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Design, Synthesis and in vitro Anti-Cancer evaluation of Novel Derivatives of 2-(2-Methyl-1,5-diaryl-1H-pyrrol-3-yl)-2-oxo-N-(pyridin-3-yl)acetamide

Author(s):

Ebrahim Saeedian Moghadam, Farhad Saravani, Ernest Hamel, Zahra Shahsavari, Mohsen Alipour, Saman Hosseinkhani, Seyednasser Ostad and Mohsen Amini*   Pages 1 - 10 ( 10 )

Abstract:


Objective: Several anti-tubulin agents were introduced for the cancer treatment so far. Despite successes in the treatment of cancer, these agents cause toxic side effects, including peripheral neuropathy. Comparing anti-tubulin agents, indibulin seemed to cause minimal peripheral neuropathy, but its poor aqueous solubility and other potential clinical problems have led to its remaining in a preclinical stage.

Methods: Here in, indibulin analogues were synthesized and evaluated for their in vitro anti-cancer activity using MTT assay (on the MCF-7, T47-D, MDA-MB231 and NIH-3T3 cell lines), annexin V/PI staining assay, cell cycle analysis, anti-tubulin assay and caspase 3/7 activation assay.

Results: One of the compounds, 4a, showed good anti-proliferative activity against MCF-7 cells (IC50: 7.5 µM) and low toxicity on a normal cell line (IC50 > 100µM). All of the tested compounds showed lower cytotoxicity on normal cell line in comparison to reference compound, indibulin. In the annexin V/PI staining assay, induction of apoptosis in the MCF-7 cell line was observed. Cell cycle analysis illustrated an increasing proportion of cells in the sub-G-1 phase, consistent with an increasing proportion of apoptotic cells. No increase in G2/M cells was observed, consistent with the absence of anti-tubulin activity. A caspase 3/7 assay protocol showed that apoptosis induction by the more potent compounds was due to activation of caspase 3.

Conclusion: newly synthesized compounds exerted acceptable anticancer activity and further investigation on current scaffold would be beneficial.

Keywords:

Apoptosis, Cancer, Caspases 3/7, Indibulin, Synthesis, Pyrrole.

Affiliation:

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, 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, 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, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Department of Advanced Medical Sciences & Technologies, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Department of Nano Biotechnology, Faculty of Biological Sciences, Tarbiat Modares University, 14115, Tehran, Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 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



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