NUGC - 3人胃癌细胞的生长并诱导凋亡性细胞死亡，但双脂肪酸磺基糖脂SQDG、GDG和DG则无此作用。SQMG和GMG可使细胞周期停滞在G1期，但MG对细胞周期无影响。本文讨论了这些化合物对DNA聚合酶的抑制作用与细胞生长效应之间的关系。
