Divergent synthesis of new α-glucosidase inhibitors obtained through a vinyl Grignard-mediated carbocyclization.
Divergent synthesis of new α-glucosidase inhibitors obtained through a vinyl Grignard-mediated carbocyclization.
复制标题
通过乙烯基格氏介导的碳环化获得新型α-葡萄糖苷酶抑制剂的发散合成。
DOI：
10.1039/c8ob01433g
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
H. H.
中科院分区：
文献类型：
--
作者：
Hedberg;C.;Knudsen;I. M. B.;Ladefoged;L. K.;Ide;D.;Brinko;A.;Eikeland;E. Z.;Kato;A.;Jensen;H. H.
从一个普通的合成中间体出发，经5-8步合成了4个新的α-葡萄糖苷酶抑制剂。这些化合物被设计为已知的葡萄糖苷酶抑制剂维列胺、伏格列波糖和米格列醇的杂合物。所有四种化合物均显示出对大鼠肠蔗糖酶的活性，其中最有效的抑制剂在低微摩尔浓度下起作用。新合成的化合物对蔗糖酶的抑制作用不如米格列醇，但对测试的糖苷酶显示出更高的选择性。最有效的抑制剂对接到一个同源性模型，建立了本研究的大鼠肠道蔗糖酶解释之间的差异，两个非对映异构体与不同方向的仲胺的效力。
Four new α-glucosidase inhibitors have been synthesised through 5–8 synthetic steps from a common synthetic intermediate obtained through a recently developed carbocyclisation. The compounds were designed as hybrids of the known glucosidase inhibitors valienamine, voglibose and miglitol. All four compounds showed activity against rat intestinal sucrase with the most potent inhibitor acting at low micromolar concentration. The newly synthesised compounds were not as potent as miglitol against sucrase but showed greater selectivity towards the tested glycosidases. The most potent inhibitors were docked into a homology model built for this study of rat intestinal sucrase explaining the difference in potency between two diastereoisomers with varying orientation of a secondary amine.