Development of Improved Synthetic Routes to Pixatimod (PG545), a Sulfated Oligosaccharide-Steroid Conjugate
Development of Improved Synthetic Routes to Pixatimod (PG545), a Sulfated Oligosaccharide-Steroid Conjugate
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DOI：
10.1021/acs.bioconjchem.1c00453
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发表时间：
2021-10-15
影响因子：
4.7
通讯作者：
Ferro, Vito
中科院分区：
文献类型：
--
作者：
Chhabra, Mohit;Wimmer, Norbert;Ferro, Vito
硫酸肝素（HS）模拟物pixatimod （PG545）是一种高效的血管生成、肿瘤生长和转移抑制剂，目前正在临床试验中用于癌症。PG545还显示出对多种hs依赖性病毒（包括SARS-CoV-2）的有效抗病毒活性，并有望成为治疗COVID-19的抗病毒药物。在结构上，PG545由一个完全硫酸化的四糖结合类固醇5 -胆甾醇-3 - β -醇组成。报道的PG545的合成存在产率低和关键糖基化步骤选择性差的问题。鉴于其临床重要性，人们开发了新的高效合成PG545及其类似物的途径。特别注意通过使用更稳定的保护基团和优化的糖基供体来改善关键的糖基化步骤。
The heparan sulfate (HS) mimetic pixatimod (PG545) is a highly potent inhibitor of angiogenesis, tumor growth, and metastasis currently in clinical trials for cancer. PG545 has also demonstrated potent antiviral activity against numerous HS-dependent viruses, including SARS-CoV-2, and shows promise as an antiviral drug for the treatment of COVID-19. Structurally, PG545 consists of a fully sulfated tetrasaccharide conjugated to the steroid 5 alpha-cholestan-3 beta-ol. The reported synthesis of PG545 suffers from a low yield and poor selectivity in the critical glycosylation step. Given its clinical importance, new efficient routes for the synthesis of PG545 and analogues were developed. Particular attention was given to improving the key glycosylation step by using more stable protecting groups and optimized glycosyl donors.