Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer

Greene,Lisa  M.; Wang,Shu; O'Boyle,Niamh  M.; Bright,Sandra  A.; Reid,Jane  E.; Kelly,Patrick; Meegan,Mary J.; Zisterer,Daniela  M.

doi:10.3892/or.2013.2379

Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer

Authors:
- Lisa M. Greene
- Shu Wang
- Niamh M. O'Boyle
- Sandra A. Bright
- Jane E. Reid
- Patrick Kelly
- Mary J. Meegan
- Daniela M. Zisterer
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Affiliations: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland, School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Published online on: April 3, 2013 https://doi.org/10.3892/or.2013.2379
Pages: 2451-2458

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Abstract

In recent years an extensive series of synthetic combretastatin A-4 (CA-4)-azetidinone (β-lactam) hybrids were designed and synthesised with a view to improve the stability, therapeutic efficacy and aqueous solubility of CA-4. Lead compounds containing a 3,4,5-trimethoxy aromatic ring at position 1 and a variety of substitution patterns at positions 3 and 4 of the β-lactam ring were screened in three adenocarcinoma-derived colon cancer cell lines (CT-26, Caco-2 and the CA-4 resistant cell line, HT-29). In both CT-26 and Caco-2 cells all β-lactam analogues analysed displayed potent therapeutic efficacy within the nanomolar range. Substitution of the ethylene bridge of CA-4 with the β-lactam ring together with the aforementioned aryl substitutions improved the therapeutic efficacy of CA-4 up to 300‑fold in the combretastatin refractory HT-29 cells. The lead compound combretazet-3 (CAZ-3); chemical name [4-(3-hydroxy-4-methoxyphenyl)-3-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one] demonstrated improved chemical stability together with enhanced therapeutic efficacy as compared with CA-4 whilst maintaining the natural biological properties of CA-4. Furthermore, CAZ-3 demonstrated significant tumour inhibition in a murine model of colon cancer. Our results suggest that combretastatin-azetidinone hybrids represent an effective novel therapy for the treatment of combretastatin resistant carcinomas.

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