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天然化合物 2,4,6-三羟基-3-香叶基苯乙酮（tHGA）作为有效的脂氧合酶抑制剂的从头至 Lead 优化：合成、构效关系（SAR）研究和计算分配。

Hits-to-Lead Optimization of the Natural Compound 2,4,6-Trihydroxy-3-geranyl-acetophenone (tHGA) as a Potent LOX Inhibitor: Synthesis, Structure-Activity Relationship (SAR) Study, and Computational Assignment.

机构信息

Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia.

School of Pharmacy, Management and Science University (MSU), University Drive, Off Persiaran Olahraga, Seksyen 13, Shah Alam 40100, Selangor, Malaysia.

出版信息

Molecules. 2018 Sep 30;23(10):2509. doi: 10.3390/molecules23102509.

DOI:10.3390/molecules23102509
PMID:30274341
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6222424/
Abstract

A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues ⁻ (half maximal inhibitory concentration (IC) values ranging from 35 μ M to 95 μ M) did not exhibit better inhibitory activity than tHGA () (IC value: 23.6 μ M) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, , with an IC value of 15.3 μ M, exhibited better LOX inhibitory activity when compared to tHGA (), which was in agreement with our previous findings. Kinetics study showed that the most active analogue () and tHGA () acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (⁻) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.

摘要

一系列新的 2,4,6-三羟基-3-香叶基苯乙酮（tHGA）类似物被合成，并对其脂氧合酶（LOX）抑制活性进行了评价。烯丙基类似物 ⁻ （半最大抑制浓度（IC）值范围为 35 μM 至 95 μM）的抑制活性并没有比 tHGA（）更好，因为当烷基链长度减小时，疏水性相互作用减少。一种香叶基化的类似物，与 tHGA（）相比，具有更好的 LOX 抑制活性，IC 值为 15.3 μM，这与我们之前的发现一致。动力学研究表明，最活跃的类似物（）和 tHGA（）作为竞争性抑制剂。基于分子对接和分子动力学模拟的计算方法的结合，表明这些类似物的亲脂性进一步增强了 LOX 抑制活性。根据吸收、分布、代谢、排泄和毒性（ADMET）以及计算机辅助技术（TOPKAT）分析的毒性预测，所有香叶基化的类似物（⁻）均无肝毒性，可生物降解，这表明它们可能是治疗炎症的潜在安全药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/7f2213efad36/molecules-23-02509-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/43d5a39c2894/molecules-23-02509-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/3d8d23c3eb95/molecules-23-02509-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/1355a72010d4/molecules-23-02509-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/694f1a64e901/molecules-23-02509-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/8bca6f18e05a/molecules-23-02509-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/b6ef97d07490/molecules-23-02509-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/0c0d09fbcffe/molecules-23-02509-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/c4af2d7ac46e/molecules-23-02509-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/7f2213efad36/molecules-23-02509-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/43d5a39c2894/molecules-23-02509-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/3d8d23c3eb95/molecules-23-02509-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/1355a72010d4/molecules-23-02509-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/694f1a64e901/molecules-23-02509-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/8bca6f18e05a/molecules-23-02509-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/b6ef97d07490/molecules-23-02509-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/0c0d09fbcffe/molecules-23-02509-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/c4af2d7ac46e/molecules-23-02509-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/6222424/7f2213efad36/molecules-23-02509-g008.jpg

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