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Synthesis and anti-breast cancer activity of novel indibulin related diarylpyrrole derivatives

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Abstract

Background

During recent years, a number of anti-tubulin agents were introduced for treatment of diverse types of cancer. Despite their potential in the treatment of cancer, drug resistance and adverse toxicity, such as peripheral neuropathy, are some of the negative effects of anti-tubulin agents. Among anti-tubulin agents, indibulin was found to cause minimal peripheral neuropathy. Thus far, however, indibulin has not entered clinical usage, caused in part by its poor aqueous solubility and other developmental problems in preclinical evaluation.

Objectives

With respect to need for finding potent and safe anticancer agents, in our current research work, we synthesized several indibulin-related diarylpyrrole derivatives and investigated their anti-cancer activity.

Methods

Cell cultur studies were perfomred using the MTT cell viability assay on the breast cancer cell lines MCF-7, T47-D, and MDA-MB231 and also NIH-3 T3 cells as representative of a normal cell line. The activity of some of the synthesized compounds for tubulin interaction was studied using colchicine binding and tubulin polymerization assays. The annexin V-FITC/PI method and flow cytometric analysis were used for studying apoptosis induction and cell cycle distribution.

Results and conclusion

Two of the synthesized compounds, 4f and 4 g, showed high activity on the MDA-MB231 cell line (IC50 = 11.82 and 13.33 μM, (respectively) and low toxicity on the normal fibroblast cells (IC50 > 100 μM). All of the tested compounds were more potent on T47-D cancer cells and less toxic on NIH-3 T3 normal cells in comparison to reference compound, indibulin. The tubulin polymerization inhibition assay and [3H]colchicine binding assay showed that the main mechanism of cell death by the potent synthesized compounds was not related to an interaction with tubulin. In the annexin V/PI staining assay, the induction of apoptosis in the MCF-7 and MDA-MB231 cell lines was observed. Cell cycle analysis illustrated an increased percentage of sub-G-1 cells in the MDA-MB231 cell line as a further indication of cell death through induction of apoptosis.

Novel Indibulin analogous as anti-breast cancer agents

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Acknowledgements

This work was financially supported by Research Council of Tehran University of Medical Sciences.

The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran

    Ebrahim Saeedian Moghadam & Mohsen Amini

  2. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA

    Ernest Hamel

  3. Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Zahra Shahsavari

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  1. Ebrahim Saeedian Moghadam
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  2. Ernest Hamel
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Correspondence to Mohsen Amini.

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Saeedian Moghadam, E., Hamel, E., Shahsavari, Z. et al. Synthesis and anti-breast cancer activity of novel indibulin related diarylpyrrole derivatives. DARU J Pharm Sci 27, 179–189 (2019). https://doi.org/10.1007/s40199-019-00260-9

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