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

Dei, Silvia; Coronnello, Marcella; Floriddia, Elisa; Bartolucci, Gianluca; Bellucci, Cristina; Guandalini, Luca; Manetti, Dina; Romanelli, Maria Novella; Salerno, Milena; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta

doi:10.1016/j.ejmech.2014.09.084

Cited by 20 publications

(36 citation statements)

References 46 publications

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“…To explore the consequences of varying the amide function, we also synthesized corresponding isosteric ester derivatives 7 – 12 and analogues 13 – 16 containing an alkylamine function (Figure ). The inserted aryl moieties were chosen because they were present in compounds previously studied and proved to be very potent multidrug resistance reversers …”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

et al. 2017

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A series of derivatives were synthesized and studied with the aim to investigate the structure–activity relationships of the two P‐glycoprotein (P‐gp) modulators elacridar and tariquidar. Then, different aryl‐substituted amides were inserted, and to explore the effects of varying the amide function, the corresponding isosteric ester derivatives and some alkylamine analogues were synthesized. The new compounds were studied to evaluate their P‐gp interaction profile and selectivity toward the two other ABC transporters, multidrug‐resistance‐associated protein‐1 (MRP‐1) and breast cancer resistance protein (BCRP). Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate‐buffered saline and human plasma. This study allowed us to evaluate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P‐gp interaction profile. We identified two P‐gp substrates, a P‐gp inhibitor, and three ester derivatives that were active on BCRP, which opens a new scenario in the development of ligands active toward this pump.

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Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

et al. 2017

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“…Equations (4)-(6) can be formulated in matrix notation as: The matrix (7) is represented by a series of abundance ratios that are determined from experimental data, by a series of characteristic constants, extracted from Table 4, and by the % concentrations of three isomers in the mixture that can then be determined.…”

Section: Specificitymentioning

confidence: 99%

“…[4][5][6] Recently, a series of N,N-bis(alkanol)amine aryl esters, as Pgp-dependent MDR inhibitors, was designed and synthesized. [7] Among several derivatives obtained, the selected compounds showed high efficacy to reverse the MDR mechanism. These compounds are characterized by the presence of two different aromatic ester moieties linked by a chain of nine components, eight methylenes and one nitrogen atom, where the position of the nitrogen atom changes according to the length of the two spacers (3, 4 and 5 methylenes).…”

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confidence: 99%

“…These compounds are characterized by the presence of two different aromatic ester moieties linked by a chain of nine components, eight methylenes and one nitrogen atom, where the position of the nitrogen atom changes according to the length of the two spacers (3, 4 and 5 methylenes). The compounds were named FRA77, GDE6 and GDE19 [7] (for structures, see Fig. 1).…”

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confidence: 99%

“…To reach this aim, a reliable quali-quantitative method to determine the selected compounds, at low concentration levels, and to describe their degradation profiles in plasma and PBS samples was developed. Since the reported tests [7] demonstrated that these compounds show activity in the low nanomolar range ([I] 0.5 = 0.04 μM) a traditional liquid chromatography approach (using ultraviolet (UV) or diodearray (DAD) detectors) would be ineffective to follow a direct degradation study in plasma at this concentration level.…”

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The power of energy‐resolved tandem mass spectrometry experiments for resolution of isomers: the case of drug plasma stability investigation of multidrug resistance inhibitors

Menicatti

Guandalini

Dei

et al. 2015

Rapid Comm Mass Spectrometry

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RATIONALE: A series of drug plasma stability experiments were carried out to evaluate the bioavailability of three multidrug resistance inhibitors. The studied compounds are positional isomers; therefore, a chromatographic separation or taking advantage of specific collisionally activated decomposition pathways, obtained by tandem mass spectrometry (MS/MS) experiments, is necessary in order to resolve them. METHODS: A method was developed for quantitative determination of the analytes in plasma using liquid chromatography (LC) coupled with a triple quadrupole mass spectrometer operating in MS/MS mode. Different collisional approaches were employed based on the potentiality of a triple quadrupole system. Aside from the classical product ion spectroscopy, energy-resolved MS/MS experiments and a post-processing mathematical algorithm tool (LEDA) were used to distinguish among different kinds of inhibitors present in the sample batch. RESULTS: The developed LC/MS/MS method showed precision between 1.8-7.9%, accuracy ranging from 92.8 to 99.9% and limit of detection (LOD) values in the range 1.0-1.4 ng mL À1 for all the analytes. The evaluation of matrix effects demonstrated that the sample preparation procedure did not affect the ionization efficiency or recovery (matrix effects and recovery larger than 88%). Finally, the LEDA tool was able to differentiate among the isomers, ensuring their proper monitoring. CONCLUSIONS: The proposed LC/MS/MS method was suitable for evaluating the stability of the analytes in plasma samples, although small concentration variations occurred. Furthermore, the investigation on the energetics of fragmentation pathways allowed the better product ions and optimal abundance ratios to be selected for LEDA application into a multi-component analysis.

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In vitro and in silico analysis of the vascular effects of asymmetrical N,N-bis(alkanol)amine aryl esters, novel multidrug resistance-reverting agents

Fusi

Spiga

Trezza

et al. 2016

Naunyn-Schmiedeberg's Arch Pharmacol

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Asymmetrical N,N-bis(alkanol)amine aryl esters (FRA77, GDE6, and GDE19) are potent multidrug resistance (MDR) reversers. Their structures loosely remind that of the Ca(2+) antagonist verapamil. Therefore, the aim of this study was to investigate their vascular activity in vitro. Their effects on the mechanical activity of fresh and cultured rat aorta rings on Cav1.2 channel current (I Ca1.2) of A7r5 cells and their cytotoxicity on A7r5 and EA.hy926 cells were analyzed. Docking at the rat α1C subunit of the Cav1.2 channel was simulated in silico. Compounds tested were cytotoxic at concentrations >1 μM (FRA77, GDE6, GDE19) and >10 μM (verapamil) in EA.hy926 cells, or >10 μM (FRA77, GDE6, GDE19) and at 100 μM (verapamil) in A7r5 cells. In fresh rings, the three compounds partly antagonized phenylephrine and 60 mM K(+) (K60)-induced contraction at concentrations ≥1 and ≥3 μM, respectively. On the contrary, verapamil fully relaxed rings pre-contracted with both agents. In cultured rings, 10 μM GDE6, GDE19, FRA77, and verapamil significantly reduced the contractile response to both phenylephrine and K60. Similarly to verapamil, the three compounds docked at the α1C subunit, interacting with the same amino acids residues. FRA77, GDE6, and GDE19 inhibited I Ca1.2 with IC50 values 1 order of magnitude higher than that of verapamil. FRA77-, GDE6-, and GDE19-induced vascular effects occurred at concentrations that are at least 1 order of magnitude higher than those effectively reverting MDR. Though an unambiguous divergence between MDR reverting and vascular activity is of overwhelming importance, these findings consistently contribute to the design and synthesis of novel and potent chemosensitizers.

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

Cited by 20 publications

References 46 publications

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

The power of energy‐resolved tandem mass spectrometry experiments for resolution of isomers: the case of drug plasma stability investigation of multidrug resistance inhibitors

In vitro and in silico analysis of the vascular effects of asymmetrical N,N-bis(alkanol)amine aryl esters, novel multidrug resistance-reverting agents

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