Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones

Malebari, Azizah M.; Duffy Morales, Gabriela; Twamley, Brendan; Fayne, Darren; Khan, Mohemmed Faraz; McLoughlin, Eavan C.; O’Boyle, Niamh M.; Zisterer, Daniela M.; Meegan, Mary J.

doi:10.3390/ph15091044

Open AccessArticle

Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones

by

Azizah M. Malebari

^1,2,

Gabriela Duffy Morales

²,

Brendan Twamley

³,

Darren Fayne

⁴,

Mohemmed Faraz Khan

⁴

,

Eavan C. McLoughlin

²

,

Niamh M. O’Boyle

²

,

Daniela M. Zisterer

⁴ and

Mary J. Meegan

^2,*

¹

Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia

²

Trinity Biomedical Sciences Institute, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, Ireland

³

School of Chemistry, Trinity College Dublin, Dublin 2, D02 PN40 Dublin, Ireland

⁴

Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, Ireland

^*

Author to whom correspondence should be addressed.

Pharmaceuticals 2022, 15(9), 1044; https://doi.org/10.3390/ph15091044

Submission received: 26 July 2022 / Revised: 16 August 2022 / Accepted: 17 August 2022 / Published: 24 August 2022

(This article belongs to the Section Medicinal Chemistry)

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Abstract

The stilbene combretastatin A-4 (CA-4) is a potent microtubule-disrupting agent interacting at the colchicine-binding site of tubulin. In the present work, the synthesis, characterisation and mechanism of action of a series of 3-fluoro and 3,3-difluoro substituted β-lactams as analogues of the tubulin-targeting agent CA-4 are described. The synthesis was achieved by a convenient microwave-assisted Reformatsky reaction and is the first report of 3-fluoro and 3,3-difluoro β-lactams as CA-4 analogues. The β-lactam compounds 3-fluoro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxy phenyl)azetidin-2-one 32 and 3-fluoro-4-(3-fluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) 33 exhibited potent activity in MCF-7 human breast cancer cells with IC₅₀ values of 0.075 µM and 0.095 µM, respectively, and demonstrated low toxicity in non-cancerous cells. Compound 32 also demonstrated significant antiproliferative activity at nanomolar concentrations in the triple-negative breast cancer cell line Hs578T (IC₅₀ 0.033 μM), together with potency in the invasive isogenic subclone Hs578Ts(i)8 (IC₅₀ = 0.065 μM), while 33 was also effective in MDA-MB-231 cells (IC₅₀ 0.620 μM). Mechanistic studies demonstrated that 33 inhibited tubulin polymerisation, induced apoptosis in MCF-7 cells, and induced a downregulation in the expression of anti-apoptotic Bcl2 and survivin with corresponding upregulation in the expression of pro-apoptotic Bax. In silico studies indicated the interaction of the compounds with the colchicine-binding site, demonstrating the potential for further developing novel cancer therapeutics as microtubule-targeting agents.

Keywords: combretastatin A-4; antiproliferative activity; fluorinated β-lactams; Reformatsky reaction; inhibition of tubulin polymerisation; breast cancer

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MDPI and ACS Style

Malebari, A.M.; Duffy Morales, G.; Twamley, B.; Fayne, D.; Khan, M.F.; McLoughlin, E.C.; O’Boyle, N.M.; Zisterer, D.M.; Meegan, M.J. Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones. Pharmaceuticals 2022, 15, 1044. https://doi.org/10.3390/ph15091044

AMA Style

Malebari AM, Duffy Morales G, Twamley B, Fayne D, Khan MF, McLoughlin EC, O’Boyle NM, Zisterer DM, Meegan MJ. Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones. Pharmaceuticals. 2022; 15(9):1044. https://doi.org/10.3390/ph15091044

Chicago/Turabian Style

Malebari, Azizah M., Gabriela Duffy Morales, Brendan Twamley, Darren Fayne, Mohemmed Faraz Khan, Eavan C. McLoughlin, Niamh M. O’Boyle, Daniela M. Zisterer, and Mary J. Meegan. 2022. "Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones" Pharmaceuticals 15, no. 9: 1044. https://doi.org/10.3390/ph15091044

APA Style

Malebari, A. M., Duffy Morales, G., Twamley, B., Fayne, D., Khan, M. F., McLoughlin, E. C., O’Boyle, N. M., Zisterer, D. M., & Meegan, M. J. (2022). Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones. Pharmaceuticals, 15(9), 1044. https://doi.org/10.3390/ph15091044

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Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones

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