Synthesis and biological activity of novel inhibitors of topoisomerase I: 2-Aryl-substituted 2-bis-1H-benzimidazoles

Singh, Manish Kumar; Tandon, Vibha

doi:10.1016/j.ejmech.2010.11.046

Cited by 74 publications

(36 citation statements)

References 35 publications

(20 reference statements)

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“…DMA was observed to be nonmutagenic and noncytotoxic to mammalian cells in comparison with the parent analog (Tawar et al, 2003(Tawar et al, , 2007. It showed inhibitory action at micromolar concentrations in a human epithelial cancer cell line (HeLa), a human breast cancer cell line (MCF7), a human glioma cell line (U87), and a human embryonic kidney cell line (HEK293) (Singh and Tandon, 2011). A half-maximal inhibitory concentration (IC 50 ) of DMA in primary human dermal fibroblasts and near-normal mammary epithelial cells (MCF 10A) was not achieved up to 72 hours, suggesting that it is less cytotoxic to normal cells in comparison with cancerous cells and can be developed as a safe therapeutic agent (Ranjan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

et al. 2015

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Radiotherapy, a therapeutic modality of cancer treatment, nonselectively damages normal tissues as well as tumor tissues. The search is ongoing for therapeutic agents that selectively reduce radiation-induced normal tissue injury without reducing tumoricidal effect, thereby increasing the therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2ʹ-(3,4-dimethoxyphenyl)-59benzimidazolyl] benzimidazole (DMA) as noncytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose-reduction factor of 1.28. An oxygen radical absorbing capacity assay confirmed its freeradical quenching ability. Single bolus dose and 28-days of repeated administration of DMA in mice for toxicity studies determined an LD 50 of .2000 mg/kg body weight (bw) and 225 mg/kg bw, respectively, suggesting DMA is safe. Histopathology, biochemical parameters, and relative organ weight analysis revealed insignificant changes in the DMA-treated animals. The pharmacokinetic study of DMA at oral and intravenous doses showed its C max 5 1 hour, bioavailability of 8.84%, elimination half-life of 4 hours, and an enterohepatic recirculation. Biodistribution study in mice with Ehrlich ascites tumors showed that 99m Tc-DMA achieved its highest concentration in 1 hour and was retained up to 4 hours in the lungs, liver, kidneys, and spleen, and in a low concentration in the tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that the single-dose treatment of tumor-bearing mice with DMA 2 hours before 8 Gy total body irradiation showed an impressive rescue of radiation-induced morbidity in terms of weight loss and mortality without a change in tumor response.

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Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

et al. 2015

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“…It is a cell membrane permeant, small groove binding, A-T base pair selective, double stranded DNA-selective binding and livecell dye (Jegham et al, 2012). Hoechst 33342 presented absorption maxima at 340 nm region (Singh & Tandon, 2011), and an emission wavelength of 460 nm (Shi et al, 2012b).…”

Section: Morphological Observation Of the Hacat Cell Nucleus After Exmentioning

confidence: 99%

Alpha-lipoic acid-loaded nanostructured lipid carrier: sustained release and biocompatibility to HaCaT cellsin vitro

Wang

Xia²

2013

Drug Delivery

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ALA-loaded nanostructured lipid carrier (ALA-NLC) was designed to improve physicochemical stability and water solubility, and promote sustained release of ALA as well as determine the biocompatibility of ALA-NLC. The ALA-NLC manufactured using hot high-pressure homogenization technique was investigated in terms of size, zeta potential, FTIR analysis and release behavior. In vitro cytotoxicity and biocompatibility were determined by incubating with HaCaT cells using the MTT assay, HE staining and Hoechst 33342 staining. Cell behavior and cellular division of HaCaT cells untreated and treated by ALA-NLC were investigated in real-time images gathered using time-lapse imaging system. The release investigation illustrated that only 6.9% of ALA released in 30 min from ALA-NLC formation, whereas it was 30.3% in free ALA system. ALA-NLC possessed a satisfactory release behavior of sustained release up to 72 h. It showed that ALA-NLC did not exert hazardous effect on HaCaT cells up to 81.9 mg/L without morphological alterations, revealing a satisfactory biocompatibility. Evidence was provided from time-lapse imaging system that cell behavior and cellular division of ALA-NLC treated HaCaT cells were in accordance with the control. These results of this investigation demonstrated that NLC encapsulated ALA formation (ALA-NLC) can improve stability, solubility and release of ALA; ALA-NLC was biocompatible to HaCaT cells.

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“…Also, the mean graph midpoint GI 50 value (arithmetical mean value of treated cancer cell lines) of the most potent compound 4f was observed to be only 2.09 lM, which is much lower than the reference anticancer agents (60 and 52 lM, respectively) suggesting that the benzimidazole endowed 1,3,4 oxadiazole compound holds promise as a potential anticancer agent. It has been reported in the literature that benzimidazole derivatives act by inhibiting DNA topoisomerase complex (Selcen et al, 2009;Singh and Tandon, 2011) and their binding mode to DNA varies from intercalation to groove binding based on the number of benzimidazole rings (Kubota et al, 1999). Therefore, there is a high probability that antiproliferative effects of compound 4f, a benzimidazole derivative which is attached to pyrimidine and 1,3,4 oxadiazole rings could be due to DNA intercalation.…”

Section: In Vitro Anticancer Screeningmentioning

confidence: 96%

Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents

Rashid

Husain

Mishra

et al. 2019

Arabian Journal of Chemistry

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Based on the heterocyclic core of bendamustine, four series (4a-g, 5a-f, 8a-b and 9a-b) of benzimidazole derivatives were designed and synthesized starting from 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide. In the rational design of target molecules, the benzimidazole ring of bendamustine was retained and the bis-(chloroethyl) amine group (mechlorethamine) was substituted with several biologically active scaffolds such as oxadiazole, thiadiazole, and triazolothiadiazines, in the hope of obtaining novel cytotoxic agents with improved efficacy and safety. Cytotoxic activities of the designed analogues were carried out at the National Cancer Institute (NCI), USA, against full NCI 60 human cell lines. Among all the tested compounds, 4f

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Synthesis and biological activity of novel inhibitors of topoisomerase I: 2-Aryl-substituted 2-bis-1H-benzimidazoles

Cited by 74 publications

References 35 publications

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

Alpha-lipoic acid-loaded nanostructured lipid carrier: sustained release and biocompatibility to HaCaT cellsin vitro

Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents

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