Synthesis, Antiprotozoal and Anticancer Activity of Substituted 2‐Trifluoromethyl‐ and 2‐Pentafluoroethylbenzimidazoles.

Andrzejewska, Mariola; Yépez‐Mulia, Lilián; Cedillo‐Rivera, Roberto; Tapia, Amparo; Vilpo, Leena; Vilpo, Juhani; Kazimierczuk, Zygmunt

doi:10.1002/chin.200320136

Cited by 32 publications

(37 citation statements)

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“…This property allows for interaction with a variety of biomolecules, resulting in the diverse range of ascribed mechanisms of action, including reduction of fumarate, glucose uptake, and microtubule inhibition (30,31). Consistent with this notion, numerous biological functions have been described for this class of compounds, including antihelminthic, antifungal, antimicrobial, antiviral, and antineoplastic activity (32)(33)(34). Given the variety of these activities, previous studies have suggested that inhibition of cellular proliferation by mebendazole may involve effects in addition to its microtubule disruption properties.…”

Section: Discussionmentioning

confidence: 85%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

128

114

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Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 Mmol/L using two chemoresistant melanoma cell lines ) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC 50 of 0.32 Mmol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent. (Mol Cancer Res 2008;6(8):1308 -15)

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Section: Discussionmentioning

confidence: 85%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

128

114

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“…Benzimidazoles containing carbamate-residue in position 2 and an H-atom in position 1, bind to tubulin and thereby inhibit its polymerization. A strong activity of halogenobenzimidazoles against Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica (all of them have a tubulin cytoskeleton) was revealed in the earlier studies (Andrzejewska et al 2002.…”

Section: Discussionmentioning

confidence: 86%

Anti-Pentatrichomonas hominis activity of newly synthesized benzimidazole derivatives — in vitro studies

Chomicz¹,

Padzik²,

Laudy³

et al. 2009

Acta Parasitologica

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Pentatrichomonas hominis, a parasitic protozoan often detected in human diarrheic stools, is the cause of severe morbidity in newborns and children, particularly in tropical zones. The flagellate is resistant to many disinfectants and anti-protozoan drugs. Therefore in this study we have synthesized three novel 4,5,6,7-tetrabromobenzimidazole (TBBI) derivatives carrying a polyfluoroalkyl substituent in position 2 of the benzimidazole scaffold, namely 2-trifluoromethyl-TBBI (CF 3 -TBBI), 2-nonafluorobutyl-TBBI (C 4 F 9 -TBBI), and 2-nonadecafluorononyl-TBBI (C 9 F 19 -TBBI), that next we tested for their in vitro activity against P. hominis. Widely applied anti-protozoal drug, metronidazole as a reference was used. All the investigated agents were added to 24 h P. hominis cultures; each of them was administered at three different concentrations. Number of the moving trichomonads was determined and compared with the control cultures. Different anti-trichomonal activity occurred depending on a kind of compound and its concentration. C 4 F 9 -TBBI was the most effective TBBI derivative tested: the agent, at the highest concentration 24.2 µg/ml, after 72 h reduced the number of viable trichomonads to 44.3%; C 9 F 19 -TBBI, at the concentration 24 µg/ml reduced the number of the flagellates to 58.5%. Paradoxically, metronidazole after the same time given at the highest concentration increased trophozoite counts by 464.6% in comparison with the control cultures (100%).

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“…3 Recently, potent anticancer, antibacterial, antifungal and antiprotozoal activities were reported for halogenated 2-trifluoromethyl-and 2-pentafluoroethyl-benzimidazoles. [4][5][6] Not only the substituted benzimidazole heterocycles themselves but also a series of modified benzimidazole nucleosides are biologically active. [7][8][9] Originally, their synthesis was encouraged by the discovery that 5,6-dimethyl-1-(α-D-erythro-pentofuranosyl)-benzimidazole is a constituent of vitamin B12.…”

Section: Introductionmentioning

confidence: 99%

“…5,6,25,26 The introduction of side chains into position-2 of halogenated or non-halogenated benzimidazoles can be achieved by different routes. 5,6,[25][26][27] One route uses non-halogenated or halogenated o-phenylenediamines as precursor which give after condensation with carboxylic acids and their derivatives (nitriles, imidates, orthoesters) the 2-substituted benzimidazoles (Scheme 1). In this manuscript compounds of Figure 4 were prepared employing this protocol.…”

Section: Introductionmentioning

confidence: 99%

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Substituted benzimidazoles: antiviral activity and synthesis of nucleosides

Budow¹,

Kozłowska²,

Górska³

et al. 2008

Arkivoc

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The antiviral activity of a series of benzimidazole derivatives and substituted benzimidazole β-Land β-D-2'-deoxyribonucleosides against selected RNA and DNA viruses including HIV-1, BVDV, YFV, DENV-2, WNV, HBV, HCV and human RSV was evaluated. In addition, the synthesis of several benzimidazole β-L-2'-deoxyribonucleosides (1-4) and 2'-deoxy-2'-fluoro-β-D-arabinofuranosyl nucleoside 5 is described. The stereoselective glycosylation of the anions of the functionalized benzimidazoles 6a, 12a and 28 with 3,5-di-O-(4-methylbenzoyl)-2-deoxy-α-L-erythro-pentofuranosyl chloride (29) furnished β-L-2'-deoxyribonucleosides 1-4 while the glycosylation of the anion of 2-bromobenzimidazole (12a) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide 34 gave the 2'-deoxy-2-fluoro-β-D-arabinofuranosyl nucleoside 5. Moreover, the crystal structure of the benzoylated 2-bromobenzimidazole 2'-deoxy-2'-fluoro-β-D-arabinofuranosyl nucleoside 35 is reported.

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Synthesis, Antiprotozoal and Anticancer Activity of Substituted 2‐Trifluoromethyl‐ and 2‐Pentafluoroethylbenzimidazoles.

Cited by 32 publications

References 1 publication

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Anti-Pentatrichomonas hominis activity of newly synthesized benzimidazole derivatives — in vitro studies

Substituted benzimidazoles: antiviral activity and synthesis of nucleosides

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