N,N-bis(Cyclohexanol)amine Aryl Esters: A New Class of Highly Potent Transporter-Dependent Multidrug Resistance Inhibitors

被引：30

作者：

Martelli, Cecilia ^{[1
]}

Alderighi, Daniela ^{[2
]}

Coronnello, Marcella ^{[3
]}

Dei, Silvia ^{[1
]}

Frosini, Maria ^{[2
]}

Le Bozec, Benedicte ^{[4
]}

Manetti, Dina ^{[1
]}

Neri, Annalisa ^{[2
]}

Romanelli, Maria Novella ^{[1
]}

Salerno, Milena ^{[4
]}

Scapecchi, Serena ^{[1
]}

Mini, Enrico ^{[3
]}

Sgaragli, Giampietro ^{[2
]}

Teodori, Elisabetta ^{[1
]}

机构：

[1] Univ Florence, Dipartimento Sci Farmaceut, I-50019 Sesto Fiorentino, FI, Italy

[2] Univ Siena, Dipartimento Neurosci, Sez Farmacol Fisiol & Tossicol, I-53100 Siena, Italy

[3] Univ Florence, Dipartimento Farmacol Preclin & Clin, I-50139 Florence, Italy

[4] Univ Paris 13, F-93017 Bobigny, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 03期

关键词：

P-GLYCOPROTEIN; ABC TRANSPORTERS; CELLS; ATP; MDR; MECHANISM; BINDING; DESIGN; IDENTIFICATION; ACCUMULATION;

D O I：

10.1021/jm8012745

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of Pgp-dependent MDR inhibitors having a N,N-bis(cyclohexanol)amine scaffold was designed on the basis of the frozen analogue approach. The scaffold chosen gives origin to different geometrical isomers. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells in the pirarubicin uptake assay. The most interesting compounds (isomers of 3) were studied further evaluating their action on the ATPase activity present in rat small intestine membrane vesicles and doxorubicin cytotoxicity potentiation on K562 cells. The latter assay was performed also on the isomers of 4. The four isomers of each set present different behavior in each of these tests. Compound 3d shows the most promising properties as it was able to completely reverse Pgp-dependent pirarubicin extrusion at low nanomolar concentration, inhibited ATPase activity at 5 x 10(-9) and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 36.4 at 3 mu M concentration.

引用

页码：807 / 817

页数：11

共 55 条

[1]

ALLEY MC, 1988, CANCER RES, V48, P589

[2]

Aszalos A, 1998, ANTICANCER RES, V18, P2937

[3] Inhibitors of multidrug resistance to antitumor agents (MDR) [J].

Avendaño, C ;

Menéndez, JC .

CURRENT MEDICINAL CHEMISTRY, 2002, 9 (02) :159-193

[4] Structure of the multidrug ABC transporter Sav1866 from Staphylococcus aureus in complex with AMP-PNP [J].

Dawson, Roger J. P. ;

Locher, Kaspar P. .

FEBS LETTERS, 2007, 581 (05) :935-938

[5] Structure of a bacterial multidrug ABC transporter [J].

Dawson, Roger J. P. ;

Locher, Kaspar P. .

NATURE, 2006, 443 (7108) :180-185

[6] Diphenyleyclohexylamine derivatives as new potent multidrug resistance (MDR) modulators [J].

Dei, S ;

Budriesi, R ;

Sudwan, P ;

Ferraroni, M ;

Chiarini, A ;

Garnier-Suillerot, A ;

Manetti, D ;

Martelli, C ;

Scapecchi, S ;

Teodori, E .

BIOORGANIC & MEDICINAL CHEMISTRY, 2005, 13 (04) :985-998

[7] Structure-activity relationships and optimisation of the selective MDR modulator 2-(3,4-dimethoxyphenyl)-5-(9-fluorenylamino)-2-(methylethyl) pentanenitrile and its N-methyl derivative [J].

Dei, S ;

Teodori, E ;

Garnier-Suillerot, A ;

Gualtieri, F ;

Scapecchi, S ;

Budriesi, R ;

Chiarini, A .

BIOORGANIC & MEDICINAL CHEMISTRY, 2001, 9 (10) :2673-2682

[8]

DEOLIVEIRA PR, 2003, J MOL STRUCT, V657, P191

[9]

Eli Lilly & Company, 2004, [No title captured], Patent No. [WO2004108677, 2004108677]

[10] Cancer cell permeability-glycoprotein as a target of MDR reverters: Possible role of novel dihydropyridine derivatives [J].

Fusi, F. ;

Saponara, S. ;

Valoti, M. ;

Dragoni, S. ;

D'Elia, P. ;

Sgaragli, T. ;

Alderighi, D. ;

Sgaragli, G. .

CURRENT DRUG TARGETS, 2006, 7 (08) :949-959

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