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 chemistry of nucleosides has been extensively studied and several analogs have been found to exhibit potential as fungicidal, antitumor, and antiviral agents [1] [2] [3] [4] [5] [6] [7] . Modifications in both the heterocyclic bases and the sugar moieties have led to active and safer nucleoside analogues that have found applications as agents effective against human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS), and also against viral infections caused by the herpes simplex virus (HSV types 1 and 2), varicella zoster virus (VZV), hepatitis C virus (HCV), human cytomegalovirus (HCMV), and Epstein-Barr virus (EBV) [8, 9] . Nucleoside and nucleotide modifications resulted in an increased interest in the regio-and stereoselective synthesis of nucleosides [10, 11] . Moreover, modified nucleosides and nucleotides with a restricted biomacromolecule for its natural ligand as well as the molecular recognition in an oligonucleotide chain (RNA/DNA) [12] [13] [14] [15] . Similar studies of anti-sense and anti-gene oligonucleotides (ONs) as potential and selective inhibitors of gene expression [16] [17] [18] [19] and their use as anti-tumor or anti-viral agents [20] [21] [22] [23] have also influenced the developments in the field of nucleic acid-based drugs. Among the nucleoside analogues with significant biological activities, dideoxynucleoside-based compounds such as 2′,3′-dideoxycytidine (ddC) [24] , 2′,3′-dideoxyinosine (ddI) [24] , and 3′-azidothymidine (AZT) [25] are effective therapeutic agents for the treatment of AIDS, while ribavirin (virazole) [26, 27] is an antiviral drug (Figure 1) . Similarly, other dideoxynucleosides such as d4T (2′,3′-didehydro-3′-deoxythymidine, stavudine) [28, 29] and AZddU (3′-azido-2′,3′-dideoxyuridine) [30] have gone through clinical studies. Different nucleosides isolated from nature such as oxazinomycin [31] , pyrazofurin [32, 33] , showdomycin [34, 35] , formycin A, and formycin B [36, 37] have shown antibiotic properties and have also been found to exhibit anticancer and/or antiviral activities ( Figure 1) . These examples and new developments in the chemistry and biology of these compounds and their analogs [38] [39] [40] [41] [42] have motivated us to work in this area and have led us to investigate the interesting chemical and biological properties of novel nucleoside-based compounds. Despite the developments in nucleoside chemistry, the clinical use of nucleosides has some drawbacks due to their side-effects and primary or acquired drug resistance [43] . Therefore, the search for the design of new and effective nucleoside-based analogues continues to motivate studies in this field. Our efforts toward this goal have led to the synthesis of twenty novel pyrazolylnucleosides with new structures and potent antiviral and antitumoral behaviors. In this regard, two regioisomers for each pyrazole derivative have been produced and characterized using spectroscopic techniques such as 1 H NMR, 13 C NMR, NOESY, HMBC, IR, and mass spectroscopy. All compounds were evaluated against the National Cancer Institute (NCI)'s panel of 60 human tumor cell lines for their anticancer activities, and for their antiviral activities against representative viruses.