Shape-selective recognition of DNA abasic sites by metallohelices: inhibition of human AP endonuclease 1.
Loss of a base in DNA leading to creation of an abasic (AP) site leaving a deoxyribose residue in the strand, is a frequent lesion that may occur spontaneously or under the action of various physical and chemical agents. Progress in the understanding of the chemistry and enzymology of abasic DNA largely relies upon the study of AP sites in synthetic duplexes. We report here on interactions of diastereomerically pure metallo-helical 'flexicate' complexes, bimetallic triple-stranded ferro-helicates [Fe2(NN-NN)3](4+) incorporating the common NN-NN bis(bidentate) helicand, with short DNA duplexes containing AP sites in different sequence contexts. The results show that the flexicates bind to AP sites in DNA duplexes in a shape-selective manner. They preferentially bind to AP sites flanked by purines on both sides and their binding is enhanced when a pyrimidine is placed in opposite orientation to the lesion. Notably, the Λ-enantiomer binds to all tested AP sites with higher affinity than the Δ-enantiomer. In addition, the binding of the flexicates to AP sites inhibits the activity of human AP endonuclease 1, which is as a valid anticancer drug target. Hence, this finding indicates the potential of utilizing well-defined metallo-helical complexes for cancer chemotherapy.
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Jaroslav
J
Malina
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK.
Peter
P
Scott
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic brabec@ibp.cz.
Viktor
V
Brabec
D015075:2-Aminopurine / Q000032:analysis; D000584:Amiloride / Q000032:analysis; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D018983:DNA Footprinting; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005296:Ferrous Compounds / Q000737:chemistry*; D009691:Nucleic Acid Denaturation
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005296:Ferrous Compounds; D015075:2-Aminopurine; D000584:Amiloride; D004247:DNA; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase