Abstract
Triazoloacridinone C-1305, a potent antitumor agent recommended for Phase I clinical trials, exhibits high activity towards a wide range of experimental colon carcinomas, in many cases associated with complete tumor regression. C-1305 is a well-established dsDNA intercalator, yet no information on its mode of binding into DNA is available to date. Herein, we present the NMR-driven and MD-refined reconstruction of the 3D structures of the d(CGATATCG)2:C-1305 and d(CCCTAGGG)2:C-1305 non-covalent adducts. In both cases, the ligand intercalates at the TA/TA site, forming well-defined dsDNA:drug 1:1 mol/mol complexes. Orientation of the ligand within the binding site was unambiguously established by the DNA/ligand proton-proton NOE contacts. A subsequent, NMR-driven study of the sequence-specificity of C-1305 using a series of DNA duplexes, allowed us to confirm a strong preference towards TA/TA dinucleotide steps, followed by the TG/CA steps. Interestingly, no interaction at all was observed with duplexes containing exclusively the AT/AT, GG/CC and GA/TC steps.
Highlights
DNA-directed, rational antineoplastic agent development has made an extensive use of the acridine pharmacophore[1]
We report the three-dimensional structures of the d(CGATATCG)2:C-1305 and d(CCCTAGGG)2:C-1305 1:1 mol/mol complexes, fully and unambiguously reconstructed on the basis of 2D NMR experiments and refined by molecular dynamics simulations restrained by NOESY-derived data
The choice fell on the d(CGATATCG)[2] duplex, on referred to as D2, which is an extended version of the d(CGATCG)[2] and d(CGTACG)[2] duplexes—the standard palindromes widely used in the structural studies on the DNA:drug intercalation c omplexes[13,17,18,19]
Summary
DNA-directed, rational antineoplastic agent development has made an extensive use of the acridine pharmacophore[1]. Chemical probing with DEPC, combined with molecular modelling studies suggested that C-1305 is able to induce substantial distortions of a dsDNA duplex while intercalating into the GGG triplets, which is a unique effect among the known topoisomerase II inhibitors. This result was strongly dependent on the protonation of the drug and was observed only in pH > 7.5, in which C-1305 is believed to exist mostly in a zwitterionic form with deprotonated 8-OH hydroxyl group and protonated tertiary nitrogen atom at the end of the sidechain[12] (Fig. 1). We present a detailed, NMR-driven study on the sequence-specificity of C-1305, providing a completely new insight into the drug’s mode of binding into dsDNA
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