870449-49-3Relevant academic research and scientific papers
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
, p. 398 - 412 (2015/01/08)
As a continuation of our research on potent and efficacious P-gp-dependent multidrug resistance (MDR) reversers, several new N,N-bis(alkanol)amine aryl esters were designed and synthesized, varying the aromatic moieties or the length of the methylenic chain. The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay, where most of the new compounds were shown to be active. In particular the asymmetrical compounds, characterized by two linkers of different length, generally showed fairly high activities as MDR reversers. Some selected compounds (isomers 15-17) were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) on the K562/DOX cell line. The results of both pharmacological assays indicate that compounds 16 (GDE6) and 17 (GDE19) could be interesting leads for the development of new P-gp dependent MDR modulators.
Structure-activity relationships studies in a series of N,N-bis(alkanol)amine aryl esters as P-glycoprotein (Pgp) dependent multidrug resistance (MDR) inhibitors
Martelli, Cecilia,Coronnello, Marcella,Dei, Silvia,Manetti, Dina,Orlandi, Francesca,Scapecchi, Serena,Romanelli, Maria Novella,Salerno, Milena,Mini, Enrico,Teodori, Elisabetta
experimental part, p. 1755 - 1762 (2010/08/06)
As a continuation of a previous research, a series of N,N-bis(alkanol)amine aryl esters, as Pgpdependent MDR inhibitors, was designed and synthesized. The aromatic ester portions are suitably modulated, and new aryl rings (Ar 1 and Ar2) were combined with trans-3-(3,4,5- trimethoxyphenyl)vinyl, 3,4,5-trimethoxybenzyl and anthracene moieties that were present in the most potent previously studied compounds. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Selected compounds (5, 6, 8, 9, and 21) were further studied, evaluating their action on doxorubicin cytotoxicity potentiation on K562 cells; they significantly enhanced doxorubicin cytotoxicity on K562/DOX cells, confirming the results obtained with pirarubicin. Compound, 9 shows the most promising properties as it was able to nearly completely reverse Pgp-dependent pirarubicin extrusion at nanomolar doses and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 19.1. at 3 μM dose.
Exploratory chemistry toward the identification of a new class of multidrug resistance reverters inspired by pervilleine and verapamil models
Teodori, Elisabetta,Dei, Silvia,Garnier-Suillerot, Arlette,Gualtieri, Fulvio,Manetti, Dina,Martelli, Cecilia,Romanelli, Maria Novella,Scapecchi, Serena,Sudwan, Paiwan,Salerno, Milena
, p. 7426 - 7436 (2007/10/03)
On the basis of the present knowledge of the substrate recognition site of ABC transporter proteins and inspired by the structures of verapamil and pervilleine A, a new class of Pgp-mediated multidrug resistance (MDR) reverters has been designed and synthesized. The new compounds are flexible molecules carrying one or two basic nitrogen atoms flanked, at properly modulated distance, by two aromatic moieties. Most of the molecules studied possess MDR inhibitory activity on anthracycline-resistant erythroleukemia K 562 cells, showing a potency that is higher than that of the reference compound verapamil and, in a few cases (7, 12, 13, 17, 20, 22, 28), is in the high nanomolar range. These compounds may be useful leads to develop new MDR reverting agents. In fact, the chemical structure of the class is fairly simple and can be implemented in a variety of ways that will allow the synthesis of new compounds that might be useful leads for the development of drugs to control Pgp-dependent MDR.
