Regioselective synthesis of amphiphilic metoprolol–saccharide conjugates by enzymatic strategy in organic media

• Published in: Process biochemistry (1991) 2011, Vol.46 (1), p.123-127
• Main Authors: Zheng, Cheng-Zhen, Wang, Jun-Liang, Li, Xia, Liu, Bo-Kai, Wu, Qi, Lin, Xian-Fu
• Format: Article
• Language: English
• Subjects: acylation; Bacillus subtilis; carbon tetrachloride; drugs; Enzymatic synthesis; galactose; glucose; maltose; mannose; Metoprolol; Metoprolol–saccharide conjugates; pancreas; partition coefficients; proteinases; pyridines; Regioselective; Solubility; solvents; succinic acid; sucrose; swine; transesterification; yields
• ISSN: 1359-5113; 1873-3298
• DOI: 10.1016/j.procbio.2010.07.028

An efficient protocol to prepare metoprolol–saccharide conjugates by a selective enzymatic synthesis method was developed. Firstly, the transesterification of metoprolol with three divinyl dicarboxylates (divinyl succinate, divinyl adipate and divinyl sebacate) was performed. The influences of organic solvents, sources of enzymes and acylating reagents on the synthesis of N-(vinyloxycarbonyl)metoprolol were investigated. A series of lipophilic metoprolol derivatives with vinyl group were obtained by using a lipase from porcine pancreas (PPL) in anhydrous tetrachloromethane at 50 °C. Subsequently, alkaline protease from Bacillus subtilis catalyzed highly regioselective acylation of three monosaccharides (glucose, mannose and galactose) and two disaccharides (maltose and sucrose) with N-(5-vinyloxycarbonylpentanoyl)metoprolol in anhydrous pyridine at 50 °C to give metoprolol–saccharide conjugates in good yields. The partition coefficients of the products were investigated. The results indicated that the aqueous solubility of metoprolol–monosaccharide and metoprolol–disaccharide conjugates was improved markedly compared with the parent drug of metoprolol, and the aqueous solubility of metoprolol–disaccharide conjugates was much better than that of metoprolol–monosaccharide conjugates.