Ebrahim Saeedian Moghadam1, Ernest Hamel2, Zahra Shahsavari3, Mohsen Amini4. 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. 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. 3. Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. 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. moamini@tums.ac.ir.
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. Graphical abstract Novel Indibulin analogous as anti-breast cancer agents.
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-Dcancer 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. Graphical abstract Novel Indibulin analogous as anti-breast cancer agents.
Authors: Romeo Romagnoli; Pier Giovanni Baraldi; Maria Kimatrai Salvador; Delia Preti; Mojgan Aghazadeh Tabrizi; Andrea Brancale; Xian-Hua Fu; Jun Li; Su-Zhan Zhang; Ernest Hamel; Roberta Bortolozzi; Giuseppe Basso; Giampietro Viola Journal: J Med Chem Date: 2011-12-21 Impact factor: 7.446
Authors: Andrew J Peloquin; Rebecca L Stone; Sarah E Avila; Erlyn R Rudico; Christopher B Horn; Kim A Gardner; David W Ball; Jane E B Johnson; Scott T Iacono; Gary J Balaich Journal: J Org Chem Date: 2012-07-10 Impact factor: 4.354
Authors: Shudong Wang; Gavin Wood; Christopher Meades; Gary Griffiths; Carol Midgley; Iain McNae; Campbell McInnes; Sian Anderson; Wayne Jackson; Mokdad Mezna; Rhoda Yuill; Malcolm Walkinshaw; Peter M Fischer Journal: Bioorg Med Chem Lett Date: 2004-08-16 Impact factor: 2.823
Authors: Daniëlle Copmans; Sara Kildgaard; Emma Roux; Michèle Partoens; Gert Steurs; Xinhui Wang; Wim M De Borggraeve; Camila V Esguerra; Alexander D Crawford; Thomas O Larsen; Peter A M de Witte Journal: Pharmaceuticals (Basel) Date: 2022-02-18