School of Life Sciences, University of Hyderabad, Hyderabad, India.
Bioorg Med Chem. 2010 Aug 15;18(16):5807-15. doi: 10.1016/j.bmc.2010.06.107. Epub 2010 Jul 6.
Ten novel mono- and di-O-prenylated chalcone derivatives were designed on the basis of a homology derived molecular model of 5-lipoxygenase (5-LOX). The compounds were docked into 5-LOX active site and the binding characteristics were quantified using LUDI. To verify our theoretical assumption, the molecules were synthesized and tested for their 5-LOX inhibitory activities. The synthesis was carried out by Claisen-Schmidt condensation reaction of mono- and di-O-prenylated acetophenones with appropriate aldehydes. 5-LOX in vitro inhibition assay showed higher potency of di-O-prenylated chalcones than their mono-O-prenylated chalcone analogs. Compound 5e exhibited good inhibition with an IC(50) at 4 microM. The overall trend for the binding energies calculated and LUDI score was in good qualitative agreement with the experimental data. Further, the compound 5e showed potent anti-proliferative effects (GI(50) at 9 microM) on breast cancer cell line, MCF-7.
基于 5-脂氧合酶（5-LOX）同源模建的分子模型，设计了 10 种新型单-和二-O-异戊烯基查尔酮衍生物。利用 LUDI 将化合物对接入 5-LOX 活性部位，并定量分析其结合特性。为验证我们的理论假设，合成了这些分子并测试其对 5-LOX 的抑制活性。通过单-O-和二-O-异戊烯基苯乙酮与合适的醛的 Claisen-Schmidt 缩合反应进行合成。5-LOX 的体外抑制试验表明，二-O-异戊烯基查尔酮比其单-O-异戊烯基查尔酮类似物具有更高的活性。化合物 5e 的抑制活性较好，IC50 为 4 μM。计算出的结合能和 LUDI 评分的总体趋势与实验数据具有良好的定性一致性。此外，化合物 5e 对乳腺癌细胞系 MCF-7 表现出很强的抗增殖作用（GI50 为 9 μM）。
