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
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DOI：
10.1111/j.1349-7006.2000.tb00887.x
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发表时间：
2000-10-01
期刊：
影响因子：
--
通讯作者：
Sakaguchi, K
中科院分区：
文献类型：
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作者：
Hanashima, S;Mizushina, Y;Sakaguchi, K
我们以前报道过，蕨类和藻类中的磺基喹诺酮酰甘油类化合物是DNA聚合酶α和β的有效抑制剂，也是有效的抗肿瘤药物。在开发磺化脂肪化学合成方法的过程中，我们合成了许多磺基喹诺酮基单酰甘油(SQMG)/磺基喹诺酮基二酰甘油(SQDG)的衍生物和立体异构体，其中一些分子比最初报道的天然化合物SQMG/SQDG具有更强的抑制作用。在这项研究中，我们研究了合成的SQMG/SQDG的结构与抑制功能的关系及其与细胞毒活性的关系。这种抑制作用可能主要依赖于我们先前报道的脂肪酸效应，虽然SQMG/SQDG中的每一个都是比SQMG/SQDG中的脂肪酸单独存在的更强的抑制作用，但其抑制作用可能受到SQMG/SQDG中脂肪酸链大小的影响，喹诺酮糖中的硫酸盐部分也对抑制作用起着重要作用。SQMG/SQDG的Lineweaver-Burk图表明，DNA聚合酶a是非竞争性抑制的，但SQMG/SQDG对DNA聚合酶β的模板-引物DNA结合和核苷酸底物结合都是有效的拮抗剂。SQMC有细胞毒作用，但被测试的SQDG没有。SQDG可能无法穿透细胞。基于这些结果，我们讨论了SQMG/SQDG的分子作用，并提出了开发新的抗肿瘤药物的药物设计策略。
We reported previously that sulfolipids in the sulfoquinovosylacylglycerol class from a fern and an alga are potent inhibitors of DNA polymerase alpha and beta 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 a 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 beta. The SQMC 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.