Interaction of Topotecan, DNA Topoisomerase I Inhibitor, with Double-Stranded Polydeoxyribonucleotides. 1. Topotecan Dimerization in Solution

摘要

Behavior of topotecan, DNA topoisomerase I inhibitor, was studied in aqueous solutions by optical methods. Topotecan absorption spectra were recorded in the pH range 0.5-11.5 and its pKa were determined. Quantum chemical calculations were made for all charge states of the topotecan molecule in lactone and carboxylate form. The calculated absorption maxima agree well with the experimental data. Protonation of the topotecan D ring (pKa approx = 3.6) was revealed. Comparison of experimental and calclated data showed topoteocan structure with a proton at the oxygen atom at C16a rather than N4 to be the most preferable. Topoteocan molecules were shown to form dimers at concentrations above 10~(-5) M. Topotecan dimerization is accompanied by an increae in the pKa of hydroxy group of the A ring from 6.5 ([TPT] = 10~(-6) M) to 7.1 ([TPT] = 10~(-4)), which indicates participation of this group in dimer stabilization, perhaps due to intermolecular hydrogen bonding with N1 of the B ring of a neighboring molecule. Probable dimer structures were proposed. The topootoeocan dimerization constant was determined, K = (4.0 (+-) 0.7) ·10~3 M~(-1).