Design and Synthesis of 5-Azacytidine Analogs
5-azacitidine is a prescription injectable drug used for the treatment of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). In this paper, we would like to report a new approach to 5-azacitidine analogs from dicyanodiamine and formic a
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Design and Synthesis of 5-Azacytidine Analogs Jianbo Xing, Hua Sun, Xijuan Liang, Yuou Teng, Peng Yu and Kui Lu
Abstract 5-azacitidine is a prescription injectable drug used for the treatment of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). In this paper, we would like to report a new approach to 5-azacitidine analogs from dicyanodiamine and formic acid or benzoic acid through several efficient reactions, such as cyclization reaction, Vorbrüggen coupling, and so on. Among those compounds, two azacytosine analogs and two 5-azacitidine analogs have not been reported yet. All products and important intermediates were characterized by 1HNMR and MS spectrums. Keywords 5-azacytidine analogs tion and Vorbrüggen coupling
Antiproliferative activity Cyclization reac-
91.1 Introduction 5-azacytidine (5-aza-CR) is well-known DNA methyltransferase inhibitor and has been approved to be prescription injectable drug for the treatment of myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myelogenous leukemia (AML) [1]. 5-azacitidine and its anologs extensively exist in nature and possess lots of biological activities like antiviral, anticarcer, J. Xing H. Sun X. Liang Y. Teng P. Yu K. Lu (&) Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin 300457, China e-mail: [email protected] J. Xing H. Sun X. Liang Y. Teng P. Yu K. Lu Tianjin Key Laboratory of Industry Microbiology, College of Biotechnology, Tianjin 300457, China J. Xing H. Sun X. Liang Y. Teng P. Yu K. Lu Tianjin University of Science & Technology, Tianjin 300457, China
T.-C. Zhang et al. (eds.), Proceedings of the 2012 International Conference on Applied Biotechnology (ICAB 2012), Lecture Notes in Electrical Engineering 250, DOI: 10.1007/978-3-642-37922-2_91, Ó Springer-Verlag Berlin Heidelberg 2014
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anti-HIV, etc. Recently, there is a growing tendency to develop some new methods for the synthesis of 5-azacitidine analogs to study their biological properties [1, 2]. Usually, the azacytosine analogs were synthesized from guanylurea with orthoesters, refluxed with the dimethylformamide [3–5]. In this paper, a new method is developed for the synthesis of azacytosine, we would like to report the design and synthesis of azacitidine analogs with cyclization and Vorbrüggen coupling as the key steps [6, 7]. The target compounds (1-3) were synthesized in three steps in 15–40 % overall yield.
91.2 Results and Discussion 91.2.1 Chemistry As illustrated in Scheme 91.1, the target compounds 1 were synthesized from dicyanodiamine through the intermediate compounds 2 and compound 3. Compound 3, 4-Amino-6-1,3,5-triazin-2(1H)-ones, prepared from the reactions of dicyanodiamine and formic acid (or acetic acid, benzoic acid), reacted with hexamethyldisilazane (HMDS) to produce N,O-bistrimethylsilylated-1,3,5-triazinones [8]. Vorbrüggen coupling of compound 2 with acylated sugars in anhydrous acetonitrile in the presence of a L
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