EVIDENCE FOR THE FORMATION OF 2 2-DRUG MG2+ DIMERS IN SOLUTION AND FOR THE FORMATION OF DIMERIC DRUG COMPLEXES ON DNA FROM THE DNA-ACCELERATED PHOTOCHEMICAL-REACTION OF ANTINEOPLASTIC QUINOBENZOXAZINES/
Ht. Yu et al., EVIDENCE FOR THE FORMATION OF 2 2-DRUG MG2+ DIMERS IN SOLUTION AND FOR THE FORMATION OF DIMERIC DRUG COMPLEXES ON DNA FROM THE DNA-ACCELERATED PHOTOCHEMICAL-REACTION OF ANTINEOPLASTIC QUINOBENZOXAZINES/, Journal of the American Chemical Society, 118(30), 1996, pp. 7040-7048
The quinobenzoxazines are a group of topoisomerase II catalytic inhibi
tors that have demonstrated promising anticancer activity in mice. The
y have been proposed to form an unprecedented 2:2 drug-Mg2+ self-assem
bly complex on DNA. We have exploited the photochemical decomposition
of the quinobenzoxazines to gain further support and insights into the
nature of 2:2 quinobenzoxazine-Mg2+ dimers and the 2:2 drug-Mg2+ comp
lex on duplex DNA. The quinobenzoxazine A-62176 undergoes photodecompo
sition to highly fluorescent products. Methyl viologen (MV(2+)) accele
rates this photoreaction almost 500-fold. The formation of 2:2 drug-Mg
2+ dimers in solution is deduced from the Mg2+-dependent difference in
the MV(2+)-facilitated photoreaction rates of racemic and scalemic A-
62176. However, both racemic and scalemic A-62176 have identical MV(2)-facilitated photoreaction rates in the presence of Mg2+ and the achi
ral fluoroquinolone norfloxacin, due to heterochemical norfloxacin/A-6
2176 dimer complex formation. DNA also accelerates the photochemical d
ecomposition of A-62176 up to 80-fold. This DNA-acceleration requires
Mg2+, duplex DNA, molecular oxygen, and intercalation of the drug into
the DNA duplex. In the proposed model for drug-DNA complexation, only
one drug molecule of each 2:2 drug-Mg2+ dimer intercalates into the D
NA duplex, the other molecule binds externally to the DNA. Norfloxacin
, which can only play the external binding role, was able to modulate
the photochemical reaction of the quinobenzoxazines on DNA. Furthermor
e, it appears that the precise positioning of the intercalated molecul
e, which is modulated by the structure and stereochemistry of the exte
rnally bound molecule, plays an important role in determining the rate
of photoreaction on DNA. The implications of the observed photochemic
al reaction of the quinobenzoxazines are described for human phototoxi
city, photodynamic therapy, mechanism of action studies, and improved
drug design for both topoisomerase and gyrase inhibitors.