Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents

Authors

Thomas F. Greene, Trinity College DublinFollow
Shu Wang, University of Dublin, Trinity CollegeFollow
Lisa M. Greene, University of Dublin, Trinity CollegeFollow
Seema M. Nathwani, Trinity College DublinFollow
Jade K. Pollock, University of Dublin, Trinity CollegeFollow
Azizah M. Malebari, Trinity College DublinFollow
Thomas McCabe, Trinity College Dublin
Brendan Twamley, Trinity College DublinFollow
Niamh O'Boyle, Technological University DublinFollow
Daniela M. Zisterer, Trinity College DublinFollow
Mary J. Meegan, Trinity College DublinFollow

Document Type

Article

Rights

This item is available under a Creative Commons License for non-commercial use only

Disciplines

1. NATURAL SCIENCES, 1.4 CHEMICAL SCIENCES, Organic Chemistry, Medicinal chemistry

Publication Details

Journal of Medicinal Chemistry, 59(1), 14 January 2016, pp. 90-113

Abstract

Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl ‘A’ ring and 4-phenyl ‘B’ ring for potent antiproliferative activity, and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC₅₀ values of 38 nM and 19 nM respectively in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualised by confocal microscopy, and caused G₂/M arrest and apoptosis. Compound 90b possessed a mean GI₅₀ value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity and was shown to interact at the colchicine-binding site on β-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesised, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.

DOI

https://doi.org/10.1021/acs.jmedchem.5b01086

Recommended Citation

Greene, T. et al (2016). Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents. Journal of Medicinal Chemistry, 59(1), 14 January 2016, pp. 90-113 doi: 10.1021/acs.jmedchem.5b01086