Inhibition of P-glycoprotein-mediated Multidrug Resistance (MDR) by N,N-bis(cyclohexanol)amine aryl esters: further restriction of molecular flexibility maintains high potency and efficacy |
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Authors: | Martelli Cecilia Dei Silvia Lambert Catherine Manetti Dina Orlandi Francesca Romanelli Maria Novella Scapecchi Serena Salerno Milena Teodori Elisabetta |
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Institution: | a Dipartimento di Scienze Farmaceutiche, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy b Laboratoire des Acides Nucléiques et Biophotonique, FRE 3207 CNRS, Université Paris 13, UFR SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France |
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Abstract: | Conformational modulation of the aryl portion of a set of N,N-bis(cyclohexanol)amine aryl esters (1a-d) that are potent Pgp-dependent MDR inhibitors has been performed. Toward this end the trans-3-(3,4,5-trimethoxyphenyl)acrylic acid present in set 1 was substituted with 3-(3,4,5-trimethoxyphenyl)propanoic and 3-(3,4,5-trimethoxyphenyl)propiolic moieties to give sets 2 and 3, respectively. While the introduction of 3-(3,4,5-trimethoxyphenyl)propanoic moiety resulted in a definite drop in potency and efficacy, esterification with 3-(3,4,5-trimethoxyphenyl)propiolic acid gave four isomers (3a-d) that maintain high potency and possess optimal efficacy. These results are discussed in terms of conformational flexibility of the different sets of compounds. |
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Keywords: | EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimmide hydrochloride DMAP 4-dimethylaminopyridine DOX doxorubicin |
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