4.1 Article

The development of β-selective glycosylation reactions with benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides: enabling practical multi-gram syntheses of 4'-Thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) to support clinical development

期刊

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
卷 40, 期 1, 页码 68-95

出版社

TAYLOR & FRANCIS INC
DOI: 10.1080/15257770.2020.1832694

关键词

4'-thio-2'-deoxycytidine; glycosylation; large scale synthesis; DNMT1; T-dCyd; aza-T-dCyd

资金

  1. National Cancer Institute, National Institutes of Health [HHSN261200800001E, HHSN261201600066C, HHSN261201700007I, NO2CM-2012-00020]

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This article describes the modification and optimization of previous methods to enable the large-scale synthesis of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides, as well as the development of reaction conditions for beta-selective glycosylation reactions with N4-benzoylcytosine and 5-aza-cytosine for practical multi-gram syntheses of clinical candidates. These synthetic developments have facilitated the preclinical and early clinical development of important anticancer agents at the National Cancer Institute.
The lack of effective methods to perform direct beta-selective glycosylation reactions with 2-deoxy-1,4-dithio-D-erythro-pentofuranosides has long been a significant stumbling block for the multi-gram synthesis of 4'-thio-2'-deoxy nucleosides. In addition, previously reported methods for the preparation of appropriately substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides have proven problematic for large scale synthesis. To address these issues, herein we describe the modification and optimization of previously reported methods to allow for the convenient large scale synthesis of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides. Furthermore, we describe the development of reaction conditions for beta-selective glycosylation reactions of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides with both N4-benzoylcytosine and 5-aza-cytosine to enable the practical multi-gram syntheses of the clinical candidates 4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd). Taken together, these new synthetic developments have made possible the preclinical and early clinical development of these important anticancer agents at the National Cancer Institute.

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