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

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.

Keywords: 2′-bichalcophenes; Salmonella typhimurium; antimutagenicity; benzo[a]pyrene; fluoroaryl-2; sodium azide; stille coupling.

Figure 1

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.

Figure 2

Synthesis of novel monocationic fluoroaryl-2,2′-bichalcophene derivatives.

Figure 3

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.