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

Abstract

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 (IC(50) reduction > or = 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.

An Unexpected Highly Stereoselective Bisaziridination of (E,E)-1,4-Dialkyl-2,3-dinitrobutadienes Followed by a Nitro Group Driven Ring Enlargement

“…On the other hand, several 1,2,4-oxadiazolone derivatives represent very promising hits as LTCC blockers 18 as well as MDR agonists. 19 …”

Piperine activates human pregnane X receptor to induce the expression of cytochrome P450 3A4 and multidrug resistance protein 1

“…For example, CYP3A4 inhibitors clotrimazole (Zhang et al, 2002) and tamoxifen (Zhao et al, 2002), the MDR1 inhibitor nifedipine (Viale et al, 2009), and the dual CYP3A4 and MDR1 inhibitor ritonavir (Bierman et al, 2010; Kumar et al, 1996) increase CYP3A4 and MDR1 gene expression by activating human PXR (hPXR) (Drocourt et al, 2001; Luo et al, 2002; Moore et al, 2000b; Sane et al, 2008), while the dual CYP3A4 and MDR1 inhibitor ketoconazole (KET) (Gibbs et al, 1999; Rautio et al, 2006) decreases CYP3A4 and MDR1 gene expression by inhibiting hPXR activity (Venkatesh et al, 2011). Dietary constituents and phytochemicals have also been shown to affect both gene expression and protein function of CYP3A4 and MDR1.…”

New Methods for the Synthesis of 3‐Amino‐6,7‐Dihydro‐5H‐Cyclopenta[c]Pyridine‐4‐Carbonitriles and Cyclopenta[d]Pyrazolo[3,4‐b]Pyridines via a Smiles‐type Rearrangement

“…This kind of research falls in our general interest in the chemistry of nitrogen‐containing heterocycles: in this field, we have studied reactivity , reaction mechanisms , synthetic applications , and biological activities of several and several penta‐atomic and hexa‐atomic heterocycles.…”