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. 2011 Aug 1;6(8):1347-50.
doi: 10.1002/cmdc.201100178. Epub 2011 Jun 28.

Warfarin glycosylation invokes a switch from anticoagulant to anticancer activity

Pauline Peltier-Pain  1 , Shannon C Timmons, Agnès Grandemange, Etienne Benoit, Jon S Thorson
Affiliations

Warfarin glycosylation invokes a switch from anticoagulant to anticancer activity

Pauline Peltier-Pain et al. ChemMedChem. .
No abstract available

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Figures

Figure 1
Figure 1
Summary of IC50 data from the high-throughput cytotoxicity assay of 1–41 (reciprocal values displayed). Comparisons were performed against warfarin (1), warfarin oxime (2) and warfarin aglycon (3). A complete table of IC50 data and corresponding error values is provided in the Supporting Information. Cell lines used for the screening are HCT-15 (human colorectal adenocarcinoma), MCF7 (human breast adenocarcinoma), H1299 (human lung adenocarcinoma), SKOV-3 (human ovarian adenocarcinoma), SF-268 (human CNS adenocarcinoma), HT-29 (human colorectal adenocarcinoma), A549 (human lung adenocarcinoma), NCI-H460 (human lung adenocarcinoma).
Figure 2
Figure 2
Vitamin K epoxide reductase activity as a function of warfarin analog concentration (µM).
Scheme 1
Scheme 1
Synthesis of neoglycosides library. a) MeONH2, pyridine, MeOH, 99%; b) t-Bu-NH2.BH3, 10% aq. HCl, ethanol/dioxane (1:3), 86%; c) reducing sugar, DMF/AcOH (3:1).
Scheme 2
Scheme 2
Synthesis of optically pure warfarin neoglycosides. a) Me3SiCHN2, CH2Cl2, 76%; b) (2R,3R)-2,3-butanediol, p-TSA, HC(OEt)3, CH2Cl2, 86%; c) TFA/H2O (4:1), 100%. d) MeONH2, pyridine, MeOH, 99%; e) t-Bu-NH2.BH3, 10% aq. HCl, ethanol/dioxane (1:3), 86%; f) reducing sugar, DMF/AcOH (3:1), 30–45%. Formation of the b-anomer was typically observed (e.g., 39: α/β 1:9; 41: α/β 1:4) and sugar conjugation was found to improve aqueous solubility of warfarin (17 µg mL−1) ~5-fold.
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