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

Zayas, Beatriz; Beyley, Juan; Terrón, María C.; Cordero, Marisol; Hernandez, Wigberto; Alegrı́a, Antonio E.; Cox, Osvaldo

doi:10.1016/j.tiv.2007.03.004

Cited by 5 publications

(7 citation statements)

References 29 publications

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“…Upon addition of HX/XO to NBQ-91, a broad shoulder builds up with a maximum at 361 nm and another at 400 nm (Figure 2). This observation, together with the evidence for uric acid formation (Figure 3), indicates that NBQ-91 was reduced by HX/XO as previously reported for other nitroquinolinium salts (28, 34). A broad absorption spectrum with two maxima at 365 and 379 nm and a shoulder at 350 nm was observed for BQ-106 in the absence of reducing agent.…”

Section: Resultssupporting

confidence: 88%

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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Section: Resultssupporting

confidence: 88%

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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“…The combinations of the evaluated biological activities suggest a nuclear promoted mechanism of cell death. The ability of these compounds especially NBQ 38 to promote DNA alterations also confirms results from previous studies in the formation of 2’-dG-NHBQ 38 adducts in naked DNA were detected [ 12 ].…”

Section: Discussionsupporting

confidence: 86%

“…Both compounds have also shown to be apoptosis inducers [6,7,11]. The formation of C8–2’-dG-BQS adducts with calf thymus DNA under hypoxic environment with NBQ-38, one of the compounds presented in this study, has also been reported [12,13]. …”

Section: Introductionmentioning

confidence: 66%

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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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“…Berberine has shown similar activities including anti cancer activity through mitochondria interactions [12]. Our previous work on other compounds from this family of benzazolo[3,2- a ]quinolinium salt (BQS) compounds has demonstrated diverse biological activities such as growth inhibition; apoptosis induction, and DNA adduct formation in cancer types such as epidermoid carcinoma [13-15]. …”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Response Triggered by the Alkaloids, 3-Amino- 7-Benzylbenzimidazo[3,2-a] Quinolinium Chloride (ABQ-48) and 3-Nitro- 7-Benzylbenzimidazo[3,2-a] Quinolinium Chloride (NBQ-48)

Otero

Zayas

Miranda

et al. 2015

Journal of Cancer Research and Therapeutic Oncology

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ABQ-48 (3-amino-7-benzylbenzimidazo[3,2-a]quinolinium chloride) and NBQ-48 (3-nitro-7-benzylbenzimidaw[3,2-a] quinolinium chloride) are un-natural alkaloids containing a planar heteroaromatic systems characterized by quaternized nitrogen fused to benzothiazole nucleus. Both compounds are structurally related to naturally occurring substances such as elliptine (from Ochrosia), and berberine (from Berberis). Previous in vitro studies have shown these agents to control tumor-cell proliferation indicating that both BQS are active but especially ABQ-48 at a 1 OuM dose with over 80% control of the proliferation of multiple cancer cell lines from various etiologies including colon, melanoma, CNS and ovarian cells. Mechanism of action studies have also been conducted however this is the first approach to evaluate immune modulatory activity of these novel BQS. Immune-based therapy is an increasing field in which scientists identify how the immunomodulatory activity of known and newly discovered compounds elicits an immune response that could be used against diseases. In this study, our main objective was to apply an in vitro model to show the immunomodulatory effects of ABQ-48 and NBQ-48 by analyzing the cytokine profile resulting after extracted murine spleen cells were treated with both BQS using a fluorescence-based multiplex ELISA approach. Screened cytokines included: G-CSF, GM-CSF, IL-1a, IL-2, IL-3, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-15, IL-17, IL-21, IL-23, IFN-γ, and TNF-α. Our study results show ABQ 48 and NBQ-48 to stimulate the release of G-CSF, IL-2, IL-6, and, IFN-γ when mouse splenocytes are incubated with serial dilutions of these agents. Our finding opens new possibilities of potentially using ABQ-48 and NBQ-48 as immunomodulatory agents; with intend to activate the immune system such as the production of neutrophils against cancer or reducing chemotherapy side effects.

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

Cited by 5 publications

References 29 publications

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

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

Immunomodulatory Response Triggered by the Alkaloids, 3-Amino- 7-Benzylbenzimidazo[3,2-a] Quinolinium Chloride (ABQ-48) and 3-Nitro- 7-Benzylbenzimidazo[3,2-a] Quinolinium Chloride (NBQ-48)

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