Design, Synthesis, and in Vitro Activity of Catamphiphilic Reverters of Multidrug Resistance:  Discovery of a Selective, Highly Efficacious Chemosensitizer with Potency in the Nanomolar Range

Abstract

On the basis of the results obtained in previous research, three series of compounds (A-C), derived from verapamil, were designed and synthesized to obtain drugs able to revert multidrug resistance (MDR), an acquired resistance that frequently impairs cancer chemotherapy. The ability of the obtained compounds to revert MDR was evaluated on anthracycline-resistant erythroleukemia K 562 cells, measuring the uptake of THP-adriamycin (pirarubicin) by continuous spectrofluorometric monitoring of the decrease of the fluorescence signal of the anthracycline at 590 nm (lambdaex = 480 nm), after incubation with cells. Cardiovascular activity, which is responsible for unwanted side effects, was also evaluated. The results obtained show that many of the compounds studied are potent reverters of MDR and are endowed with reduced cardiovascular activity. One of the compounds (7, MM36) presents a pharmacological profile (unprecedented nanomolar potency, high reversal of MDR, low cardiovascular activity) that makes it a promising drug candidate to treat MDR and a useful tool for studying P-glycoprotein.

(R)- and (S)-Verapamil Differentially Modulate the Multidrug-resistant Protein MRP1

“…Furthermore, iodination has been achieved on the B-phenyl ring of the molecule, known to be important for cardiocytotoxicity (30). Therefore, the synthesis of the iodinated R-and S-enantiomers of verapamil is in progress.…”

Multidrug resistance (MDR) reversers: High activity and efficacy in a series of asymmetrical N,N-bis(alkanol)amine aryl esters

“…K562/DOX cells resistant to doxorubicin overexpress a unique membrane glycoprotein, P-gp [37e39]. The uptake of THP-adriamycin (pirarubicin) was measured by a continuous spectrofluorometric signal of anthracycline at 590 nm (l ex ¼ 480 nm) after cell incubation, following the protocols reported in previous papers [40,41]. The activity of the studied compounds on pirarubicin uptake is expressed by: i) a max , which represents the efficacy of the modulator and is the maximum increase that can be obtained in the nuclear concentration of pirarubicin in resistant cells with a given compound.…”

Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agents

“…This apoptosis was triggered through stimulation of MRP1-mediated GSH extrusion, and cells were committed to die as they became deprivated in their intracellar GSH. 63 The NMeOHI 2 , which was modified on the verapamil B ring known to be important for cardiovascular effects, 64 behaved as a powerful agent with a tenfold higher potency than verapamil (IC 50 0.1 mM). This newly described mechanism of induced apoptosis in MDR cells may represent a novel approach for the selective treatment of MRP1-positive tumors.…”