Phytosterols are stucturally correlated to the endogenous ligands of Liver X Receptor (LXR), a ligand-activated nuclear receptor that has emerged as an attractive drug target due to its ability to integrate metabolic and inflammatory signaling. Natural and semi-synthetic phytosterol derivatives characterized by the presence of side-chain oxygenated functions have shown to be able to modulate LXR activity. Here, we describe the efficient synthesis of four stigmastane derivatives, endowed with a hydroxyl group at C24 position, namely (24R)- and (24S)-stigmasta-5,28-diene-3β,24-ols (also referred to as saringosterols, 10a and 10b) and (24R)- and (24S)-stigmasta-5-ene-3β,24-ols (11a and 11b), starting from the readily available stigmasterol. Thanks to X-ray crystallography the absolute configuration of the newly created chiral centers was definitively assigned for all the four compounds. The subsequent luciferase assays with GAL-4 chimeric receptors evidenced the ability of the two 24(S)-epimers, 10b and 11b, to interact with LXRs, showing the same degree of affinity as (22R)-hydroxycholesterol (1). With regard to the isoform selectivity both the derivatives 10b and 11b showed a preference for LXRβ, up to 4-fold in terms of efficacy for 11b. The gene expression profiling of (24S)-stigmasta-5,28-diene-3β,24-ol (10a) and (24S)-stigmasta-5-ene-3β,24-ol (11a) demonstrated the capability of both the compounds to induce the expression of four well-known LXR target genes, such as ABCA1, SREBP1c, FASN, and SCD1 in U937 monocytic cell line, thus supporting the hypothesis they were LXR positive modulators.

植物固醇与肝脏X受体（LXR）的内源性配体在结构上相关，该受体是一种配体激活的核受体，由于其整合代谢和炎症信号的能力而成为有吸引力的药物靶标。天然和半合成的植物甾醇衍生物的特征在于存在侧链氧化功能，已显示出能够调节LXR活性。在这里，我们描述了四种在C24位置带有羟基的柱头甾烷衍生物的有效合成方法，即（24 R）-和（24 S）-stigmasta-5,28-diene-3β，24-ols（也称为如saringosterols，10a和10b）和（24 R）-和（24 S）-stigmasta-5-ene-3β，24-ols（11a和11b），从容易获得的豆甾醇开始。多亏了X射线晶体学，为所有这四种化合物确定了新创建的手性中心的绝对构型。随后用GAL-4嵌合受体进行的萤光素酶分析证明了两个24（S）-受体10b和11b与LXR相互作用的能力，显示出与（22 R）-羟基胆固醇相同的亲和力（1）。关于同工型选择性，衍生物10b和11b都显示出对LXRβ的偏爱，就11b的功效而言，高达4倍。（24 S）-stigmasta-5,28-diene-3β，24-ol（10a）和（24 S）-stigmasta-5-ene-3β，24-ol（11a）的基因表达谱显示了这两种化合物均可诱导U937单核细胞系中四个著名的LXR靶基因如ABCA1，SREBP1c，FASN和SCD1的表达，从而支持了它们是LXR阳性调节剂的假设。