Reductive activation of benzazolo[3,2-a]-quinolinium chlorides

Alegrı́a, Antonio E.; Cox, Osvaldo; Santiago, Vanessa; Colón, Mariel; Reyes, Zelideth; Zayas, Luis; Rivera, Luís E.; Dumas, JoséA.

doi:10.1016/0891-5849(93)90124-d

Cited by 11 publications

(9 citation statements)

References 26 publications

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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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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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“…A small anaerobic ferricytochrome c reduction rate increase by a quinolinium derivative without nitro-substitution, in the presence of xanthine/XO, has been previously reported, which suggests the possibility of BQ-106 reduction by HX/XO (35). Because of the lack of a nitro-group, BQ-106 + (represented here as the cation of BQ-106, that is, without the accompanying chloride anion), remains essentially unreduced until a large amount of HX/XO has been added.…”

Section: Resultsmentioning

confidence: 82%

Role of the Nitro Functionality in the DNA Binding of 3-Nitro-10-methylbenzothiazolo[3,2-a]quinolinium Chloride

Colón

González

Cordero

et al. 2008

Chem. Res. Toxicol.

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Interest in DNA binding drugs has increased in recent years due to their importance in the treatment of genome-related diseases, like cancer. A new family of water-soluble DNA binding compounds, the benzothiazolo[3,2-a]quinolinium chlorides (BQCls), is studied here as potential candidates for chemical treatment of solid tumor cells that may encounter low-oxygen environments, a condition known as hypoxia. These compounds are good DNA intercalators; however, no studies have been made of these compounds under hypoxic conditions. This work demonstrates the importance of the nitro-functionality in the DNA binding of 3-nitro-10-methylbenzothiazolo[3,2-a]quinolinium chloride (NBQ-91), which possesses nitro-functionality, and 10-methylbenzothiazolo[3,2-a] quinolinium chloride (BQ-106), which does not. Both NBQ-91 and BQ-106 have similar noncovalent binding affinity toward DNA. Dialysis experiments show that NBQ-91 binds DNA under N 2 -saturated conditions with increasing concentrations of reducing agent, presumably due to reduction of the nitro-functionality. Conversely, because of the lack of nitro-functionality, the presence of a reducing agent had no effect on BQ-106 binding to DNA under both aerobic and N 2 -saturated conditions. Clonogenic assays were performed to determine the quinolinium chloride cytotoxicities under both aerobic (95% air and 5% CO 2 ) and hypoxic (80% N 2 and 20% CO 2 ) conditions. The calculated ratios of cellular toxicity under aerobic to hypoxic conditions caused by the same concentration of test agent (CTR values) show greater levels of cell death under hypoxia than under aerobic conditions for mitomycin C (MC) (CTR = 0.7 at 1 µM) and NBQ-91 (CTR = 0.4 at 200 µM) than for BQ-106 (CTR = 1.0 at 200 µM), which agreed with the previously reported data for MC and confirmed the importance of nitro-functionality for reactivity under hypoxic conditions. There was no correlation between noncovalent binding affinity constants and their cytotoxicity under hypoxic conditions. Adduct formation between the NBQ-91 and 2′-dG was also assessed by reacting 2′-dG or DNA with NBQ-91 and BQ-106 under N 2 -saturated conditions in the presence of hypoxanthine and xanthine oxidase (HX/XO). DNA covalent adduct formation was analyzed by two techniques: LC-ESI-MS and Sephadex size exclusion column. LC-ESI-MS results clearly indicate the formation of a prominent molecular ion at masses of 266.0 and 530.58 Da, corresponding to the [M + H] +2 and [M] + molecular ions of the monitored 2′-dG-NBQ-91 adduct. Results from the Sephadex size exclusion chromatography support these findings because the NBQ-91 elution percentage increases in the presence of HX/XO due to the reduction of the nitro-functionality, which results in covalent binding to DNA. This study reports evidence of the DNA binding capacity of this bioreductive drug. The preferential N 2 -saturated over aerobic conditions for DNA binding makes NBQ-91 a potential bioreductive compound for hypoxic cell killing.

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“…The nitro substituted benzazolo[3,2- a ]quinolinium salts (NBQ) were synthesized as reported previously [9,12, 15]. Cytogenetically profiled adherent A431 epidermoid-carcinoma cell line was purchased from American Type Culture Collection (ATCC CRL-1555) and grown on RPMI 1640 from Cellgro (Manassas, Va) with glucose and HEPES.…”

Section: Methodsmentioning

confidence: 99%

Novel Nitrobenzazolo[3,2-a]quinolinium Salts Induce Cell Death through a Mechanism Involving DNA Damage, Cell Cycle Changes, and Mitochondrial Permeabilization

Vélez¹,

Cox²,

Rosado-Berrios³

et al. 2013

OJApo

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This study reports the capacity of three nitro substituted benzazolo[3,2-a]quinolinium salts NBQs: NBQ 95 (NSC-763304), NBQ 38 (NSC 763305), and NBQ 97 (NSC-763306) as potential antitumor agents. NBQ’s are unnatural alkaloids possessing a positive charge that could facilitate interaction with cell organelles. The anticancer activities of these compounds were evaluated through the National Cancer Institute (NCI) 60 cell line screening which represents diverse histologies. The screening was performed at 10 µM on all cell lines. Results from the NCI screening indicated cytotoxicity activity on six cell lines. In order to explore a possible mechanism of action, a detailed biological activity study of NBQ 95 and NBQ 38 was performed on A431 human epidermoid carcinoma cells to determine an apoptotic pathway involving, cell cycle changes, DNA fragmentation, mutations, mitochondrial membrane permeabilization and caspases activation. DNA fragmentation, cell cycle effects, mutagenesis, mitochondrial permeabilization and activation of caspases were determined by fluorimetry and differential imaging. Our data showed that A431 growth was inhibited with an average IC50 of 30 µM. In terms of the mechanism, these compounds interacted with DNA causing fragmentation and cell cycle arrest at sub G0/G1 stage. Mutagenesis was higher for NBQ 38 and moderate for NBQ 95 Mitochon-drial permeabilization was observed with NBQ 38 and slightly for NBQ 95. Both compounds caused activation of Caspases 3 and 7 suggesting an apoptotic cell death pathway through an intrinsic mechanism. This study reports evidence of the toxicity of these novel compounds with overlapping structural and mechanistic similarities to ellipticine, a known anti-tumor compound.

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Reductive activation of benzazolo[3,2-a]-quinolinium chlorides

Cited by 11 publications

References 26 publications

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

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

Role of the Nitro Functionality in the DNA Binding of 3-Nitro-10-methylbenzothiazolo[3,2-a]quinolinium Chloride

Novel Nitrobenzazolo[3,2-a]quinolinium Salts Induce Cell Death through a Mechanism Involving DNA Damage, Cell Cycle Changes, and Mitochondrial Permeabilization

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