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 |
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Authors: | Alisa A. Nevskaya Maria D. Matveeva Prof. Tatiana N. Borisova Dr. Mauro Niso Prof. Nicola A. Colabufo Dr. Angelina Boccarelli Dr. Rosa Purgatorio Dr. Modesto de Candia Prof. Saverio Cellamare Prof. Leonid G. Voskressensky Prof. Cosimo D. Altomare |
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Affiliation: | 1. Organic Chemistry Department, Peoples' Friendship University of Russia, Moscow, Russia;2. Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Bari, Italy;3. Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy |
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Abstract: | 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. |
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Keywords: | efflux transporters multidrug resistance P-glycoproteins pyrrolo[2,1-a]isoquinolines structure– activity relationships |
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