Multinuclear NMR Measurements and DFT Calculations for Capecitabine Tautomeric Form Assignment in a Solution.

Piotr Cmoch,Piotr Krzeczyński,Andrzej Leś

doi:10.3390/molecules23010161

Abstract

The molecular structure of capecitabine (a widely applied prodrug of 5-fluorouracil) was studied by multinuclear NMR measurements and DFT quantum mechanical calculations. One or two tautomeric forms in a solution were detected depending on the solvent used. In the organic solvents, a mixture of two forms of capecitabine was observed: carbamate and imine tautomers. In the aqueous solution, only the carbamate form was found. The methylation of capecitabine yields mainly two products in different proportions: N3-methylcapecitabine and N7-methylcapecitabine. The protonation of capecitabine in organic solvents with perchloric acid occurs at the N3 nitrogen atom. DFT calculations strongly support the results coming from the analysis of the NMR spectra.

Highlights

Capecitabine 1 refers to pentyl (1-((2R,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydro- furan-2-yl)5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate, known as Xeloda® (Figure 1), and was first synthesized by Miwa et al in 1998 [1]
Both these sets confirm the existence of capecitabine in one of the possible tautomeric forms, but which one can only be deduced on the basis of X-ray measurements
The comparison of 15 N chemical shifts in the solid state for 1 with the corresponding chemical shifts measured for cytidine 4 and 50 -deoxy-5-fluorocytidine 5 in DMSO (Figure S1, Supplementary Material), as well as cytidine 50 -monophosphate in water [17], leads to the suggestion that the presence of more than one tautomeric form of capecitabine in a solution should be expected

Summary

Introduction

Capecitabine 1 refers to pentyl (1-((2R,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydro- furan-2-yl)5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate, known as Xeloda® (by Roche) (Figure 1), and was first synthesized by Miwa et al in 1998 [1]. The main idea that accompanied designing this chemotherapeutic substance commonly used in medicine was to improve the selectivity and bioavailability of its parent compound, 5-fluorouracil (5-FU). The 5-FU was designed as an oncological drug, which should selectively disrupt DNA replication in tumor cells. Capecitabine undergoes transformation to 5-fluorouracil in the course of enzymatic processes during which, as the first step, the carbamate side chain is hydrolyzed by liver carboxyesterase to form. The steps take place in the liver as well as in tumor cells and rely on the action of cytidine deaminase leading to 50 -deoxy-5-fluorouridine, and further on capecitabine is released as a result of the thymidine phosphorylase enzymatic reaction in tumors [2,3]

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