Titre du document / Document title

Self-assembly of a quinobenzoxazine-Mg²⁺ complex on DNA : a new paradigm for the structure of a drug-DNA complex and implifications for the structure of the quinolone bacterial gyrase-DNA complex

Auteur(s) / Author(s)

JUN-YAO FAN ; DAEKYU SUN ; HONGTAO YU ; KERWIN S. M. ; HURLEY L. H. ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

Univ. Texas Austin, coll. pharmacy, div. medicinal chemistry, Austin TX 78712-1074, ETATS-UNIS

Résumé / Abstract

The quinobenzoxazine compounds A-62176 and A-85226 belong to a novel class of antineoplastic agents that are catalytic inhibitors of topoisomerase II and also structural analogs of the antibacterial DNA gyrase inhibitor Norfloxacin. In vitro studies have shown that their antineoplastic activity is dependent upon the presence of divalent metal ions such as Mg²⁺ and Mn²⁺, although the precise role of these ions in the mechanism of action is unknown. In this study we have investigated the structures of the binary complex between the quinobenzoxazines and Mg²⁺ and the ternary complex between quinobenzoxazine-Mg²⁺ and DNA. The stoichiometry of the binary and ternary complexes and the biophysical studies suggest that a 2 :2 drug :Mg²⁺ complex forms a heterodimer complex with respect to DNA in which one drug molecule is intercalated into DNA and the second drug molecule is externally bound, held to the first molecule by two Mg²⁺ bridges, which themselves are chelated to phosphates on DNA. There is a cooperativity in binding of the quinobenzoxazines to DNA, and a 4 :4 drug :Mg²⁺ complex is proposed in which the two externally bound molecules from two different 2 :2 dimers interact via π-π interactions. The externally bound quinobenzoxazine molecules can be replaced by the quinolone antibacterial compound Norfloxacin to form mixed-structure dimers on DNA. Based upon the proposed model for the 2 :2 quinobenzoxazine :Mg²⁺ complex on DNA, a parallel model for the antibacterial quinolone-Mg²⁺-DNA gyrase complex is proposed that relies upon the ATP-fueled unwinding of DNA by gyrase downstream of the cleavable complex site. These models, which have analogies to leucine zippers, represent a new paradigm for the structure of drug-DNA complexes. In addition, these models have important implications for the design of new gyrase and topoisomerase II inhibitors, in that optimization for structure-activity relationships should be carried out on two different quinolone molecules rather than a single molecule

Revue / Journal Title

Journal of medicinal chemistry   ISSN 0022-2623   CODEN JMCMAR 

Source / Source

1995, vol. 38, n^o3, pp. 408-424 (52 ref.)

Langue / Language

Anglais

Editeur / Publisher

American Chemical Society, Washington, DC, ETATS-UNIS  (1963) (Revue)

Mots-clés anglais / English Keywords

Structure activity relation ; Antineoplastic agent ; Intercalating agent ; Enzyme inhibitor ; DNA topoisomerase (ATP-hydrolysing) ; Antibacterial agent ; Fluoroquinolone derivative ; Oxygen nitrogen heterocycle ; Tetracyclic compound ; Aromatic compound ; Autoassembly ; Biological fixation ; Molecular interaction ; DNA ; Magnesium Complexes ; Organic ligand ; Chelating agent ; In vitro ; Modeling ; Molecular structure ; Mechanism of action ; Isomerases ; Enzyme ; Alkaline earth metal Complexes ;

Mots-clés français / French Keywords

Relation structure activité ; Anticancéreux ; Agent intercalant ; Inhibiteur enzyme ; DNA topoisomerase (ATP-hydrolysing) ; Antibactérien ; Norfloxacine ; Fluoroquinolone dérivé ; Hétérocycle oxygène azote ; Composé tétracyclique ; Composé aromatique ; Autoassemblage ; Fixation biologique ; Interaction moléculaire ; DNA ; Magnésium Complexe ; Coordinat organique ; Chélateur ; In vitro ; Modélisation ; Structure moléculaire ; Mécanisme action ; Pyrido[3,2,1-k]phénoxazine-5-carboxylique acide dérivé ; A 62176 ; A 85226 ; Isomerases ; Enzyme ; Métal alcalinoterreux Complexe ;

Mots-clés espagnols / Spanish Keywords

Relación estructura actividad ; Anticanceroso ; Agente intercalante ; Inhibidor enzima ; DNA topoisomerase (ATP-hydrolysing) ; Antibacteriano ; Fluoroquinolone derivado ; Heterociclo oxígeno nitrógeno ; Compuesto tetracíclico ; Compuesto aromático ; Autoensamble ; Fijación biológica ; Interacción molecular ; DNA ; Magnesio Complejo ; Ligando orgánico ; Quelante ; In vitro ; Modelización ; Estructura molecular ; Mecanismo acción ; Isomerases ; Enzima ; Metal alcalino-térreo Complejo ;

Localisation / Location

INIST-CNRS, Cote INIST : 9165, 35400005361473.0030