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.

Autor: Nevskaya AA; Organic Chemistry Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, 117198, Russia., Matveeva MD; Organic Chemistry Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, 117198, Russia., Borisova TN; Organic Chemistry Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, 117198, Russia., Niso M; Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy., Colabufo NA; Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy., Boccarelli A; Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124, Bari, Italy., Purgatorio R; Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy., de Candia M; Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy., Cellamare S; Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy., Voskressensky LG; Organic Chemistry Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, 117198, Russia., Altomare CD; Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2018 Aug 10; Vol. 13 (15), pp. 1588-1596. Date of Electronic Publication: 2018 Jul 04.
DOI: 10.1002/cmdc.201800177
Abstrakt: 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 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 IC 50 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.)
Databáze: MEDLINE
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