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.
Ovchinnikov
D V
DV
Department of Organic Chemistry, St. Petersburg State Institute of Technology, St. Petersburg, Russia.
Baranovsky
S F
SF
Rozvadovska
A O
AO
Rogova
O V
OV
Veselkov
K A
KA
Ermolaev
D V
DV
Parkes
H
H
Davies
D B
DB
Evstigneev
M P
MP
D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010078:Oxazines / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D007364:Intercalating Agents; D010078:Oxazines; C020456:phenoxazinone; D004247:DNA