Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina.
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina.
Bioorg Med Chem. 2018 Mar 1;26(5):1092-1101. doi: 10.1016/j.bmc.2018.01.025. Epub 2018 Jan 31.
The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl-3β-hydroxycholenamide (DMHCA) arised as a promising LXR ligand. This compound was able to dissociate certain beneficial LXRs effects from those undesirable ones involved in triglyceride metabolism. Here, we synthetized a series of DMHCA analogues with different modifications in the steroidal nucleus involving the A/B ring fusion, that generate changes in the overall conformation of the steroid. The LXRα and LXRβ activity of these analogues was evaluated by using a luciferase reporter assay in BHK21 cells. Compounds were tested in both the agonist and antagonist modes. Results indicated that the agonist/antagonist profile is dependent on the steroid configuration at the A/B ring junction. Notably, in contrast to DMHCA, the amide derived from lithocholic acid (2) with an A/B cis configuration and its 6,19-epoxy analogue 4 behaved as LXRα selective agonists, while the 2,19-epoxy analogues with an A/B trans configuration were antagonists of both isoforms. The binding mode of the analogues to both LXR isoforms was assessed by using 50 ns molecular dynamics (MD) simulations. Results revealed conformational differences between LXRα- and LXRβ-ligand complexes, mainly in the hydrogen bonding network that involves the C-3 hydroxyl. Overall, these results indicate that the synthetized DMHCA analogues could be interesting candidates for a therapeutic modulation of the LXRs.
肝 X 受体 (LXRs) 是核受体家族的成员，在胆固醇转运、脂质代谢和炎症反应调节中发挥着重要作用。近年来，合成类固醇 N,N-二甲基-3β-羟基胆酰胺 (DMHCA) 作为一种有前途的 LXR 配体出现。该化合物能够将某些有益的 LXR 作用与涉及甘油三酯代谢的不利作用分离。在这里，我们合成了一系列甾体核中不同修饰的 DMHCA 类似物，涉及 A/B 环融合，这会改变甾体的整体构象。通过 BHK21 细胞中的荧光素酶报告基因测定评估了这些类似物对 LXRα 和 LXRβ 的活性。化合物以激动剂和拮抗剂两种模式进行了测试。结果表明，激动剂/拮抗剂特性取决于 A/B 环连接处的甾体构型。值得注意的是，与 DMHCA 相比，具有 A/B 顺式构型的石胆酸衍生酰胺 (2) 及其 6,19-环氧类似物 4 表现为 LXRα 选择性激动剂，而具有 A/B 反式构型的 2,19-环氧类似物则为两种同工型的拮抗剂。通过使用 50ns 分子动力学 (MD) 模拟评估了类似物与两种 LXR 同工型的结合模式。结果表明，LXRα 和 LXRβ 配体复合物之间存在构象差异，主要表现在涉及 C-3 羟基的氢键网络中。总的来说，这些结果表明，合成的 DMHCA 类似物可能是 LXR 治疗调节的有前途的候选物。
