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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
Author(s) -
Nevskaya Alisa A.,
Matveeva Maria D.,
Borisova Tatia.,
Niso Mauro,
Colabufo Nicola A.,
Boccarelli Angelina,
Purgatorio Rosa,
de Candia Modesto,
Cellamare Saverio,
Voskressensky Leonid G.,
Altomare Cosimo D.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800177
Subject(s) - isoquinoline , multiple drug resistance , chemistry , cytotoxicity , p glycoprotein , stereochemistry , in vitro , ic50 , aryl , combinatorial chemistry , biochemistry , organic chemistry , alkyl , antibiotics
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 (IC 50 : 0.19 μ m ). 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 IC 50 value of 1.01 μ m . 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.