β-Lactams with antiproliferative and antiapoptotic activity in breast and chemoresistant colon cancer cells

  • Eur J Med Chem. 2020 Mar 1;189:112050. doi: 10.1016/j.ejmech.2020.112050.
Azizah M Malebari  1 ,  Darren Fayne  2 ,  Seema M Nathwani  2 ,  Fiona O'Connell  3 ,  Sara Noorani  4 ,  Brendan Twamley  5 ,  Niamh M O'Boyle  4 ,  Jacintha O'Sullivan  3 ,  Daniela M Zisterer  2 ,  Mary J Meegan  4
Affiliations
  • 1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland. Electronic address: [email protected].
  • 2. School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland.
  • 3. Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, Dublin 2, Ireland.
  • 4. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland.
  • 5. School of Chemistry, Trinity College Dublin, Dublin 2, Ireland.
PMID: 31954879 DOI: 10.1016/j.ejmech.2020.112050
Abstract

A series of novel 1,4-diaryl-2-azetidinone analogues of combretastatin A-4 (CA-4) have been designed, synthesised and evaluated in vitro for antiproliferative activity, antiapoptotic activity and inhibition of tubulin polymerisation. Glucuronidation of CA-4 by uridine 5-diphosphoglucuronosyl transferase Enzymes (UGTs) has been identified as a mechanism of resistance in Cancer cells. Potential sites of ring B glucuronate conjugation are removed by replacing the B ring meta-hydroxy substituent of selected series of β-lactams with alternative substituents e.g. F, Cl, Br, I, CH3. The 3-phenyl-β-lactam 11 and 3-hydroxy-β-lactam 46 demonstrate improved activity over CA-4 in CA-4 resistant HT-29 colon Cancer cells (IC50 = 9 nM and 3 nM respectively compared with IC50 = 4.16 μM for CA-4), while retaining potency in MCF-7 breast Cancer cells (IC50 = 17 nM and 22 nM respectively compared with IC50 = for 4 nM for CA-4). Compound 46 binds at the colchicine site of tubulin, and strongly inhibits tubulin assembly at micromolar concentrations comparable to CA-4. In addition, compound 46 induced mitotic arrest at low concentration in both cell lines MCF-7 and HT-29 together with downregulation of expression of antiapoptotic proteins Mcl-1, Bcl-2 and Survivin in MCF-7 cells. These novel antiproliferative and antiapoptotic β-lactams are potentially useful scaffolds in the development of tubulin-targeting agents for the treatment of breast cancers and chemoresistant colon cancers.

Keywords
1,4-Diaryl-2-azetidinone; Antiproliferative activity; Cell cycle arrest; Combretastatin A-4; Microtubule targeting agent; Tubulin polymerisation.
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