Quinolinium Chloride Research Articles

Enhancing corrosion inhibition performance of benzyl quinolinium chloride by the use of allicin in lactic acid

The synergistic inhibitive effect of benzyl quinolinium chloride (BQC) with allicin on N80 specimens in 15 % lactic acid environment at 363 K was investigated using weight loss experiments, electrochemical tests, and surface analysis techniques (including scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray Photoelectron Spectroscopy (XPS), and contact angle measurement), quantum chemical calculation as well as molecular dynamics (MD) simulation instruments. In the presence of allicin, the inhibition performance of BQC was significantly improved. The inhibition efficacy (IE) reached 96.49 % at the optimal mass ratio of 5:1(BQC/allicin) with the total inhibitor mass fraction of 0.1 %. Electrochemical testing demonstrated that the composite inhibitor impeded the corrosion process and the composite corrosion inhibitor was belong to hybrid inhibition type. Surface analysis techniques indicated that the composite corrosion inhibitor formed a hydrophobic adsorptive protective film to avoid the erosion of corrosion factors on the metal surface. The mechanism of the synergistic corrosion inhibition effect was further clarified, in terms of electrostatic attraction, intermolecular interactions and adsorption process through molecular dynamics simulation (MD) as well as density functional theory (DFT). The composite corrosion inhibitor composed of BQC and allicin formed a complete and dense adsorption protective film on the metal surface under the combined effect of physical and chemical adsorptions. The combination of BQC and allicin in proper ratio shows promising application potential as an efficient corrosion inhibitor in lactic acid based acidizing fluids.

Study on the corrosion inhibition properties of some quinoline derivatives as acidizing corrosion inhibitors for steel

In this paper, four quinoline quaternary ammonium salts were synthesized using quaternization reaction, which were benzyl quinolion (BQL), naphthylmethyl quinolinium chloride (NQL), benzyl-8-hydroxy quinolinium chloride (BHQ) and naphthylmethyl 8-hydroxy quinolinium chloride (NHQ). The corrosion inhibition properties of the quinoline derivatives as corrosion inhibitors on P110 steel in 20% HCl solution at 60°C at different concentrations were investigated by weight loss and electrochemical measurements. The results showed that as the concentration of corrosion inhibitor increases, the corrosion rate decreased and the inhibition efficiency improved. Among various corrosion inhibitors at the same concentration, their inhibition efficiencies can be ranked from lowest to highest as follows: QL(quinoline)<8-HQ(8-hydroxyquinoline)<BQL<BHQ<NQL<NHQ. The inhibitors synthesized from 1-chloromethyl naphthalene, NQL and NHQ, exhibited excellent inhibition property, in which the inhibition efficiencies reached to 99.8% and 99.9% even with concentration of 0.1%. It also demonstrated the adsorption of all inhibitors on the steel surface followed Langmuir adsorption isotherms, in which QL and 8-QH exhibited as physical adsorption, BQL and BHQ exhibited as mixed adsorption and NQL and NHQ exhibited as chemical adsorption. The inhibition mechanism of inhibitors was also investigated with scanning electron microscopy (SEM), quantum chemical analyses and molecular dynamics simulations, which proved BHQ and NHQ can facilitate an increase in electron cloud density on the benzene ring, thereby enhancing corrosion inhibition performance.

Corrosion Inhibition of Benzyl Quinoline Chloride Derivative-Based Formulation for Acidizing Process

Summary Due to the severe and rapid corrosion of metallic equipment by strong acids at high temperatures, a high concentration of acidizing corrosion inhibitors (ACIs) is required during acidizing processes. There is always a need to develop more effective and environmentally friendly ACIs than current products. In this work, a highly effective ACI obtained from a novel main component and its synergistic effect with paraformaldehyde (PFA) and potassium iodide (KI) is presented. The ACI was prepared from the crude product of benzyl quinolinium chloride derivative (BQD) synthesized from benzyl chloride and quinoline in a simple way. The new ACI formulation, named “synergistic indolizine derivative mixture” (SIDM), which consists of BQD, PFA, and KI, showed superior corrosion inhibition effectiveness (IE) and temperature stability compared with commercially available ACI. More importantly, the SIDM formulation eliminates the need for commonly used highly toxic synergists (e.g., propargyl alcohol and As2O3). In a 20 wt% hydrochloric acid (HCl) solution, the addition of 0.5 wt% SIDM mitigates the corrosion rate of N80 steel down to less than 0.00564 lbm·ft−2 at 194°F, while the corrosion rate at 320 °F is 0.0546 lbm·ft−2·when 4.0 wt% SIDM is added.

A quinoline-based quaternary ammonium salt dimer as corrosion inhibitor for N80 steel in lactic acid solution

In an effort to develop an effective corrosion inhibitor which is applicable to the chelating acidizing fluids in petroleum production, a novel heterocyclic quaternary ammonium salt dimer (TQD) was synthesized through the reaction of quinoline with 4-chloromethylthiazole hydrochloride. An analogue compound, benzyl quinolinium chloride dimer (BQD), was also prepared for comparison. Their anti-corrosion performances in 15% lactic acid solution were investigated through weight-loss experiments, electrochemical tests, surface morphology observation and simulation calculations. The outcomes demonstrate that inhibition efficiency of 99.38% has been achieved with 0.1% TQD at 363 K, which is much higher than that of BQD at the same condition. Both inhibitors were consistent with the Langmuir model, and both were hybrid adsorption, including physical and chemical adsorptions. According to the results of surface analysis (SEM, AFM, XPS, contact angle) and theoretical calculation (DFT and MD), TQD can effectively slow down the metal corrosion in lactic acid and thus is a promising inhibitor for oil and gas well acidizing purpose. The stronger adsorption capacity of TQD may come out of the contribution of thiazole rings in the molecules.

Abstract 5602: Markers of hypoxic cells: Testing a pre-clinical detection assay

Abstract The proposed project aims to test the applicability of a novel set of patented organic compounds as markers of hypoxic circulating tumor cells (H-CTC) with potential pre-clinical relevance. Circulating tumor cells (CTC) are individual cells or clusters that can move from tumors to circulation invading other tissues. Often cells in the tumor need to adapt to low oxygen levels, generating a population of cells known as hypoxic cells that can survive low oxygen levels. These hypoxic cells can produce more cell junction proteins, augmenting connections between cells causing them to break away in clusters rather than individually. Clustered CTCs are much more efficient at metastasis formation. Release of CTC can also be stimulated by cancer treatments such as radiation and chemotherapy. To date, our research has generated in-vitro studies with a set of 3-nitrobenzazolo[3,2- a]quinolinium chloride salts (NBQS) demonstrating its capacity as markers of hypoxic human cancer cells in vitro. Comparison with the control Pimonidazole demonstrated the advantages of novel NBQ-TOM compounds as hypoxic marker. We here, aim to test the applicability of NBQS to identify hypoxic cells among circulating tumor cells (H-CTC). To date limited commercially CTC detection methods are available. Our application can be described as pre-clinical detection technology of hypoxic cancer cells serving also in cancer management. To determine the capacity of novel compound, NBQ-345 TOM as hypoxic fluorescent marker, colon tumor cells (COLO 205) are culture under hypoxic and aerobic environment and treated with NBQ-345TOM (25uM) for 24 hours. After treatment fluorescence is measured with an OPTIMA BMG Fluorimeter. Fluorescence emission results demonstrated significant formation of the NBQ-234 TOM fluorescent metabolite on hypoxic tumor cells in contrast to cells treated under aerobic environment. Also, fluorescence microscopy analysis of colon cancer cells treated for 24 hours with NBQ-345 TOM at hypoxic and aerobic conditions confirmed the stronger fluorescence generation at hypoxic conditions in contrast to cells at aerobic conditions. Citation Format: Beatriz Zayas, Karoline Rios, Luis Ortiz, Osvaldo Cox. Markers of hypoxic cells: Testing a pre-clinical detection assay. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5602.

TELLURO-INDUCED CYCLIZATION OF 2-ALLYLTHIOQUINOLINECARBALDEHYDE

It is known that thiazolopyrimidines with an exocyclic aryl tellurium moiety exhibit antimalarial activity against the deadliest strain of Plasmodium falciparum. For expanding the number of potentially biologically active compounds with an exocyclic aryl tellurium moiety, a study of tellurium-induced heterocyclization of 2-allylthioquinoline-3-carbaldehyde with p-methoxyphenylteltur trichloride was performed. The selection of this synton is motivated by the fact that quinoline derivatives are used as drugs in the treatment of malaria.&#x0D; The starting compound 2-allylthioquinoline-3-carbaldehyde contains several nucleophilic centers for passing tellurium-induced cyclization, namely the multiple bond of the allyl moiety and the endocyclic nitrogen atom of quinoline. Thus cyclization reaction can lead to the formation of both addition and cyclization products. The reaction of the allyl thioether with p-methoxyphenyltelluriumtrichloride was performed in glacial acetic acid and under stirring the reagents at room temperature for 8 hours. It was found that the tellurium-induced cyclization of 2-allylthioquinoline-3-carbaldehyde with p-methoxyphenyltellurium trichloride leads to the formation of angular thiazoloquinoline with an exocyclic aryltellurium fragment ― 1-(dichloro(4-methoxyphenyl)-tellanyl)methyl)-4-formyl-1,2-dihydrothiazolo[3,2-a]quinolin-10-ium chloride. Based on the spectral data, it is proved that the reaction produces a complex of 1-(dichloro(4-methoxyphenyl)-tellanyl)methyl)-4-formyl-1,2-dihydrothiazolo[3,2-a]quinolin-10-ium chloride with p-methoxyphenyltellturium trichloride with composition 1: 1. It should be noted that the formation and composition of this complex does not depend on the ratio of starting reagents.&#x0D; In order to evaluate the biological activity of 1-(dichloro(4-methoxyphenyl)-tellanyl)methyl)-4-formyl-1,2-dihydrothiazolo[3,2-a]quinolin-10-ium chloride, the theoretical bioscreening was performed using online resource Way2Drug. Analysis of the obtained bioactivity data showed the potential antioxidant, antibacterial and antiviral activity of exotellurofunctionalized thiazolo[3,2-a]quinoline-10-ium.&#x0D; Keywords: 2-allylthioquinoline-3-carbaldehyde; p-methoxyphenyltellurium trichloride; electrophilic heterocyclization; annulation, thiazolo[3,2-a]quinolinium chloride.

Dimer Indolizine Derivatives of Quaternary Salt Corrosion Inhibitors: Enlightened High-Effective Choice for Corrosion Prevention of Steel in Acidizing

Summary For decades, increasingly severe downhole conditions call for superior and less-expensive corrosion inhibitors (CIs) for acidizing in petroleum production. Inhibitors that exhibit satisfactory protective ability at relatively low concentration are of great interest to most scholars in this area. In this work, two newly obtained dimer indolizine derivatives that were derived from the conventional quaternary quinolinium salts were introduced as potential highly efficient acidizing CIs. The indolizine derivatives could perform well alone, even without any synergistic component, in concentrated hydrochloric acid (HCl). Two quinoline ammonium salts, ethyl acetate quinolinium chloride (EAQC) and n-butyl quinolinium chloride (BuQC), were synthesized in advance by means of the quaternarization process. Afterward, in the presence of alkali, the ammonium salts could then get converted into the corresponding novel dimer indolizine derivatives easily by means of a 1,3-dipolar cycloaddition reaction in a relatively high yield. The derivatives were purified and their accurate chemical structures were confirmed by elementary analysis, nuclear magnetic resonance (NMR), and mass spectrometry (MS). Dimer derivatives of two quinoline salts were prepared successfully and characterized separately as C26H23N2O4Cl and C26H27N2Cl. Corrosion-inhibition performance of the quaternary quinoline salts as well as the related dimer indolizine derivatives in concentrated HCl for N80 steel was investigated by gravimetric research, electrochemical method, and scanning electron microscopy (SEM) energy dispersive X-ray analysis. The thermodynamic aspect of the inhibition was also discussed. The structure of EAQC and BuQC are very close to the quinolinium salt inhibitors that are commonly used as key components in commercially accessible acid CI products. However, under alkaline condition, EAQC and BuQC would easily be transformed to dimer indolizine derivatives that possess a general “indolizine” structure. That is the reason why the targeted molecules are recognized as “dimer indolizine derivatives.” Both the derivatives have good thermal stability at approximately 248°F and are easily soluble in acid solution. The surprising difference in the anticorrosion effect between the original quinoline salts and their dimer derivatives was proved by weight-loss experiments in 15 wt% HCl at 194 and 248°F with dosage ranges from 0.01 to 0.5 wt%. The derivatives could retard the corrosion of steel considerably at a much lower concentration compared with their precursors. A 0.1-wt% dosage of indolizine derivatives could increase the inhibition efficiency (IE) of N80 steel remarkably, to approximately 99.0% in 15 wt% HCl at 194°F. Results obtained from gravimetric tests and electrochemical methods are in good agreement and confirmed the well-behaved inhibition of the derivatives. We predict that the inhibition will be enhanced apparently when similar quinoline or pyridine ammonium salt are converted via the similar 1,3-dipolar cycloaddition mechanism. We have determined that the use of dimer indolizine derivatives provides a creative new choice for low-cost corrosion prevention, and the protective compounds can be applied as main component of acidizing CIs in the coming years.

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

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.

Effect of composition and microstructure of duplex stainless steel on adsorption behaviour and efficiency of corrosion inhibitors in 4 molar hydrochloric acid. Part I: Standard DSS 2205

We investigate relationships between the elemental composition and microstructure of DSS 2205 materials and their acid corrosion behaviour (4 M HCl) in the absence and presence of inhibitor (naphthylmethyl quinolinium chloride, NMQCl). Without inhibitor, the corrosion rate decreases with increasing Ni and austenite content. The austenite content is mainly controlled by Ni and N contents. In the presence of inhibitor, at concentrations 4–11.1 mM, the corrosion rate decreases with increasing Ni content and inhibition efficiencies are 94.5–99%. When the inhibitor dosage is 20 mM, the corrosion rate becomes independent of Ni content and inhibition efficiencies are ≥99%.

Structure of a novel Benzyl Quinolinium Chloride derivative and its effective corrosion inhibition in 15 wt.% hydrochloric acid

A novel quaternary ammonium (BQD) with good inhibitive performance is separated from the synthesis of N-Benzylquinolinium Chloride (BQC). The formula of BQD was C32H23N2Cl and its structure is characterized by NMR, LC-HRMS, FT-IR. The formation mechanism of BQD is proposed. The corrosive inhibition of BQD is investigated in 15% HCl. The corrosion rate is 1.98gm−2h−1 when the concentration of BQD is 0.744mmolL−1. The adsorption of BQD on the steel obeyed Langmuir adsorption isotherm. The standard free energy of adsorption of BQD is −54.48kJmol−1, indicating a strong chemisorption of BQD onto the steel.

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).

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.

Anti-tumour and pharmacokinetics study of 2-Formyl-8-hydroxy-quinolinium chloride as Galipea longiflora alkaloid analogue

The quinolinium chloride salt of 8-hydroxyqinolinecarbaldehyde (2-Formyl-8-hydroxy-quinolinium chloride) was prepared as Galipea longiflora alkaloid analogue and its anticancer activity was evaluated both in vitro and in vivo. This chloride salt was found to show certain degree of selectivity between hepatoma cells and normal hepatocytes in vitro. Athymic nude mice Hep3B xenograft model further demonstrated that this 2-Formyl-8-hydroxy-quinolinium chloride could execute strong anti-tumour activity with the identification of extensive necrotic feature from the tumour xenograft and limited adverse toxicological effect.

Antimycobacterial and Photosynthetic Electron Transport Inhibiting Activity of Ring-Substituted 4-Arylamino-7-Chloroquinolinium Chlorides

In this study, a series of twenty-five ring-substituted 4-arylamino-7-chloroquinolinium chlorides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts and also primary in vitro screening of the synthesized compounds was performed against mycobacterial species. 4-[(2-Bromophenyl)amino]-7-chloroquinolinium chloride showed high biological activity against M. marinum, M. kansasii, M. smegmatis and 7-chloro-4-[(2-methylphenyl)amino]quinolinium chloride demonstrated noteworthy biological activity against M. smegmatis and M. avium subsp. paratuberculosis. The most effective compounds demonstrated quite low toxicity (LD50 > 20 μmol/L) against the human monocytic leukemia THP-1 cell line within preliminary in vitro cytotoxicity screening. The tested compounds were found to inhibit PET in photosystem II. The PET-inhibiting activity expressed by IC50 value of the most active compound 7-chloro-4-[(3-trifluoromethylphenyl)amino]quinolinium chloride was 27 μmol/L and PET-inhibiting activity of ortho-substituted compounds was significantly lower than this of meta- and para-substituted ones. The structure-activity relationships are discussed for all compounds.

Synthesis of Benzo[f]indolo[2, 3-a]quinoliziniums as Inhibitors for Protein Kinase CKII

The synthesis of the 14-amino-6, 7-dihydro-12H-benzo[f]indolo[2, 3-a] quinolizinium chloride (2a) and substituted derivatives is described. The compounds were evaluated as inhibitors of protein kinase CKII and structure-activity relationships were studied. The most potent compound was 14-amino-6, 7-dihydro-12H-4-chlorobenzo[f]indolo-[2, 3-a]quinolizinium chloride (2e) with an IC50 of 0.0064 mM.

Azinyl sulfides — CXVIII. Antimicrobial activity of novel 1-methyl-3-thio-4-aminoquinolinium salts

Synthesis and antimicrobial activity of novel 1-methyl-3-alkylthio-4-aminoquinolinium salts 2 and 1-methyl-3-acylthio-4-aminoquinolinium salts 4 are described. Compounds 2 were obtained by reacting 1-methyl-3,4-(dimethylthio)quinolinium chloride 1 with amines and by reacting 1-methyl-4-aminoquinolinium-3-thiolates 3 with alkylating agents. Compounds 4 were obtained by the reaction of 1-methyl-4-aminoquinolinium-3-thiolates 3 with acylating agents. Antimicrobial activity of compounds 2 and 4 was determined using G+ (Staphylococcus aureus, Enterococcus faecalis) and G(-) (Escherichia coli, Pseudomonas aeruginosa) strains as well as Candida albicans yeast. The compounds show greatest activity against S. aureus whereas the lowest against P. aeruginosa.

Regioselective photocyclization of (e)‐2‐(2,3,6‐trichlorostyryl)‐benzothiazole and synthesis of 3,4‐dichloro‐ and 4‐chlorobenzothiazolo[3,2‐α]quinolinium chlorides: A synthetic and theoretical study

Abstractmagnified imageA high degree of regioselectivity is observed in the photochemically induced cyclization of (E)‐2‐(2,3,6‐trichlorostyryl)benzothiazole (1a). According to the proposed mechanism, this compound was expected to afford two products, 3,4‐dichloro‐ and 1,4‐dichlorobenzothiazolo[3,2‐α]quinolinium chlorides (4a and 4a', respectively). However, this reaction produced 3,4‐dichlorobenzazolo[3,2‐α]quinolinium chloride (4a) as the sole product. On the other hand, irradiation of (E)‐2‐(2,3,5‐trichlorostyryl)benzothiazole (1b) failed to produce the expected 1,3‐dichlorobenzothiazolo[3,2‐α]quinolinium chloride (4b). Furthermore, (E)‐2,3‐difluorostrylbenzothiazole (1c) also failed to give the corresponding 1‐fluorobenzothiazolo[3,2‐α]quinolinium fluoride (4c). Interestingly, the irradiation of 2,6‐dichlorostyrylbenzothialole (1d) produced 4‐chlorobenzothiazolo[3,2‐α]quinolinium chloride (4d) in excellent yield. This paper presents the results of these investigations and a mechanistic rationale for the outcome of this reaction based on steric arguments and theoretical studies using a combination of molecular mechanics (MM+) and semiempirical quantum mechanical calculations (PM3/RHF/CI). Two‐dimensional high field nmr methods were employed to make complete assignments of the proton and carbon spectra of all new compounds.

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

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 N2-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 N2-saturated conditions. Clonogenic assays were performed to determine the quinolinium chloride cytotoxicities under both aerobic (95% air and 5% CO2) and hypoxic (80% N2 and 20% CO2) 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 microM) and NBQ-91 (CTR = 0.4 at 200 microM) than for BQ-106 (CTR = 1.0 at 200 microM), 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 N2-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 chromatography. 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 N2-saturated over aerobic conditions for DNA binding makes NBQ-91 a potential bioreductive compound for hypoxic cell killing.

1-Alkyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium Salts — Synthesis and Transformations

- The reaction of l-alkyl-4-(phenylamino)quinolinium 3-thiolates (2) with benzoyl chloride leads to 1 -alkyl-3-benzoylthio-4-(phenylamino)quinolinium chloride (6). In the presence of DABCO, compounds (6) split off hydrogen chloride yielding l-alkyl-3-benzoylthio-l,4-dihydro-4-(phenylimino)quinoline (7). Alkylation of 4-(phenylimino)quinoline (7) with ethyl bromide leads to 1-alkyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide (10). The structure of the obtained compounds were analyzed using H NMR (NOE) and 15 N NMR spectral methods. The structure of compound (lOa) was confirmed by X-ray analysis.

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

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.

Quantum chemical study of the reaction mechanism of the methylmercury cation with 2-mercapto-2-methyltetrahydro-1,4-thiazino[2,3,3,4-i,j]quinolinium chloride in aqueous media

The detoxication properties of 2-mercapto-2-methyltetrahydro-1,4-thiazino[2,3,3,4-i,j]quinolinium chloride (II) with respect to the methylmercury cation (I) in the presence of six water molecules have been studied using the density functional theory (DFT) method. Interaction between I and II leads to generation of the hydroxonium cation, which catalyzes the demethylation process. The elementary stages of two reaction routes have been localized, and their thermodynamic and kinetic characteristics have been determined.