Nucleoside analogues. Part 12. The anomalous 19F NMR spectrum of B.3996, a molecular combination of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea and synthesis of its N′-nitroso isomer and related compounds
Abstract
In an attempt to explain the two signals in the 19F NMR spectrum of the 5-fluorouracil (5-FU)/N(2-chloroethyl)-N-nitrosourea (CNU) molecular combination B.3996, we synthesised the isomeric N(2-Chloroethyl)-N′-nitrosourea (isoCNU) by an unequivocal route involving N-nitrosation of an aryl carbamate bearing the appropriate pyrimidine-containing N-substituent. In the event, this isoCNU was not responsible for the second peak in the 19F NMR spectrum, but itself showed two peaks. The 1H NMR spectra at 300 MHz of these sulphides and the two corresponding N′-isomers and the two methoxy CNU analogues confirmed that a combination of methylthio/N3-substitution is necessary for the duplication pattern. In the compounds which show this behaviour, it is suggested that the Z and E isomers (around the N–NO system) equilibrate at a rate slower than the NMR time scale. This may have implications for the mechanism of biological action of 8.3996.