Key Laboratory of Marine Drugs of Ministry of Education, Shandong Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003 China.
School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore.
J Am Chem Soc. 2024 May 1;146(17):11811-11822. doi: 10.1021/jacs.4c00537. Epub 2024 Apr 18.
The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf) catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with -, -, -, -, and -nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo- and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.
新型免疫调节作用药物的开发是应对全球健康炎症风暴日益威胁的有效途径。为了合成具有潜在免疫调节作用的醚键连接的假甾体糖苷，我们开发了一种通过应变释放促进的新型甾体供体的高效脱氧官能化（甾化）方法，利用具有成本效益且易于获得的 Sc(OTf) 催化作用。这种转化产生了瞬态甾体-3-基碳阳离子，它可以很容易地与 - 、 - 、 - 、 - 和 - 亲核试剂反应，生成结构多样的甾体衍生物。进行了 DFT 计算以阐明区域选择性的机理细节，揭示了一种受受体依赖性甾化模式。该方法可以很容易地扩展到糖醇的醚化，从而能够以良好至优异的收率实现具有多样性导向的、类似流水线的假甾体糖苷的合成，具有完全的立体和区域选择性控制，用于发现抗炎剂。免疫学研究表明，精心设计的胆固醇二糖可以显著抑制巨噬细胞中白细胞介素-6 的分泌，与阴性对照相比，抑制率高达 99%。这些发现证实了假甾体糖苷作为新型抗炎药物开发的潜在先导药物类别。
