Recently, Prof. Li Wei and Prof. Sun Haopeng from the School of Pharmaceutical Sciences have published a paper on the stereoselective synthesis of 2'-deoxynucleosides in the prestigious journal Journal of the American Chemical Society. Xintong Tang and Yueer Zhou, master's students of School of Pharmaceutical Sciences, and Dr. Yingjie Wang of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, are the co-first authors of the paper, while Prof. Li Wei and Prof. Haopeng Sun are the co-corresponding authors, and China Pharmaceutical University (CPU) is the only corresponding organization.
2'-Deoxyriboside, commonly known as deoxyriboside, is not only an important component of DNA, but also has an important position in drug development. However, the stereoselective synthesis of 2'-deoxyribosides and their analogs is a challenge in glycochemistry, and the existing methods suffer from the deficiencies of low yield, poor stereoselectivity, and narrow substrate applicability, which impede the related drug development and production. In addition, previous studies have basically focused on β-2'-deoxyriboside possessing the natural β-configuration; while its unnatural isomer α-2'-deoxyriboside lacks effective access and has not attracted sufficient attention. Based on the previous work (Angew. Chem., Int. Ed. 2022, 61, e202206128; Chin. J. Chem. 2022, 40, 443), the researchers of this dissertation introduced diphenylphosphinoyl (DPP) on 2-deoxyribose by using inexpensive commercial reagent groups, the highly stereoselective synthesis of α- and β-2'-deoxyribonucleosides can be realized, respectively, which is especially suitable for the rapid preparation of α-2'-deoxyribonucleosides.
In vitro antiproliferative experiments revealed an antitumor α-2'-deoxyriboside with IC50 values in the low micromolar range against CNS tumor cell lines SH-SY5Y and LN229, whereas its b-isomer showed no inhibitory effect at a concentration of 100 μM. The above results indicate that the non-natural conformation of α-2'-deoxyriboside has stronger inhibitory effects on some tumor cells than the natural conformation of b-2'-deoxyriboside, and the introduction of the DPP moiety has led to a significant enhancement of the antitumor activity of a series of compounds. This study initially reveals the potential application of α-nucleosides in drug discovery and development.
This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China (NSFC), the Natural Science Foundation of Jiangsu Province, and the “333 High-level Talent Cultivation Project” of Jiangsu Province.
