Modulation of the spacer in N,N-bis(alkanol)amine aryl ester heterodimers led to the discovery of a series of highly potent P-glycoprotein-based multidrug resistance (MDR) modulators

Dei, Silvia; Braconi, Laura; Trezza, Alfonso; Menicatti, Marta; Contino, Marialessandra; Coronnello, Marcella; Chiaramonte, Niccolò; Manetti, Dina; Perrone, Maria Grazia; Romanelli, Maria Novella; Udomtanakunchai, Chatchanok; Colabufo, Nicola Antonio; Bartolucci, Gianluca; Spiga, Ottavia; Salerno, Milena; Teodori, Elisabetta

doi:10.1016/j.ejmech.2019.03.054

Cited by 28 publications

(38 citation statements)

References 49 publications

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“…For this purpose, a series of experiments were carried out, adding a known amount of analyte in both phosphate buffer solution (PBS) and in human plasma. The samples were analysed by LC-MS/MS method operating in Multiple Reaction Monitoring (MRM) mode 55 .…”

Section: Chemical Stability Testmentioning

confidence: 99%

“…Since under the proposed experimental conditions, a half-life over 240 min is not correctly evaluated, it is reasonable to consider that their half-life values could be equal or greater than 240 min. Furthermore, the half-life value of ketoprofene ethylester (KEE), used as reference compound, demonstrated that the employed human batch was enzymatically active (t 1/2 < 2 h) 55 .…”

Section: Chemical Stability Testmentioning

confidence: 99%

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6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

Braconi

Bartolucci

Contino

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Aiming to deepen the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.

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Section: Chemical Stability Testmentioning

confidence: 99%

Section: Chemical Stability Testmentioning

confidence: 99%

6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

Braconi

Bartolucci

Contino

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…We incorporated coumarin or benzene sulfonamide moieties in a typical scaffold of P-glycoprotein ligands that were previously studied by some of us. For many years one of our research group has been involved in the study of P-gp ligands with the aim to discover potent MDR modulators [33][34][35][36][37][38][39]. For this purpose, we designed and synthesized several compounds carrying the structural elements considered important for P-gp interaction, such as high lipophilicity, the presence of hydrogen bond acceptor groups, aromatic moieties and one or more protonable nitrogen atoms [40].…”

Section: Introductionmentioning

confidence: 99%

“…For this purpose, we designed and synthesized several compounds carrying the structural elements considered important for P-gp interaction, such as high lipophilicity, the presence of hydrogen bond acceptor groups, aromatic moieties and one or more protonable nitrogen atoms [40]. The structure of these molecules is characterized by the presence of a basic nitrogen atom linked to aromatic ester residues by spacers of different flexibility and length [33][34][35][36][37][38][39]. Most of these compounds are N,N-bis(alkanol)amine aryl diesters that were potent and efficient P-gp-dependent multidrug resistance reversers on the doxorubicin-resistant erythroleukemia K562 cell line (Structure A, Chart 1) [35][36][37][38][39].…”

Section: Introductionmentioning

confidence: 99%

“…The structure of these molecules is characterized by the presence of a basic nitrogen atom linked to aromatic ester residues by spacers of different flexibility and length [33][34][35][36][37][38][39]. Most of these compounds are N,N-bis(alkanol)amine aryl diesters that were potent and efficient P-gp-dependent multidrug resistance reversers on the doxorubicin-resistant erythroleukemia K562 cell line (Structure A, Chart 1) [35][36][37][38][39]. Acetazolamide and other classical CA inhibitors contain an aromatic sulfonamide moiety, which coordinates the zinc ion buried at the bottom of the conical CA active site [28].…”

Section: Introductionmentioning

confidence: 99%

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Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells

et al. 2020

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A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.

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Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

Zhang

Ashby

et al. 2020

Medicinal Research Reviews

202

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Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR.

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Modulation of the spacer in N,N-bis(alkanol)amine aryl ester heterodimers led to the discovery of a series of highly potent P-glycoprotein-based multidrug resistance (MDR) modulators

Cited by 28 publications

References 49 publications

6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells

Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

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