A New Class of 1-Aryl-5,6-dihydropyrrolo[2,1-a]isoquinoline Derivatives as Reversers of P-Glycoprotein-Mediated Multidrug Resistance in Tumor Cells

A number of aza-heterocyclic compounds, which share the 5,6-dihydropyrrolo[2,1-a]isoquinoline (DHPIQ) scaffold with members of the lamellarin alkaloid family, were synthesized and evaluated for their ability to reverse in vitro multidrug resistance in cancer cells through inhibition of P-glycoprotein (P-gp) and/or multidrug-resistance-associated protein 1. Most of the investigated DHPIQ compounds proved to be selective P-gp modulators, and the most potent modulator, 8,9-diethoxy-1-(3,4-diethoxyphenyl)-3-(furan-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde, attained sub-micromolar inhibitory potency (IC50: 0.19 μm). Schiff bases prepared by the condensation of some 1-aryl-DHPIQ aldehydes with p-aminophenol also proved to be of some interest, and one of them, 4-((1-(4-fluorophenyl)-5,6-dihydro-8,9-dimethoxypyrrolo[2,1-a]isoquinolin-2-yl)methyleneamino)phenol, had an IC50 value of 1.01 μm. In drug combination assays in multidrug-resistant cells, some DHPIQ compounds, at nontoxic concentrations, significantly increased the cytotoxicity of doxorubicin in a concentration-dependent manner. Studies of structure–activity relationships and investigation of the chemical stability of Schiff bases provided physicochemical information useful for molecular optimization of lamellarin-like cytotoxic drugs active toward chemoresistant tumors as well as nontoxic reversers of P-gp-mediated multidrug resistance in tumor cells. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Авторы
Nevskaya A.A. 1 , Matveeva M.D. 1 , Borisova T.N. 1 , Niso M.2 , Colabufo N.A.2 , Boccarelli A.3 , Purgatorio R.2 , De Candia M. , Cellamare S.2 , Voskressensky L.G. 1 , Altomare C.D.2
Редакторы
-
Журнал
Издательство
John Wiley and Sons Ltd
Номер выпуска
15
Язык
Английский
Страницы
1588-1596
Статус
Опубликовано
Подразделение
-
Номер
-
Том
13
Год
2018
Организации
  • 1 Organic Chemistry Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, 117198, Russian Federation
  • 2 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, Bari, 70125, Italy
  • 3 Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Piazza Giulio Cesare 11, Bari, 70124, Italy
Ключевые слова
efflux transporters; multidrug resistance; P-glycoproteins; pyrrolo[2,1-a]isoquinolines; structure–activity relationships
Дата создания
19.10.2018
Дата изменения
19.10.2018
Постоянная ссылка
https://repository.rudn.ru/ru/records/article/record/6461/