A series of derivatives were synthesized and studied with the aim to investigate the structure–activity relationships of the two P-glycoprotein(P-gp) modulators elacridar and tariquidar. Then, different aryl-substituted amides were inserted, and to explore the effects of varying the amide function, the corre- sponding isosteric ester derivatives and some alkylamine ana- logues were synthesized. The new compounds were studied to evaluatetheir P-gp interaction profile and selectivity toward the two other ABC transporters, multidrug-resistance-associat- ed protein-1(MRP-1)and breast cancer resistance protein (BCRP).Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate-buf- fered saline and human plasma. This study allowed us to eval- uate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P-gp interaction profile. We identified two P-gp substrates, a P-gp inhibitor, and three ester derivatives that were active on BCRP, which opens anew scenario in the development of li- gands active toward this pump.

Structure-Activity Relationship Studies on 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers / Teodori, Elisabetta; Dei, Silvia; Bartolucci, Gianluca; Perrone, Maria Grazia; Manetti, Dina; Romanelli, Maria Novella; Contino, Marialessandra; Colabufo, Nicola Antonio. - In: CHEMMEDCHEM. - ISSN 1860-7179. - ELETTRONICO. - 12:(2017), pp. 1369-1379. [10.1002/cmdc.201700239]

Structure-Activity Relationship Studies on 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

TEODORI, ELISABETTA;DEI, SILVIA;BARTOLUCCI, GIAN LUCA;MANETTI, DINA;ROMANELLI, MARIA NOVELLA;
2017

Abstract

A series of derivatives were synthesized and studied with the aim to investigate the structure–activity relationships of the two P-glycoprotein(P-gp) modulators elacridar and tariquidar. Then, different aryl-substituted amides were inserted, and to explore the effects of varying the amide function, the corre- sponding isosteric ester derivatives and some alkylamine ana- logues were synthesized. The new compounds were studied to evaluatetheir P-gp interaction profile and selectivity toward the two other ABC transporters, multidrug-resistance-associat- ed protein-1(MRP-1)and breast cancer resistance protein (BCRP).Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate-buf- fered saline and human plasma. This study allowed us to eval- uate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P-gp interaction profile. We identified two P-gp substrates, a P-gp inhibitor, and three ester derivatives that were active on BCRP, which opens anew scenario in the development of li- gands active toward this pump.
2017
12
1369
1379
Teodori, Elisabetta; Dei, Silvia; Bartolucci, Gianluca; Perrone, Maria Grazia; Manetti, Dina; Romanelli, Maria Novella; Contino, Marialessandra; Colabufo, Nicola Antonio
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1093459
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