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, 9 (5), 843-852
eCollection

Synthesis and Biological Evaluation of New 3-amino-2-azetidinone Derivatives as Anti-Colorectal Cancer Agents

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Synthesis and Biological Evaluation of New 3-amino-2-azetidinone Derivatives as Anti-Colorectal Cancer Agents

Farida Tripodi et al. Medchemcomm.

Abstract

Several synthetic combretastatin A4 (CA-4) derivatives were recently prepared to increase the drug efficacy and stability of the natural product isolated from the South African tree Combretum caffrum. A group of ten 3-amino-2-azetidinone derivatives, as combretastatin A4 analogues, was selected through docking experiments, synthesized and tested for their anti-proliferative activity against the colon cancer SW48 cell line. These molecules, through the formation of amide bonds in position 3, allow the synthesis of various derivatives that can modulate the activity with great resistance to hydrolytic conditions. The cyclization to obtain the 3-aminoazetidinone ring is highly diastereoselective and provides a trans biologically active isomer under mild reaction conditions with better yields than the 3-hydroxy-2-azetidinone synthesis. All compounds showed IC50 values ranging between 14.0 and 564.2 nM, and the most active compound showed inhibitory activity against tubulin polymerization in vitro, being a potential therapeutic agent against colon cancer.

Figures

Fig. 1
Fig. 1. The main component of combretastatins: combretastatin A4 and its phosphate derivative.
Fig. 2
Fig. 2. Triaryl derivatives of azetidinone proposed by O'Boyle and coworkers.
Fig. 3
Fig. 3. Azetidinone derivatives proposed by Tripodi and coworkers.
Fig. 4
Fig. 4. SS an RR enantiomers of compound 2, previously tested as anticancer agents.
Fig. 5
Fig. 5. Superimposition of docking poses of compounds 11a (blue), 11b (red), 11c (orange), 11e (yellow), 11h (green), and 11j (purple).
Fig. 6
Fig. 6. Interactions of the compound 11a. In the illustration, tubulin α (orange) and β (cyan) subunits are represented. Trimethoxyphenyl group came into contact with residues Cysβ241 and Valβ238, as well as HB with residue Metβ259. This interaction pattern was common to compounds 11a, 11b, 11c, 11e, 11h, and 11j.
Fig. 7
Fig. 7. Interactions of compound 11i. In the illustration, tubulin α (orange) and β (cyan) subunits were represented. Trimethoxyphenyl group is in contact with residues Cysβ241 and Valβ238. Moreover, two hydrogen bonds were observed between the amide group in position 3 and Asnα101 as well as between the ketone oxygen of the scaffold and Aspβ251. This interaction pattern was common to compounds 11i and 2b.
Fig. 8
Fig. 8. Superimposition of 11i (blue) and 2a (red) docking poses.
Scheme 1
Scheme 1. Reagents and conditions: a) anhydrous EtOH; b) Et3N/CH2Cl2; c) NH2NH2·2HCl, Et3N, MeOH, 60 °C; d) N,N′-disuccinimidyl carbonate, Et3N, CH3CN; e) NH2NH2·2HCl, Et3N, MeOH, r.t.

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