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Article

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
  • View Affiliations / Copyright

    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
  • Pages: 2451-2458
    |
    Published online on: April 3, 2013
       https://doi.org/10.3892/or.2013.2379
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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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Copy and paste a formatted citation
Spandidos Publications style
Greene LM, Wang S, O'Boyle NM, Bright SA, Reid JE, Kelly P, Meegan MJ and Zisterer DM: Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer. Oncol Rep 29: 2451-2458, 2013.
APA
Greene, L.M., Wang, S., O'Boyle, N.M., Bright, S.A., Reid, J.E., Kelly, P. ... Zisterer, D.M. (2013). Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer. Oncology Reports, 29, 2451-2458. https://doi.org/10.3892/or.2013.2379
MLA
Greene, L. M., Wang, S., O'Boyle, N. M., Bright, S. A., Reid, J. E., Kelly, P., Meegan, M. J., Zisterer, D. M."Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer". Oncology Reports 29.6 (2013): 2451-2458.
Chicago
Greene, L. M., Wang, S., O'Boyle, N. M., Bright, S. A., Reid, J. E., Kelly, P., Meegan, M. J., Zisterer, D. M."Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer". Oncology Reports 29, no. 6 (2013): 2451-2458. https://doi.org/10.3892/or.2013.2379
Copy and paste a formatted citation
x
Spandidos Publications style
Greene LM, Wang S, O'Boyle NM, Bright SA, Reid JE, Kelly P, Meegan MJ and Zisterer DM: Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer. Oncol Rep 29: 2451-2458, 2013.
APA
Greene, L.M., Wang, S., O'Boyle, N.M., Bright, S.A., Reid, J.E., Kelly, P. ... Zisterer, D.M. (2013). Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer. Oncology Reports, 29, 2451-2458. https://doi.org/10.3892/or.2013.2379
MLA
Greene, L. M., Wang, S., O'Boyle, N. M., Bright, S. A., Reid, J. E., Kelly, P., Meegan, M. J., Zisterer, D. M."Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer". Oncology Reports 29.6 (2013): 2451-2458.
Chicago
Greene, L. M., Wang, S., O'Boyle, N. M., Bright, S. A., Reid, J. E., Kelly, P., Meegan, M. J., Zisterer, D. M."Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer". Oncology Reports 29, no. 6 (2013): 2451-2458. https://doi.org/10.3892/or.2013.2379
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