Synthesis and biological evaluation of (20S,24R)-epoxy-dammarane-3β,12β,25-triol derivatives as α-glucosidase and PTP1B inhibitors.
Synthesis and biological evaluation of (20S,24R)-epoxy-dammarane-3β,12β,25-triol derivatives as α-glucosidase and PTP1B inhibitors.
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(20S,24R)-环氧-达玛烷-3β,12β,25-三醇衍生物作为α-葡萄糖苷酶和 PTP1B 抑制剂的合成和生物学评价
DOI：
10.1007/s00044-021-02836-0
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Chen JJ
中科院分区：
文献类型：
--
作者：
Yang XT;Li TZ;Geng CA;Liu P;Chen JJ
从青钱柳（Cyclocarya paliurus）中分离得到的达玛烷三萜（20 S，24 R）-环氧-达玛烷-3 β，12 β，25-三醇对α-葡萄糖苷酶具有体外抑制活性，在200 μM浓度下抑制率为32.2%。为了揭示化合物的构效关系，得到活性更高的化合物，对（20 S，24 R）-环氧-达玛烷-3 β，12 β，25-三醇的C-3和C-12位羟基、A环和E环进行化学修饰，合成了42个衍生物，并测定了它们的α-葡萄糖苷酶和PTP 1B抑制活性。两个化合物（8，26）增加对α-葡萄糖苷酶的活性，并且四个化合物（8，15，26，42）显著抑制PTP 1B。结果表明，化合物8和26对α-葡萄糖苷酶和PTP 1B具有双靶点抑制作用，其IC 50值分别为489.8，467.7 μM（α-葡萄糖苷酶）和319.7，269.1 μM（PTP 1B）。酶动力学研究表明，化合物26是α-葡萄糖苷酶的混合型抑制剂，是PTP 1B的非竞争型抑制剂。化合物42对PTP 1B有选择性抑制作用，其IC 50值为134.9 μM，是阳性对照苏拉明钠（IC 50 339.0 μM）的2.5倍，但对α-葡萄糖苷酶无抑制作用。
The dammarane triterpenoid (20S,24R)-epoxy-dammarane-3β,12β,25-triol obtained from Cyclocarya paliurus in our previous study showed inhibitory activity on α-glucosidase in vitro with an inhibitory ratio of 32.2% at the concentration of 200 μM. In order to reveal the structure-activity relationships (SARs) and get more active compounds, 42 derivatives of (20S,24R)-epoxy-dammarane-3β,12β,25-triol were synthesized by chemical modification on the hydroxyls (C-3 and C-12), rings A and E, and assayed for their α-glucosidase and PTP1B inhibitory activities. Two compounds (8, 26) increased activity against α-glucosidase, and four compounds (8, 15, 26, 42) significantly inhibited PTP1B. It was noted that compounds 8 and 26 could inhibit both α-glucosidase and PTP1B as dual-target inhibitors with IC50 values of 489.8, 467.7 μM (α-glucosidase) and 319.7, 269.1 μM (PTP1B). Compound 26 was revealed to be a mix-type inhibitor on α-glucosidase and a noncompetitive-type inhibitor on PTP1B based on enzyme kinetic study. Furthermore, compound 42 could selectively inhibited PTP1B as a mix-type inhibitor with IC50 value of 134.9 μM, which was 2.5-fold higher than the positive control, suramin sodium (IC50 339.0 μM), but not inhibit α-glucosidase.
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