Diastereomeric 5',8-cyclo-2'-deoxypurines: brief overview of synthetic strategies, modelling and in vitro biological activity

Diastereomeric 5',8-cyclo-2'-deoxypurines: brief overview of synthetic strategies, modelling and in vitro biological activity. 5?,8-cyclo-2?-deoxypurines (cdPus) are typical DNA lesions resulting from endogenous and environmental free radical stress. The interest in these lesions is connected with the mechanism of their formation due to the HOo attack at the H5? atom of the 2-deoxyribose moiety, followed by intramolecular cyclization between C5?-C8 bond and subsequent oxidation of the resulting N7-radical.[1,2] Two diastereomeric cdPus are formed in the 5?R and 5?S forms (Fig.1). The two diastereomeric forms are repaired by nucleotide excision repair (NER) with different efficiency, the 5?R isomer being 2 times more efficiently repaired than the 5?S isomer. Molecular dynamics simulation elucidated that 5?R diastereoisomeric forms cause greater DNA backbone distortions than the 5?S diastereomers, thus theoretically supporting a different efficiency of NER[3] mechanism. We recently discovered that DNA polymerase ? (pol ?) has different behavior with 5?R-cdA lesion (efficiently bypassed) than 5?S-cdA (inefficiently bypassed) during DNA replication and base excision repair (BER),[4,5] highlighting that the nature of the DNA lesion can play a crucial role in biological processes. The diastereoisomeric 5?S- and 5?R-cdPus lesions are discussed in terms of differences in: i.Synthetic strategy and automated synthesis efficiency. ii.Physical-chemical properties (MD simulations, NMR, Melting Temperature) iii.Biological Activity in vitro References [1] Chatgilialoglu, C.;Ferreri, C.; Terzidis, M.A. Chem.Soc.Rev. 2011, 40, 1153. [2]Boussicault, F.; Kaloudis, P.; Caminal, C.; Mulazzani, Q. G.; Chatgilialoglu C. J. Am Chem. Soc. 2008, 130, 8377. [3]Kropachev, K.; Ding, S.; Terzidis, M.A.; Masi, A.; Liu, Z.; Cai, Y.; Kolbanovskiy, M.; Chatgilialoglu, C.; Broyde, S.; Nicholas E. Geacintov, N.E.; Shafirovich, V. Nucleic Acids Research, 2014, 42, 5020. [4]Xu, M.; Lai, Y.; Jiang, Z.; Terzidis, M.A.; Masi, A.; Chatgilialoglu, C.; Liu, Y. Nucleic Acids Research, 2014. 42,13749 [5]Jiang, Z.; Xu, M.; Lai, Y.; Laverde, E.E.; Terzidis, M.A.; Masi, A.; Chatgilialoglu, C.; Liu, Y. DNA Repair, 2015, 33, 24.