title: 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.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. greeneli@tcd.ie
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Greene
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Niamh M
authors.initials: NM
authors.lastname: O'Boyle
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Bright
authors.forename: Jane E
authors.initials: JE
authors.lastname: Reid
authors.forename: Patrick
authors.initials: P
authors.lastname: Kelly
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001384:Azetidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004355:Drug Stability; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006139:Guaiacol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C583997:4-(3-hydroxy-4-methoxyphenyl)-3-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one; D000970:Antineoplastic Agents; D001384:Azetidines; D006139:Guaiacol