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

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.

• Authors: Lisa M Greene, Shu Wang, Niamh M O'Boyle, Sandra A Bright, Jane E Reid, Patrick Kelly, Mary J Meegan, Daniela M Zisterer
• Journal: Oncology reports (Oncol Rep) Vol. 29 Issue 6 Pg. 2451-8 (Jun 2013) ISSN: 1791-2431 [Electronic] Greece
• PMID: 23564200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(3-hydroxy-4-methoxyphenyl)-3-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one
• Antineoplastic Agents
• Azetidines
• Guaiacol

Topics

• Animals
• Antineoplastic Agents (administration & dosage, metabolism, pharmacology)
• Autophagy (drug effects)
• Azetidines (administration & dosage, metabolism, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Drug Stability
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Guaiacol (administration & dosage, analogs & derivatives, metabolism, pharmacology)
• Humans
• Hydrogen-Ion Concentration
• Inhibitory Concentration 50
• Injections, Intraperitoneal
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microsomes, Liver (metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays