Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRβ isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRβ, while it was virtually inactive at LXRα (EC50 = 14.51 μM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively.一系列以C-22位和/或C-23位带有含氧官能团为特征的豆甾醇（stigmasterol）与麦角固醇（ergosterol）衍生物，被设计为潜在的肝X受体（liver X receptor, LXR）激动剂。所有对应化合物中新生成手性中心的绝对构型均已得到明确归属。在16种合成化合物中，化合物21、27和28被鉴定为选择性LXRα激动剂，而化合物20、22和25则对LXRβ亚型展现出优异的选择性。尤为值得关注的是，化合物25在LXRβ靶点上的效能与22R-HC（化合物3）相当，但其对LXRα几乎无激活活性（半最大效应浓度EC₅₀ = 14.51 μM）。有趣的是，化合物13、19、20和25属于LXR靶基因选择性调节剂：它们可强力诱导三磷酸腺苷结合盒转运体A1（ABCA1）的表达，却分别仅微弱激活或无法激活生脂基因固醇调节元件结合蛋白1（SREBP1）、硬脂酰辅酶A去饱和酶1（SCD1）以及脂肪酸合酶（FASN）。