Egbewande Folake A, Nilsson Niclas, White Jonathan M, Coster Mark J, Davis Rohan A
Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark.
Bioorg Med Chem Lett. 2017 Jul 15;27(14):3185-3189. doi: 10.1016/j.bmcl.2017.05.021. Epub 2017 May 17.
The plant natural product, valerenic acid (1) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as LogP, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library (2-12) was subsequently generated using parallel solution-phase synthesis and Ghosez's reagent. The chemical structures of all semi-synthetic analogues (2-12) were elucidated following analysis of the NMR, MS, UV and IR data. The structures of compounds 8 and 11 were also confirmed by X-ray crystallographic analysis. All library members were evaluated for their ability to inhibit the release of IL-8 and TNF-α. Six analogues showed moderate activity in the IL-8 assay with IC values of 2.8-8.3μM, while none of the tested compounds showed any significant effect on inhibiting TNF-α release.
植物天然产物缬草烯酸（1）因其类药物的物理化学参数（如脂水分配系数、氢键供体/受体数量和分子量），被选为构建新型筛选文库的理想骨架。随后使用平行溶液相合成法和戈塞试剂生成了一个由11个成员组成的酰胺文库（2 - 12）。通过对核磁共振（NMR）、质谱（MS）、紫外（UV）和红外（IR）数据的分析，阐明了所有半合成类似物（2 - 12）的化学结构。化合物8和11的结构也通过X射线晶体学分析得到了证实。对文库中的所有成员进行了抑制白细胞介素-8（IL-8）和肿瘤坏死因子-α（TNF-α）释放能力的评估。六种类似物在IL-8测定中表现出中等活性，IC值为2.8 - 8.3μM，而所测试的化合物均未对抑制TNF-α释放显示出任何显著效果。
