Synthesis of and Biological Study of 7-Benzyl-3-aminobenzimidazo[3,2- a]quinolinium Chloride (ABQ-48: NSC D-763307) and 7-benzyl-3- nitrobenzimidazo[3,2-a]quinolinium Chloride (NBQ 48: NSC D-763303)

Cox, Osvaldo; Vélez, Christian; Kumar, Vineet; Malhotra, Sanjay V.; Rivera, Luís E.; Hernandez, Wigberto; Martínez, José Rodríguez; Cordero, Marisol; Zayas, Beatriz

doi:10.2174/1573407210666141126204355

Cited by 5 publications

(7 citation statements)

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“…These results suggest a structure – activity variation among both test drugs. This finding is in accordance with our previous work with other cell lines which demonstrated that ABQ-48 has greater biological activity in comparison to its Nitro analog [ 9 ].…”

Section: Resultssupporting

confidence: 93%

“…The tested compounds NBQ-48 and ABQ-48 are novel compounds synthethized and characterized as described in previously published study [ 9 ]. Compounds were prepared in stock solutions of 3mM concentration prepared with sterile, filtered, and deionized water.…”

Section: Methodsmentioning

confidence: 99%

“…Additional reported activity includes formation of dG – BQS adducts with DNA in an hypoxic environment [ 7 ]; this BQS-DNA interaction is similar to what has been reported with ellipticine [ 8 ]. These previous studies with nitro-substituted BQS (NBQ) have shown possible DNA mediated mechanism of action, the amino-substituted compounds however have shown greater toxicity and some activity towards blood cancer as described by the NCI screening panel [ 9 ]. In this study we assess the cell death mechanism of action of these novel compounds including apoptosis related endpoints such as cell cycle arrest, mitochondrial damage, caspases activation, RNS and ROS generation and the activity of main apoptosis related proteins.…”

Section: Introductionmentioning

confidence: 99%

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Toxicity and Apoptosis Related Effects of Benzimidazo [3,2-α] Quinolinium Salts Upon Human Lymphoma Cells

Vélez

Soto

Rios

et al. 2017

TOMCJ

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Objectives:The present study evaluates novel cationic quinoline derivatives known as benzimidazo[3,2-a]quinolinium salts (BQS) named NBQ-48 and ABQ-48 that have structural similarities to known anti-cancer substances such as ellipticine and berberine.Methods:Toledo human lymphoma (ATCC CRL2631) cells were treated for 24 to 48 hours. Apoptosis related endpoints such as cell cycle arrest, mitochondrial damage, RNS and ROS generation and the activity of several apoptosis related proteins such as caspases and apoptosis inducing factor (AIF) were studied using fluorescence staining and western blot respectively.Results:Results indicated a higher toxicity from the amino substituted ABQ-48 versus the NBQ-48 (GI50’s of 50uM versus 100uM respectively). Both compounds induced cell death through various apoptosis related endpoints including a decrease in mitochondrial membrane potential with an increase in ROS and activation of the effector caspase 3. Interestingly, AIF release was observed on cells treated with the amino substituted ABQ-48 but not on the nitro substituted NBQ-48 samples suggesting a caspase independent mechanism for ABQ-48.Conclusions:The results obtained presents the toxic effects of two novel benzimidazo[3,2-a]quinolinium salts in human lymphoma tumor cells. The identified mechanism of action includes multiple apoptosis related effects. Furthermore the data presents a clear variation in caspase dependent or independent mechanism for each compound.

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Section: Resultssupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Toxicity and Apoptosis Related Effects of Benzimidazo [3,2-α] Quinolinium Salts Upon Human Lymphoma Cells

Vélez

Soto

Rios

et al. 2017

TOMCJ

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“…3-amino-7-benzylbenzimidazo [3,2- a] quinolinium chloride (ABQ-48: NSC D-763307) and 3 nitro-7-benzylbenzimidazo [3,2- a ] quinolinium chloride (NBQ-48: NSC D -763303) were prepared as described by Cox et al [10]. …”

Section: Methodsmentioning

confidence: 99%

“…In this study we report the immunomodulatory responses of two unnatural alkaloids 3-amino-7-benzylbenzimidaw[3,2- a ] quinolinium chloride (ABQ-48: NSC D-763307) and 3-nitro-7-benzylbenzimidazo[3,2- a ]quinolinium chloride (NBQ-48: NSC D -763303). The included NSC D number relates to the NCI designation as presented in Cox et al [10]. …”

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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Novel NBQ-48 as marker of hypoxic cells in 2D and 3D colon cancer cells

Zayas

Lebron

Vélez

et al. 2020

JCPCR

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This study presents the applicability of a novel nitro-substituted heterocyclic compound NBQ48, member of the family of compounds identified as 3 nitrobenzazolo[3,2-a] quinolinium chloride salts (NBQS) as a screening tool to identify hypoxic tumor cells. The applicability was tested on COLO 205 colon cancer cells 2D and 3D cultures treated with NBQ48 to assess the formation of a bio-reduction fluorescent metabolite under hypoxic conditions in contrast, to those under aerobic environment. Hypoxic environment was created applying a controlled hypoxic gas chamber. Prior to testing the applicability of NBQ48 as a hypoxic fluorescent marker, cytotoxic studies where performed to identify a low-toxicity dose at 24 hours under aerobic and hypoxic environments that would allow the bio-reduction process with little toxicity. The differences in fluorescence emission after treatment was measured by fluorometer and fluorescence microscopy. Results indicated that cell treatments up to 24 hours with NBQ48 under aerobic environment did not reach an IC50 dose in COLO205 cells, however under hypoxic environment the IC50 reached at 100μM. The significant fluorescence increment after 24 and 48 hrs in 2D and 3D cultures treated with NBQ48 (75uM) at hypoxic in contrast to aerobic environments clearly demonstrated the need of a low oxygen content for the bio-reduction of the parent NBQ48. This study confirms the applicability of NBQ48 as markers for hypoxia in metabolically active 2D and 3D cultures. This hydrophilic hypoxic marker could additionally aid researchers in testing hypoxia activated pro-drugs for therapeutic applications in cancer as well as on other diseases where cellular hypoxia is a significant risk factor.

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Synthesis of and Biological Study of 7-Benzyl-3-aminobenzimidazo[3,2- a]quinolinium Chloride (ABQ-48: NSC D-763307) and 7-benzyl-3- nitrobenzimidazo[3,2-a]quinolinium Chloride (NBQ 48: NSC D-763303)

Cited by 5 publications

References 0 publications

Toxicity and Apoptosis Related Effects of Benzimidazo [3,2-α] Quinolinium Salts Upon Human Lymphoma Cells

Toxicity and Apoptosis Related Effects of Benzimidazo [3,2-α] Quinolinium Salts Upon Human Lymphoma Cells

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)

Novel NBQ-48 as marker of hypoxic cells in 2D and 3D colon cancer cells

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