Next Article in Journal
Relevance of In Vitro Metabolism Models to PET Radiotracer Development: Prediction of In Vivo Clearance in Rats from Microsomal Stability Data
Next Article in Special Issue
Magnetic Graphene Oxide Nanocarrier for Targeted Delivery of Cisplatin: A Perspective for Glioblastoma Treatment
Previous Article in Journal
Strategies for the Development of Glycomimetic Drug Candidates
Previous Article in Special Issue
Protective Effect of Cashew Gum (Anacardium occidentale L.) on 5-Fluorouracil-Induced Intestinal Mucositis
Open AccessArticle

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

1
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2 DO2R590, Ireland
2
Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
3
School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2 DO2R590, Ireland
4
School of Chemistry, Trinity College Dublin, Dublin 2 DO2R590, Ireland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Pharmaceuticals 2019, 12(2), 56; https://doi.org/10.3390/ph12020056
Received: 1 March 2019 / Revised: 2 April 2019 / Accepted: 7 April 2019 / Published: 11 April 2019
(This article belongs to the Special Issue Anticancer Drugs)
Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 μM for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents. View Full-Text
Keywords: Combretastatin A-4; β-lactam; 3-vinylazetidin-2-ones; antiproliferative activity; tubulin; antimitotic Combretastatin A-4; β-lactam; 3-vinylazetidin-2-ones; antiproliferative activity; tubulin; antimitotic
Show Figures

Graphical abstract

MDPI and ACS Style

Wang, S.; Malebari, A.M.; Greene, T.F.; O’Boyle, N.M.; Fayne, D.; Nathwani, S.M.; Twamley, B.; McCabe, T.; Keely, N.O.; Zisterer, D.M.; Meegan, M.J. 3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells. Pharmaceuticals 2019, 12, 56. https://doi.org/10.3390/ph12020056

AMA Style

Wang S, Malebari AM, Greene TF, O’Boyle NM, Fayne D, Nathwani SM, Twamley B, McCabe T, Keely NO, Zisterer DM, Meegan MJ. 3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells. Pharmaceuticals. 2019; 12(2):56. https://doi.org/10.3390/ph12020056

Chicago/Turabian Style

Wang, Shu; Malebari, Azizah M.; Greene, Thomas F.; O’Boyle, Niamh M.; Fayne, Darren; Nathwani, Seema M.; Twamley, Brendan; McCabe, Thomas; Keely, Niall O.; Zisterer, Daniela M.; Meegan, Mary J. 2019. "3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells" Pharmaceuticals 12, no. 2: 56. https://doi.org/10.3390/ph12020056

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop