Inhibition of MDR1 Activity in Vitro by a Novel Class of Diltiazem Analogues: Toward New Candidates

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• 作者：Maurizio Viale ; Cinzia Cordazzo ; Barbara Cosimelli ; Daniela de Totero ; Patrizio Castagnola ; Cinzia Aiello ; Elda Severi ; Giovanni Petrillo ; Maurizio Cianfriglia ; Domenico Spinelli
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：January 22, 2009
• 年：2009
• 卷：52
• 期：2
• 页码：259-266
• 全文大小：183K
• 年卷期：v.52,no.2(January 22, 2009)
• ISSN：1520-4804

文摘

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.