Reductive activation and thiol reactivity of benzazolo[3,2-a]quinolinium salts

Alegrı́a, Antonio E.; Flores, Wilmarie; Cordones, Emelyn; Rivera, Lizmarie; Sanchez-Cruz, Pedro; Cordero, Marisol; Cox, Osvaldo

doi:10.1016/j.tox.2003.11.017

Cited by 4 publications

(2 citation statements)

References 41 publications

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“…Derivatives of benzolo[3,2-a]quinolinium salts (QSDs) (Fig. 11), incorporating a nitro group, are reductively activated by enzymatic agents (Alegria et al, 2004). Oxygen consumption rates correlate with QSD redox potentials when NADH dehydrogenase is used as a reducing agent.…”

Section: Other Nitroheterocyclesmentioning

confidence: 99%

Nitroaromatic compounds: Environmental toxicity, carcinogenicity, mutagenicity, therapy and mechanism

Kovacic

Somanathan

2014

J of Applied Toxicology

374

183

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Vehicle pollution is an increasing problem in the industrial world. Aromatic nitro compounds comprise a significant portion of the threat. In this review, the class includes nitro derivatives of benzene, biphenyls, naphthalenes, benzanthrone and polycyclic aromatic hydrocarbons, plus nitroheteroaromatic compounds. The numerous toxic manifestations are discussed. An appreciable number of drugs incorporate the nitroaromatic structure. The mechanistic aspects of both toxicity and therapy are addressed in the context of a unifying mechanism involving electron transfer, reactive oxygen species, oxidative stress and antioxidants.

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Section: Other Nitroheterocyclesmentioning

confidence: 99%

Nitroaromatic compounds: Environmental toxicity, carcinogenicity, mutagenicity, therapy and mechanism

Kovacic

Somanathan

2014

J of Applied Toxicology

374

183

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“…Of these, 3-nitrobenzothiazolo[3,2-a]quinolinium chloride (NBQ-2) has shown potential as an anticancer agent (Cox et al, 1982). It has been shown that these planar heterocyclic cationic nitroarenes can be reduced electrochemically or bioreduced in the presence of HX/XO (Cox et al, 1999,Alegria et al, 1993,Alegria et al, 2004. However, nothing is known regarding the possibility of DNA alkylation mediated through nitro reduction by this family of compounds.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the nucleic acid covalent binding capacity of two nitro-substituted benzazolo[3,2-a]quinolinium salts upon enzymatic reduction

Zayas

Beyley

Terrón

et al. 2007

Toxicology in Vitro

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The DNA binding capacity of two nitro-substituted benzazolo[3,2-a]quinolinium chlorides (NBQs), NBQ-38 and NBQ-95, was evaluated upon their enzymatic reduction with hypoxanthine (HX)/ xanthine oxidase (XO) under anaerobic conditions. In the presence of 2'-deoxyguanosine (2'-dG) or calf thymus DNA, covalent-addition products were monitored. Reactions of each NBQ with 2'-dG or DNA differed in the NBQ to HX molar ratio. Control reactions, one without HX/OX and another under aerobic conditions, were also analyzed. Adducts were isolated and characterized by high performance liquid chromatography (HPLC) and electrospray ionization-mass spectrometry (ESI-MS). Authentic samples of the reduced forms of these NBQs, identified as ABQ-38 and ABQ-95, were synthesized as standards to monitor bioreduction processes. HPLC analysis showed that the yield of formation of an unknown product (possibly, 2'-dG-NHBQ-38 adduct) from the reaction of NBQ-38 with 2'-dG and DNA was proportional to the HX to NBQ-38 molar ratio. ESI-MS analysis of the DNA hydrolysates showed evidence of an adduct formed upon bioreduction of NBQ-38 by the ions detection at m/z 528.3 and 454.8, consistent with chemical structures of a 2'-dG-NHBQ-38 adduct and a fragment ion. DNA adducts were not observed with NBQ-95, although the corresponding bioreduction product ABQ-95 was detected by ESI-MS. This study provides mechanistic information of these bioreductively-activated pro-drugs with potential therapeutic applications.

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