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

• Main Authors: Shu Wang (Author), Azizah M. Malebari (Author), Thomas F. Greene (Author), Niamh M. O'Boyle (Author), Darren Fayne (Author), Seema M. Nathwani (Author), Brendan Twamley (Author), Thomas McCabe (Author), Niall O. Keely (Author), Daniela M. Zisterer (Author), Mary J. Meegan (Author)
• Format: Book
• Published: MDPI AG, 2019-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 <b>7s</b> 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 <b>7s</b> 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 <b>7s</b> 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 <b>7s</b> is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam <b>7s</b> in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

Item Description

1424-8247
10.3390/ph12020056