Synthetic, Structural, and Anticancer Activity Evaluation Studies on Novel Pyrazolylnucleosides

Yadav, Yogesh; Sharma, Deepti; Kaushik, Kumar; Kumar, Vineet; Jha, Amitabh; Prasad, Ashok K.; Len, Christophe; Malhotra, Sanjay V.; Wengel, Jesper; Parmar, Virinder S.

The structural identification of the isomeric disubstituted pyrazolyl nucleosides, based on their 1 H NMR spectral data (See Supplementary Materials), has been reported in the literature [46] [47] [48] . It has been observed that the anomeric protons in the isomeric pyrazolyl nucleosides exhibit different proton chemical shifts. The anomeric proton adjacent to N-1 of the pyrazole compounds 3a-e and 5a-e would appear downfield when compared to the anomeric proton adjacent to N-2 of the pyrazole compounds 4a-e and 6a-e [46] [47] [48] . In addition to using 1 H NMR chemical shifts, extensive NOE and 2D NMR experiments have been employed to confirm the structures of the isomeric pyrazolyl nucleosides. Using 1 H and 13 C NMR studies, we confirmed the positional assignments of the isomeric pyrazolyl nucleosides synthesized in the present work (Tables 1-3 ). The anomeric proton of the analogues 5a-e generally appeared at 0.14-0.19 ppm upfield when compared to the corresponding proton in the 1 H NMR spectra of its corresponding 6 series isomers. This is in agreement with observations for other 1,5-and 1,3-disubstituted pyrazole nucleosides [46] [47] [48] . We found that the effect was less pronounced in the 3 series of nucleosides as compared to the 4 series nucleosides where this difference was in the range of 0.04-0.14 ppm. The 13 C chemical shift of the -CH 2 CN bearing pyrazole carbon atom can help distinguish between positional isomers. In the 3 and 5 series of nucleosides, this carbon signal was 4-11 ppm downfield relative to the corresponding signal in the 4 and 6 series nucleosides. In most cases, the aryl bearing pyrazole carbon in the 3 and 5 series was 4-7 ppm upfield relative to the corresponding carbon in the 4 and 6 series. However, in the case of 3d versus 4d, the difference was small and reversed, making the aryl bearing pyrazole carbon less reliable for use in positional assignments. Table 1 . Chemical shift values of the anomeric protons in the 1 H NMR spectra and chemical shift values of the Ar-and CH 2 CN bearing carbons of the pyrazole ring in the 13 C NMR spectra of the isomeric pyrazolyl nucleosides 3a-e, 4a-e, 5a-e, and 6a-e in CDCl 3 on a Bruker Avance 300 spectrometer.