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Enzymatic Synthesis of Bufadienolide O ‐Glycosides as Potent Antitumor Agents Using a Microbial Glycosyltransferase
Author(s) -
Li Kai,
Feng Jin,
Kuang Yi,
Song Wei,
Zhang Meng,
Ji Shuai,
Qiao Xue,
Ye Min
Publication year - 2017
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201700777
Subject(s) - chemistry , glycoside , bufalin , stereochemistry , glycosylation , lipophilicity , electrospray ionization , enzyme , biochemistry , mass spectrometry , chromatography , apoptosis
Bufadienolides are a class of natural cardiotonic steroids and are well known for their antitumor activities. Their clinical use has been hindered by poor water solubility. Enzymatic glycosylation is a favorable approach to improve the solubility of natural products. In this work, we describe the highly efficient one‐step synthesis of bufadienolide O ‐glucosides and O ‐galactosides using a microbial glycosyltransferase YjiC1, with conversion rates from 63% to 99%. Altogether 24 glycosides including 17 new compounds were obtained from 14 substrates, and their structures were identified by extensive NMR and high‐resolution electrospray ionization mass spectrometry (HR‐ESI‐MS) analyses. These products belong to five types: glycosylation at 3β‐OH, 7β‐OH, 3β,7β‐di‐OH, 11α‐OH, and 12β‐OH. The C‐7β or C‐11α O ‐glycosides of bufadienolide are reported for the first time. Moreover, the 3‐ O ‐glycosides exhibited significant cytotoxic activities against A549 and MCF7 human cancer cell lines, and showed potent inhibitory activities against Na + /K + ‐ATPase with IC 50 values in the range 0.053–0.76 μM. In particular, bufalin 3‐ O ‐β‐ d ‐glucoside showed enhanced water solubility (25‐fold increase from bufalin) and potent antitumor activities (30% inhibition rate, 1.4 mg kg −1 , i.p .) on A549 human lung cancer xenograft Balb/c nude mice model, and could be a promising drug candidate.