Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Nature-Inspired 1-phenylpyrrolo[2,1-A]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance

Alisa A. Nevskaya
ORCID logo ,
Rosa Purgatorio
ORCID logo ,
Arina Obydennik
,
Lada Anikina
,
Elena Yu. Nevskaya
,
Tatiana N. Borisova
,
Alexey V. Varlamov
,
Mauro Niso
,
Nicola Antonio Colabufo
,
Antonio Carrieri
ORCID logo ,
Marco Catto
ORCID logo ,
Modesto De Candia
ORCID logo ,
Leonid G. Voskressensky
,
Cosimo D. Altomare
* ORCID logo
Version 1 : Received: 7 March 2024 / Approved: 8 March 2024 / Online: 8 March 2024 (04:15:49 CET)

A peer-reviewed article of this Preprint also exists.

Nevskaya, A.A.; Purgatorio, R.; Borisova, T.N.; Varlamov, A.V.; Anikina, L.V.; Obydennik, A.Y.; Nevskaya, E.Y.; Niso, M.; Colabufo, N.A.; Carrieri, A.; Catto, M.; de Candia, M.; Voskressensky, L.G.; Altomare, C.D. Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance. Pharmaceuticals 2024, 17, 539. Nevskaya, A.A.; Purgatorio, R.; Borisova, T.N.; Varlamov, A.V.; Anikina, L.V.; Obydennik, A.Y.; Nevskaya, E.Y.; Niso, M.; Colabufo, N.A.; Carrieri, A.; Catto, M.; de Candia, M.; Voskressensky, L.G.; Altomare, C.D. Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance. Pharmaceuticals 2024, 17, 539.

Abstract

Previous studies showed 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 tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, we synthesized and evaluated for their antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and ability of inhibiting P-gp-mediated MDR some ten diversely substituted 1-Ph-DHPIQ derivatives bearing at position 2 carboxylate groups (COOH, COOEt), nitriles (CN) and Mannich bases (e.g., morpholinomethyl derivatives). Lipophilicity parametrization and molecular docking calculations improved the understanding of the structure-activity relationships in cytotoxicity and P-gp inhibition of the investigated 1-Ph-DHPIQs, which led us to disclose a novel Mannich base HCl salt (8b’), which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 M) and to inhibit in-vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 M, respectively.

Keywords

pyrrolo[2,1-a]isoquinolines; Mannich bases; cytotoxicity; P-glycoprotein; inhibition; multidrug resistance reversal.

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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