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

Hongtao Yu, Laurence Hurley, Sean M. Kerwin

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31 Citations (Scopus)

Abstract

The quinobenzoxazines are a group of topoisomerase II catalytic inhibitors that have demonstrated promising anticancer activity in mice. They have been proposed to form an unprecedented 2:2 drug-Mg2+ self-assembly 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+ complex on duplex DNA. The quinobenzoxazine A-62176 undergoes photodecomposition to highly fluorescent products. Methyl viologen (MV2+) accelerates this photoreaction almost 500-fold. The formation of 2:2 drug-Mg2+ dimers in solution is deduced from the Mg2+-dependent difference in the MV2+-facilitated photoreaction rates of racemic and scalemic A-62176. However, both racemic and scalemic A-62176 have identical MV2+-facilitated photoreaction rates in the presence of Mg2+ and the achiral fluoroquinolone norfloxacin, due to heterochemical norfloxacin/A-62176 dimer complex formation. DNA also accelerates the photochemical decomposition 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 DNA 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. Furthermore, it appears that the precise positioning of the intercalated molecule, which is modulated by the structure and stereochemistry of the externally bound molecule, plays an important role in determining the rate of photoreaction on DNA. The implications of the observed photochemical reaction of the quinobenzoxazines are described for human phototoxicity, photodynamic therapy, mechanism of action studies, and improved drug design for both topoisomerase and gyrase inhibitors.

Original languageEnglish (US)
Pages (from-to)7040-7048
Number of pages9
JournalJournal of the American Chemical Society
Volume118
Issue number30
DOIs
StatePublished - Jul 31 1996
Externally publishedYes

Fingerprint

Photochemical reactions
A 62176
Dimers
Antineoplastic Agents
DNA
Pharmaceutical Preparations
Norfloxacin
Molecules
Topoisomerase Inhibitors
Topoisomerase II Inhibitors
Phototoxic Dermatitis
Decomposition
Type II DNA Topoisomerase
Photodynamic therapy
Stereochemistry
Paraquat
Molecular oxygen
Drug Design
Fluoroquinolones
Photochemotherapy

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

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title = "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",
abstract = "The quinobenzoxazines are a group of topoisomerase II catalytic inhibitors that have demonstrated promising anticancer activity in mice. They have been proposed to form an unprecedented 2:2 drug-Mg2+ self-assembly 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+ complex on duplex DNA. The quinobenzoxazine A-62176 undergoes photodecomposition to highly fluorescent products. Methyl viologen (MV2+) accelerates this photoreaction almost 500-fold. The formation of 2:2 drug-Mg2+ dimers in solution is deduced from the Mg2+-dependent difference in the MV2+-facilitated photoreaction rates of racemic and scalemic A-62176. However, both racemic and scalemic A-62176 have identical MV2+-facilitated photoreaction rates in the presence of Mg2+ and the achiral fluoroquinolone norfloxacin, due to heterochemical norfloxacin/A-62176 dimer complex formation. DNA also accelerates the photochemical decomposition 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 DNA 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. Furthermore, it appears that the precise positioning of the intercalated molecule, which is modulated by the structure and stereochemistry of the externally bound molecule, plays an important role in determining the rate of photoreaction on DNA. The implications of the observed photochemical reaction of the quinobenzoxazines are described for human phototoxicity, photodynamic therapy, mechanism of action studies, and improved drug design for both topoisomerase and gyrase inhibitors.",
author = "Hongtao Yu and Laurence Hurley and Kerwin, {Sean M.}",
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