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Evaluation of the biological activity of novel monocationic fluoroaryl-2,2'-bichalcophenes and their analogues.

Hussin WA, Ismail MA, Alzahrani AM, El-Sayed WM - Drug Des Devel Ther (2014)

Bottom Line: The fluoroaryl derivatives significantly reduced the NaN3-induced and B[a]P-induced mutagenicity under pre-exposure and co-exposure conditions.Monocationic fluoroarylbichalcophenes were superior to the corresponding mononitriles in reducing B[a]P-induced mutagenicity.Some of these compounds could be selected for further anticancer studies.

View Article: PubMed Central - PubMed

Affiliation: King Faisal University, College of Science, Departments of Chemistry and Biological Sciences, Hofuf, Saudi Arabia ; Al-Azhr University, Faculty of Science, Department of Botany and Microbiology, Cairo, Egypt.

ABSTRACT
A series of bichalcophene fluorobenzamidines 5a-e was synthesized from the corresponding mononitriles 4a-e via a direct reaction with lithium bis(trimethylsilyl)amide LiN(TMS)2 followed by de-protection with ethanolic HCl (gas). Bichalcophene fluorobenzonitriles 4a-e were prepared adopting a Stille coupling reaction between the bromo compounds 3a-c and 2-(tri-n-butylstannyl)furan or analogues. As an approach to drug discovery, the structure-antimutagenicity relationship of novel fluoroarylbichalcophenes was examined using the Ames Salmonella/microsomal assay. At nontoxic concentrations (10 and 20 μM), all derivatives alone or in combination with sodium azide (NaN3; 2 μg/plate) or benzo[a]pyrene (B[a]P; 20 μM) in the presence of S9 mix were not mutagenic. The fluoroaryl derivatives significantly reduced the NaN3-induced and B[a]P-induced mutagenicity under pre-exposure and co-exposure conditions. The recorded antimutagenic activity of fluoroaryl derivatives varied depending on the kind of mutagen and the exposure regimen. Monocationic fluoroarylbichalcophenes were superior to the corresponding mononitriles in reducing B[a]P-induced mutagenicity. Nevertheless, mononitriles were more active against NaN3, especially at low concentrations and under pre-exposure treatments. The antimutagenic activity was congruent with a high antioxidant activity that could promote the DNA repair system. The fluorine substitution changed the antimutagenic signature of bichalcophenes. Some of these compounds could be selected for further anticancer studies.

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Total antioxidant activity of fluoroaryl-2,2′-bichalcophene derivatives at 25 μM expressed as the percentage of equivalent ascorbate activity at the same concentration.Notes: 4a–4e are the mononitrile derivatives and 5a–5e are the corresponding monocationic derivatives. Assays were performed in triplicate.
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f3-dddt-8-963: Total antioxidant activity of fluoroaryl-2,2′-bichalcophene derivatives at 25 μM expressed as the percentage of equivalent ascorbate activity at the same concentration.Notes: 4a–4e are the mononitrile derivatives and 5a–5e are the corresponding monocationic derivatives. Assays were performed in triplicate.

Mentions: Mutation frequency is highly correlated to mutation rate. All fluoroarylbichalcophenes reduced the mutant frequency caused by NaN3 by 8%–87% (Table 5). Most of the monocationic compounds were more effective than the mononitrile compounds in reducing the mutant frequency under co-exposure conditions. With regard to the reduction of mutant frequency with B[a]P, the investigated compounds were not as effective as they were against NaN3 and caused a reduction between 6% and 69% in the recorded mutant frequency (Table 6). The recorded antimutagenic activity of the investigated compounds could be attributed to various mechanisms. These compounds could interfere with the azide absorption into the bacteria by modifying the cell membrane or they could prevent the azide binding to DNA. Another mechanism is the direct binding and protection of DNA from the electrophilic mutagen or its metabolites,23 given that the fluoroaryl derivatives are nucleophilic. One of the possible mechanisms is the inhibition of CYP4501A activity that metabolically activates B[a]P, based on the inhibition of enzymatic oxidation at the site of F-substitution due to its electron-withdrawing nature.13,24 Another possible mechanism could be the elevation in the antioxidant milieu of the cells, thus promoting the DNA repair system.25 Testing the total antioxidant activity of fluoroaryl compounds showed that compounds 5a–e were in the lead, with antioxidant activity of ∼46%–73% of that of ascorbic acid at the same concentration (Figure 3). The promising antioxidant activity could provide a protective effect of fluoroaryl derivatives against oxidative DNA damage.26 In summary, novel fluoroarylbichalcophenes in the current study provided a significant antigenotoxic activity against the DNA-intercalation caused by NaN3 and prevented the adduct formation for B[a]P metabolites probably through inhibiting the microsomal-dependent activation of the mutagen.


Evaluation of the biological activity of novel monocationic fluoroaryl-2,2'-bichalcophenes and their analogues.

Hussin WA, Ismail MA, Alzahrani AM, El-Sayed WM - Drug Des Devel Ther (2014)

Total antioxidant activity of fluoroaryl-2,2′-bichalcophene derivatives at 25 μM expressed as the percentage of equivalent ascorbate activity at the same concentration.Notes: 4a–4e are the mononitrile derivatives and 5a–5e are the corresponding monocationic derivatives. Assays were performed in triplicate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109633&req=5

f3-dddt-8-963: Total antioxidant activity of fluoroaryl-2,2′-bichalcophene derivatives at 25 μM expressed as the percentage of equivalent ascorbate activity at the same concentration.Notes: 4a–4e are the mononitrile derivatives and 5a–5e are the corresponding monocationic derivatives. Assays were performed in triplicate.
Mentions: Mutation frequency is highly correlated to mutation rate. All fluoroarylbichalcophenes reduced the mutant frequency caused by NaN3 by 8%–87% (Table 5). Most of the monocationic compounds were more effective than the mononitrile compounds in reducing the mutant frequency under co-exposure conditions. With regard to the reduction of mutant frequency with B[a]P, the investigated compounds were not as effective as they were against NaN3 and caused a reduction between 6% and 69% in the recorded mutant frequency (Table 6). The recorded antimutagenic activity of the investigated compounds could be attributed to various mechanisms. These compounds could interfere with the azide absorption into the bacteria by modifying the cell membrane or they could prevent the azide binding to DNA. Another mechanism is the direct binding and protection of DNA from the electrophilic mutagen or its metabolites,23 given that the fluoroaryl derivatives are nucleophilic. One of the possible mechanisms is the inhibition of CYP4501A activity that metabolically activates B[a]P, based on the inhibition of enzymatic oxidation at the site of F-substitution due to its electron-withdrawing nature.13,24 Another possible mechanism could be the elevation in the antioxidant milieu of the cells, thus promoting the DNA repair system.25 Testing the total antioxidant activity of fluoroaryl compounds showed that compounds 5a–e were in the lead, with antioxidant activity of ∼46%–73% of that of ascorbic acid at the same concentration (Figure 3). The promising antioxidant activity could provide a protective effect of fluoroaryl derivatives against oxidative DNA damage.26 In summary, novel fluoroarylbichalcophenes in the current study provided a significant antigenotoxic activity against the DNA-intercalation caused by NaN3 and prevented the adduct formation for B[a]P metabolites probably through inhibiting the microsomal-dependent activation of the mutagen.

Bottom Line: The fluoroaryl derivatives significantly reduced the NaN3-induced and B[a]P-induced mutagenicity under pre-exposure and co-exposure conditions.Monocationic fluoroarylbichalcophenes were superior to the corresponding mononitriles in reducing B[a]P-induced mutagenicity.Some of these compounds could be selected for further anticancer studies.

View Article: PubMed Central - PubMed

Affiliation: King Faisal University, College of Science, Departments of Chemistry and Biological Sciences, Hofuf, Saudi Arabia ; Al-Azhr University, Faculty of Science, Department of Botany and Microbiology, Cairo, Egypt.

ABSTRACT
A series of bichalcophene fluorobenzamidines 5a-e was synthesized from the corresponding mononitriles 4a-e via a direct reaction with lithium bis(trimethylsilyl)amide LiN(TMS)2 followed by de-protection with ethanolic HCl (gas). Bichalcophene fluorobenzonitriles 4a-e were prepared adopting a Stille coupling reaction between the bromo compounds 3a-c and 2-(tri-n-butylstannyl)furan or analogues. As an approach to drug discovery, the structure-antimutagenicity relationship of novel fluoroarylbichalcophenes was examined using the Ames Salmonella/microsomal assay. At nontoxic concentrations (10 and 20 μM), all derivatives alone or in combination with sodium azide (NaN3; 2 μg/plate) or benzo[a]pyrene (B[a]P; 20 μM) in the presence of S9 mix were not mutagenic. The fluoroaryl derivatives significantly reduced the NaN3-induced and B[a]P-induced mutagenicity under pre-exposure and co-exposure conditions. The recorded antimutagenic activity of fluoroaryl derivatives varied depending on the kind of mutagen and the exposure regimen. Monocationic fluoroarylbichalcophenes were superior to the corresponding mononitriles in reducing B[a]P-induced mutagenicity. Nevertheless, mononitriles were more active against NaN3, especially at low concentrations and under pre-exposure treatments. The antimutagenic activity was congruent with a high antioxidant activity that could promote the DNA repair system. The fluorine substitution changed the antimutagenic signature of bichalcophenes. Some of these compounds could be selected for further anticancer studies.

Show MeSH
Related in: MedlinePlus