Structural basis for the binding affinity of a homologous series of synthetic phenoxazone drugs with DNA: NMR and molecular mechanics analysis.

The molecular basis of the marked structure-activity relationship for a homologous series of DNA-binding phenoxazone drugs (ActII-ActIV) has been investigated by NMR spectroscopy and molecular mechanics. The spatial structures of the complexes between the drugs and a model deoxytetranucleotide, 5'-d(TpGpCpA), have been determined by molecular mechanics methods using homonuclear (1)H-(1)H 2D-NOESY and heteronuclear (1)H-(31)P (HMBC) NMR spectroscopic data. Observed intermolecular NOE contacts and equilibrium binding studies confirm that the binding affinity of the synthetic phenoxazone derivatives with d(TGCA) decreases with an increase in the number of CH(2) groups in the dimethylaminoalkyl side chains, i.e., ActII > ActIII > ActIV, in agreement with the observed biological activity of these compounds. Molecular mechanics calculations of the spatial structures of the intercalated complexes of ActII-ActIV with d(TGCA) indicate that the different binding constants of the phenoxazone derivatives with the DNA oligomer are due to the different degrees of intercalation of the chromophore and the different steric arrangements of aminoalkyl side chains in the minor groove of the tetramer duplex; this results in different distances between the negatively-charged phosphates of the DNA duplex and the terminal positively-charged N(CH(3))(2) groups of the side chains.

[Structural analysis of the complex of phenoxazone antibiotic actinocyl-bis-(2-deoxytetranucleotide 5'-d(TpGpCpA) by the methods of two dimensional 1H-NMR-spectroscopy and molecular mechanics].

The spatial structures of intercalated complexes of synthetic phenoxazone antibiotic actinocyl-bis-(2-dimethylaminoethyl) amide with self-complementary deoxytetranucleotide 5'-d(TpGpCpA) have been investigated. Analysis has been made using two-dimensional NMR (2D-NOESY) data in aqueous solution and molecular mechanics simulation. Distinctive features of the conformation of drug-DNA complexes have been determined at two possible orientations of the chromophore of phenoxazone antibiotic at the intercalation site.