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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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Structure of some biologically important cationic bichalcophene compounds.Notes: Compound I is 5′-(4-amidinophenyl)-2,2′-bifuran-5-carboxamidine. Compound II is 4-(2,2′-bifuran-5-yl)benzamidine.
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f1-dddt-8-963: Structure of some biologically important cationic bichalcophene compounds.Notes: Compound I is 5′-(4-amidinophenyl)-2,2′-bifuran-5-carboxamidine. Compound II is 4-(2,2′-bifuran-5-yl)benzamidine.

Mentions: New anticancer compounds without undesirable side effects are urgently needed. Aromatic diamidines, such as pentamidine, are used extensively against several human ailments.1,2 However, some pentamidine derivatives have been withdrawn from further human trials due to associated renal and hepatic toxicities.3 A series of furamidine derivatives was synthesized by replacing the phenyl group(s) with pyridyl group(s). Several of these aza-analogues were more active than the furamidine itself.4,5 Recently, bifuran diamidine I (Figure 1) has been shown to recognize G-quadruplex DNA.6 More recently, monocationic bifuran II was proven to be more effective against methicillin-resistant Staphylococcus aureus infection in mice than was vancomycin.7 Promising antimutagenic activity against sodium azide (NaN3) and benzo[a]pyrene (B[a]P)-induced mutagenicity was shown for many of these bichalcophenes.8 Although thiophene and furan rings are known for their broad biological activities,9 we have shown that replacing the furan ring with a thiophene ring increased the activity.10 To improve the pharmacological properties, and as an approach to drug discovery of the previously investigated compounds, we synthesized a series of fluoroarylbichalcophenes. Fluorine substitution can alter the biological and chemical properties of compounds, and this led to the development of a vast number of novel fluorinated drugs. The high electronegativity of fluorine substituent can modify the electron distribution in a molecule, which affects its absorption, distribution, and metabolism.11 The presence of a fluorine atom usually increases lipophilicity and hence biological availability.12 Through microsomal inhibition, fluorine substitution was shown to abolish quinolone mutagenicity.13


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)

Structure of some biologically important cationic bichalcophene compounds.Notes: Compound I is 5′-(4-amidinophenyl)-2,2′-bifuran-5-carboxamidine. Compound II is 4-(2,2′-bifuran-5-yl)benzamidine.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-8-963: Structure of some biologically important cationic bichalcophene compounds.Notes: Compound I is 5′-(4-amidinophenyl)-2,2′-bifuran-5-carboxamidine. Compound II is 4-(2,2′-bifuran-5-yl)benzamidine.
Mentions: New anticancer compounds without undesirable side effects are urgently needed. Aromatic diamidines, such as pentamidine, are used extensively against several human ailments.1,2 However, some pentamidine derivatives have been withdrawn from further human trials due to associated renal and hepatic toxicities.3 A series of furamidine derivatives was synthesized by replacing the phenyl group(s) with pyridyl group(s). Several of these aza-analogues were more active than the furamidine itself.4,5 Recently, bifuran diamidine I (Figure 1) has been shown to recognize G-quadruplex DNA.6 More recently, monocationic bifuran II was proven to be more effective against methicillin-resistant Staphylococcus aureus infection in mice than was vancomycin.7 Promising antimutagenic activity against sodium azide (NaN3) and benzo[a]pyrene (B[a]P)-induced mutagenicity was shown for many of these bichalcophenes.8 Although thiophene and furan rings are known for their broad biological activities,9 we have shown that replacing the furan ring with a thiophene ring increased the activity.10 To improve the pharmacological properties, and as an approach to drug discovery of the previously investigated compounds, we synthesized a series of fluoroarylbichalcophenes. Fluorine substitution can alter the biological and chemical properties of compounds, and this led to the development of a vast number of novel fluorinated drugs. The high electronegativity of fluorine substituent can modify the electron distribution in a molecule, which affects its absorption, distribution, and metabolism.11 The presence of a fluorine atom usually increases lipophilicity and hence biological availability.12 Through microsomal inhibition, fluorine substitution was shown to abolish quinolone mutagenicity.13

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