Inhibition of MDR1 activity in vitro by a novel class of diltiazem analogues: Toward new candidates

Maurizio Viale, Cinzia Cordazzo, Barbara Cosimelli, Daniela De Totero, Patrizio Castagnola, Cinzia Aiello, Elda Severi, Giovanni Petrillo, Maurizio Cianfriglia, Domenico Spinelli

Research output: Contribution to journalArticlepeer-review


The reversal of multidrug resistance by 22 molecules [8-aryl-8-hydroxy-5- R′-8H-[1,4]thiazino[3,4-c]-[1,2,4]oxadiazol-3-ones (1a-i) and 8-aryl-8-alkoxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (2a-m)] related to myocardial-calcium-channel-modulator diltiazem was studied in multidrug resistant A2780/DX3 and their sensitive counterpart A2780 cells. MTT, cytofluorimetry assays, and fluorescence microscopy analyses were used to define activity and accumulation of doxorubicin with or without the diltiazem-like modulators. Of the 22 molecules, 1a, 2f, 2g, and 2m were able to overcome the established criteria for the selection in A2780/DX3 cells (IC50 reduction ≥25%), but only 2f, 2g, and 2m caused a significant increase of intracellular accumulation of doxorubicin. In conclusion, experiments lead to the identification of three diltiazem-like molecules able to increase the intracellular accumulation of doxorubicin by inhibiting the MDR1 function, thus potentiating its antiproliferative activity in multidrug resistant A2780/DX3 cells.

Original languageEnglish
Pages (from-to)259-266
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number2
Publication statusPublished - Jan 22 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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