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.

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

“…combretazet-3 (CAZ-3, 4-(3-hydroxy-4-methoxyphenyl)-3-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) displayed chemical stability along with the higher bioactivity compared with CA-4. Moreover, this compound also demonstrated significant tumor inhibition in a murine model of colon cancer [76].…”

Microtubule targeting agents in glioma

“…During the last three years, aided by the increasing availability and sophistication of in silico modeling algorithms and of high-throughput cell based screening assays, intense efforts to discover new antimitotic therapeutic agents have led to the discovery of a vast array of novel analogs of colchicine and combretastatin-A, some displaying both anti-mitotic as well as anti-vascular activity like: MDS-11P (39), indole compounds II and IAT (40), cis-constrained analogs of combretastatin A4: compounds 11 and 19 (41), cis 3-b (42), DAT-230 (43), ketone 24-b (44), phenothiazine derivative 21 (45), 1,1-diaryl-2-methoxyethylenes 4b and 4e (46), combretazet-3 (CAZ-3) (47), benzoimidazole analog 5 (48), compound 3-HCl (AG119) (49), furocoumarin analogs of combretastatins: compounds 2 and 3 (50), and the IsoCombretaQuinazolines (isoCoQ) compounds 4b, 4c and 4d (51).…”

Some natural sources of substances with antitumor effects

“…16,17 Neke biljne supstance su ispitivane u kom stepenu usporavaju karcionegenezu (kurkumin, rezveratrol). Antitumorsko delovanje kurkumina izolovanog iz Curcuma longa je detaljno proučavano i na kulturama ćelija i na životinjskim modelima,1 zbog čega su predloženi i unapređeni modeli sa nanočesticama kao nosačima za biljnu komponentu.…”