Synthesis and biological evaluation of modified purine homo-N-nucleosides containing pyrazole or 2-pyrazoline moiety

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 29; no. 1; pp. 109 - 117
• Main Authors: Thalassitis, Andreas, Katsori, Anna-Maria, Dimas, Konstantinos, Hadjipavlou-Litina, Dimitra J., Pyleris, Fokion, Sakellaridis, Nikolaos, Litinas, Konstantinos E.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.02.2014; Taylor & Francis
• Subjects: 3-dipolar cycloaddition reaction; 9-Allylpurines; Drug Evaluation, Preclinical; homo-N-nucleosides; lipid peroxidation inhibitors; Magnetic Resonance Spectroscopy; Medicin och hälsovetenskap; nitrile imines; Purine Nucleosides - chemical synthesis; Purine Nucleosides - chemistry; Purine Nucleosides - pharmacology; pyrazole; Pyrazoles - chemistry; pyrazoline; Spectrometry, Mass, Electrospray Ionization; thrombin inhibitors
• ISSN: 1475-6366; 1475-6374; 1475-6374
• DOI: 10.3109/14756366.2012.755623

Abstract 9-Substituted (pyrazol-5-yl)methyl- or (2-pyrazolin-5-yl)methyl-9H-purines were synthesized from 9-allyl-6-chloro-9H-purine through the 1,3-dipolar cycloaddition reaction with nitrile imines, prepared in situ from the corresponding hydrazone and NBS/Et3N under MW or from hydrazinoylchloride and Et3N under reflux. The coupling of new 6-chloropurines with amines in H2O under microwaves resulted quantitatively to modified pyrazol-5-yl- or 2-pyrazolin-5-yl adenine homo-N-nucleosides. The new compounds were tested in vitro for their ability to: (i) interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), (ii) inhibit lipid peroxidation, (iii) inhibit the activity of soybean lipoxygenase, (iv) inhibit in vitro thrombin and for (v) their antiproliferative and cytotoxic activity. Pyrazolines were found to be more potent in vitro. Compound 7a exhibited satisfactory combined antioxidant and anti-lipid peroxidation activity, inhibition of lipoxygenase (89%) and thrombin inhibitory ability, whereas compound 7b exhibited high lipoxygenase inhibitory activity in combination to significant anti-thrombin activity. No compound exhibited a significant cytotoxic activity, while all showed moderate antiproliferative activity.