6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

被引：13

作者：

Braconi, Laura ^{[1
]}

Bartolucci, Gianluca ^{[1
]}

Contino, Marialessandra ^{[2
]}

Chiaramonte, Niccolo ^{[1
]}

Giampietro, Roberta ^{[2
]}

Manetti, Dina ^{[1
]}

Perrone, Maria Grazia ^{[2
]}

Romanelli, Maria Novella ^{[1
]}

Colabufo, Nicola Antonio ^{[2
]}

Riganti, Chiara ^{[3
]}

Dei, Silvia ^{[1
]}

Teodori, Elisabetta ^{[1
]}

机构：

[1] Univ Florence, NEUROFARBA Dept, Sect Pharmaceut & Nutraceut Sci, Via Ugo Schiff 6, I-50019 Florence, Italy

[2] Univ Bari A Moro, Dept Pharm Drug Sci, Bari, Italy

[3] Univ Turin, Dept Oncol, Turin, Italy

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2020年 / 35卷 / 01期

关键词：

Tetrahydroisoquinoline; MDR reversers; P-gp modulators; co-administration assay; cytotoxicity; P-GLYCOPROTEIN; VALSPODAR PSC-833; ABC TRANSPORTERS; ARYL ESTERS; CANCER; DERIVATIVES; MRP1; MECHANISMS; POTENCY; AGENTS;

D O I：

10.1080/14756366.2020.1747449

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Aiming to deepen the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles. [GRAPHICS] .

引用

页码：974 / 992

页数：19

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