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
2011
Martelli, Cecilia | Dei, Silvia | Lambert, Catherine | Manetti, Dina | Orlandi, Francesca | Romanelli, Maria Novella | Scapecchi, Serena | Salerno, Milena | Teodori, Elisabetta
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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