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Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistanceстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 19 июня 2024 г.
- Авторы: Nevskaya Alisa A., Purgatorio Rosa, Borisova Tatiana N., Varlamov Alexey V., Anikina Lada V., Obydennik Arina Yu, Nevskaya Elena Yu, Niso Mauro, Colabufo Nicola A., Carrieri Antonio, Catto Marco, de Candia Modesto, Voskressensky Leonid G., Altomare Cosimo D.
- Журнал: Pharmaceuticals
- Том: 17
- Номер: 4
- Год издания: 2024
- Издательство: MDPI
- Местоположение издательства: Basel, Switzerland
- Номер статьи: 539
- DOI: 10.3390/ph17040539
- Аннотация: Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure\u2013activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base (8c) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 \u03bcM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 \u03bcM, respectively.
- Добавил в систему: Малошицкая Ольга Александровна