Structure-activity relationships of a series of tariquidar analogs as multidrug resistance modulators.

Tariquidar (XR9576) analogs, modulators of cancer multidrug resistance (MDR), were subjected to QSAR and 3D-QSAR analyses. The structural features contributing to anti-MDR activity were identified by the Free-Wilson analysis and pharmacophore search using Hoechst 33342 as a template. 3D-QSAR CoMFA and CoMSIA models were derived and tested. The best models yielded an external predictivity of 0.66-0.75 squared correlation coefficient and outlined HB-acceptor, steric, and hydrophobic fields as the most important 3D properties. On the basis of the QSAR and 3D-QSAR analyses it was suggested that the strong inhibitory potency of the compounds studied is related to the presence of a bulky aromatic ring system with a 3rd positioned heteroatom toward the anthranilamide nucleus in the opposite end of the tetrahydroquinoline group. The results can help in directing the rational design of new generations of potent P-glycoprotein MDR modulators.

[1]  C. Higgins,et al.  The molecular interaction of the high affinity reversal agent XR9576 with P‐glycoprotein , 1999, British journal of pharmacology.

[2]  I. Pajeva,et al.  A Comparative Molecular Field Analysis of Propafenone‐type Modulators of Cancer Multidrug Resistance , 1998 .

[3]  I. Tsakovska.  QSAR and 3D-QSAR of phenothiazine type multidrug resistance modulators in P388/ADR cells. , 2003, Bioorganic & medicinal chemistry.

[4]  I K Pajeva,et al.  Structure-activity relationships of multidrug resistance reversers. , 2001, Current medicinal chemistry.

[5]  T. Tsuruo,et al.  Enhancement of vincristine- and adriamycin-induced cytotoxicity by verapamil in P388 leukemia and its sublines resistant to vincristine and adriamycin. , 1982, Biochemical pharmacology.

[6]  H. Coley,et al.  Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. , 2003, Cancer control : journal of the Moffitt Cancer Center.

[7]  Christoph Globisch,et al.  Structure-function relationships of multidrug resistance P-glycoprotein. , 2004, Journal of medicinal chemistry.

[8]  I. Pajeva,et al.  Molecular modeling of phenothiazines and related drugs as multidrug resistance modifiers: a comparative molecular field analysis study. , 1998, Journal of medicinal chemistry.

[9]  S. Ekins,et al.  Application of three-dimensional quantitative structure-activity relationships of P-glycoprotein inhibitors and substrates. , 2002, Molecular pharmacology.

[10]  P. Charlton,et al.  Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives. , 1999, Bioorganic & medicinal chemistry letters.

[11]  M. Delaforge,et al.  Characterization of two pharmacophores on the multidrug transporter P-glycoprotein. , 2002, Molecular pharmacology.

[12]  I. Pajeva,et al.  Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance: explanation of structural variety (hypothesis). , 2002, Journal of medicinal chemistry.

[13]  W. Stein,et al.  Optimizing chemotherapy by measuring reversal of P-glycoprotein activity in plasma membrane vesicles. , 2003, Biotechnology and bioengineering.

[14]  B. David Silverman.  The Thirty-one Benchmark Steroids Revisited: Comparative Molecular Moment Analysis (CoMMA) with Principal Component Regression , 2000 .

[15]  C. Higgins,et al.  Communication between multiple drug binding sites on P-glycoprotein. , 2000, Molecular pharmacology.

[16]  P. Charlton,et al.  In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. , 2001, Cancer research.

[17]  Gerhard Klebe,et al.  Comparative Molecular Similarity Index Analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries , 1999, J. Comput. Aided Mol. Des..

[18]  R. Callaghan,et al.  Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy. , 2004, European journal of cancer.

[19]  Erik Evensen,et al.  A computational ensemble pharmacophore model for identifying substrates of P-glycoprotein. , 2002, Journal of medicinal chemistry.