Development of small-molecule P-gp inhibitors of the N-benzyl 1,4-dihydropyridine type: Novel aspects in SAR and bioanalytical evaluation of multidrug resistance (MDR) reversal properties

被引：34

作者：

Baumert, Christiane ^{[1
]}

Guenthel, Marianne ^{[1
]}

Krawczyk, Soeren ^{[1
]}

Hemmer, Marc ^{[1
]}

Wersig, Tom ^{[1
]}

Langner, Andreas ^{[1
]}

Molnar, Josef ^{[2
]}

Lage, Hermann ^{[3
]}

Hilgeroth, Andreas ^{[1
]}

机构：

[1] Univ Halle Wittenberg, Inst Pharm, D-06120 Halle, Germany

[2] Univ Szeged, Dept Med Microbiol, H-6720 Szeged, Hungary

[3] Univ Hosp Charite, Inst Pathol, D-10117 Berlin, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 01期

关键词：

Structure-activity relationships (SAR); Multidrug resistance (MDR); P-glycoprotein (P-gp); Inhibitor; Efflux pump inhibition; CHANNEL BLOCKERS; CANCER; TRANSPORTERS; ANTAGONISTS; MECHANISMS; MODULATORS;

D O I：

10.1016/j.bmc.2012.10.041

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：

Novel series of N-benzyl 1,4-dihydropyridines have been prepared by facile syntheses. All relevant substituents of the molecular scaffold have been varied. The resulting compounds were biologically evaluated as P-glycoprotein (P-gp) inhibitors. Substitutions of the N-benzyl residue favour biological activity beside respective 3-ester functions. Most active compounds were further evaluated as multidrug resistance (MDR) modulators to restore the cytotoxic properties of varying daunorubicin applications. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：166 / 177

页数：12

共 27 条

[1]

Avendano C., 2004, MED CHEM REV ONLINE, V1, P419, DOI DOI 10.2174/1567203043401608

[2] DIETHYL 3,6-DIHYDRO-2,4-DIMETHYL-2,6-METHANO-1,3-BENZOTHIAZOCINE-5,11-DICARBOXYLATES AS CALCIUM ENTRY ANTAGONISTS - NEW CONFORMATIONALLY RESTRAINED ANALOGS OF HANTZSCH 1,4-DIHYDROPYRIDINES RELATED TO NITRENDIPINE AS PROBES FOR RECEPTOR-SITE CONFORMATIONE [J].

BALDWIN, JJ ;

CLAREMON, DA ;

LUMMA, PK ;

MCCLURE, DE ;

ROSENTHAL, SA ;

WINQUIST, RJ ;

FAISON, EP ;

KACZOROWSKI, GJ ;

TRUMBLE, MJ ;

SMITH, GM .

JOURNAL OF MEDICINAL CHEMISTRY, 1987, 30 (04) :690-695

[3] An efficient palladium-catalyzed synthesis of cinnamaldehydes from acrolein diethyl acetal and aryl iodides and bromides [J].

Battistuzzi, G ;

Cacchi, S ;

Fabrizi, G .

ORGANIC LETTERS, 2003, 5 (05) :777-780

[4] Recent Advances in the Development of P-gp Inhibitors [J].

Baumert, Christiane ;

Hilgeroth, Andreas .

ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, 2009, 9 (04) :415-436

[5] ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal [J].

Choi, Cheol-Hee .

CANCER CELL INTERNATIONAL, 2005, 5 (1)

[6]

CORNWELL MM, 1987, J BIOL CHEM, V262, P2166

[7] ABC Efflux Pump-Based Resistance to Chemotherapy Drugs [J].

Eckford, Paul D. W. ;

Sharom, Frances J. .

CHEMICAL REVIEWS, 2009, 109 (07) :2989-3011

[8] CRYSTAL-STRUCTURES AND PHARMACOLOGIC ACTIVITIES OF 1,4-DIHYDROPYRIDINE CALCIUM-CHANNEL ANTAGONISTS OF THE ISOBUTYL METHYL 2,6-DIMETHYL-4-(SUBSTITUTED PHENYL)-1,4-DIHYDROPYRIDINE-3,5-DICARBOXYLATE (NISOLDIPINE) SERIES [J].

FOSSHEIM, R ;

JOSLYN, A ;

SOLO, AJ ;

LUCHOWSKI, E ;

RUTLEDGE, A ;

TRIGGLE, DJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1988, 31 (02) :300-305

[9] The molecular basis of multidrug resistance in cancer: The early years of P-glycoprotein research [J].

Gottesman, MM ;

Ling, V .

FEBS LETTERS, 2006, 580 (04) :998-1009

[10] PHASE-I AND PHARMACOLOGICAL STUDY OF LIPOSOMAL DAUNORUBICIN (DAUNOXOME) [J].

GUAGLIANONE, P ;

CHAN, K ;

DELAFLORWEISS, E ;

HANISCH, R ;

JEFFERS, S ;

SHARMA, D ;

MUGGIA, F .

INVESTIGATIONAL NEW DRUGS, 1994, 12 (02) :103-110

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