Synthesis and Cytotoxic Activity of N,N′-(Arylmethylene)bisamides

Abstract

N,N′-(Arylmethylene)bisamides were prepared by an acid-catalyzed reaction of arylaldehydes with cinnamamide or acrylamides. The reaction was carried out in refluxing toluene for a few hours, and simple collection of the precipitate gave the desired products. The bisamides were designed as cytotoxic molecules based on the structure of the potently cytotoxic marine natural product (–)-zampanolide. The activities of the bisamides against two cancer cell lines were evaluated, and several compounds were found to show medium potency with IC₅₀ values in the lower micromolar level.

Key words

amides - medicinal chemistry - cytotoxins - condensation - bisamides

• References


For retro-inverso peptides, see:
• 1a Fletcher MD, Campbell MM. Chem. Rev. 1998; 98: 763
• 1b Chorev M, Willson CG, Goodman M. J. Am. Chem. Soc. 1977; 99: 8075
• 1c Pallai PV, Struthers RS, Goodman M, Moroder L, Wunsch E, Vale W. Biochemistry 1985; 24: 1933
• 1d Rodriguez M, Dubreuil P, Bali JP, Martinez J. J. Med. Chem. 1987; 30: 758
• 2 Tanaka J.-i, Higa T. Tetrahedron Lett. 1996; 37: 5535
• 3a Field JJ, Singh AJ, Kanakkanthara A, Halafihi T, Northcote PT, Miller JH. J. Med. Chem. 2009; 52: 7328
• 3b Ghosh AK, Cheng X, Bai R, Harmel E. Eur. J. Org. Chem. 2012; 4130

For X-ray studies on the complex, see:
• 4a Prota AE, Bargsten K, Zurwerra D, Field JJ, Diaz JF, Altmann K.-H, Steinmetz MO. Science 2013; 339: 587
• 4b Field JJ, Pera B, Carvo E, Canales A, Zurwerra D, Trigili C, Rodríguez-Salarichs J, Matesanz R, Kanakkanthara A, Wakefield StJ, Singh AJ, Jiménez-Barbero J, Northcote PT, Miller JH, López E, Hamel E, Barasoain I, Altmann K.-H, Diaz JF. Chem. Biol. 2012; 19: 686
• 5 Uenishi J, Iwamoto T, Tanaka J. Org. Lett. 2009; 11: 3262

For total syntheses of (–)-zampanolide, see:
• 6a Hoye TR, Hu M. J. Am. Chem. Soc. 2003; 125: 9576
• 6b Ghosh AK, Cheng X. Org. Lett. 2013; 13: 4108
• 6c Zurwerra D, Glaus F, Betschart L, Schuster J, Gertsch J, Ganci W, Altmann K.-H. Chem. Eur. J. 2012; 18: 16868
• 7a Gilbert ER. Synthesis 1972; 30
• 7b Fernández AH, Alvarez RM, Abajo TM. Synthesis 1996; 1299
• 7c Zhu SZ, Xu GL, Chu QL, Xu Y, Qui CY. J. Fluorine Chem. 1999; 93: 69
• 7d Anary-Abbasinejad M, Mosslemin MH, Hassanabadi A. J. Chem. Res. 2009; 218
• 7e Anary-Abbasinejad M, Mosslemin MH, Hassanabadi A, Safa ST. Synth. Commun. 2010; 40: 2209
• 7f Karimi-Jaberi Z, Pooladian BA. Monatsh. Chem. 2013; 144: 659
• 7g Pernak J, Błazej M, Józef W. Synthesis 1994; 1415
• 7h Schäfer G, Leu L, Bode JW. Heterocycles 2015; 90: 1375
• 8 For a recent review on (–)-zampanolide, see: Chen Q.-H, Kingston DG. I. Nat. Prod. Rep. 2014; 31: 1202