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Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs

[Image: see text] The search for new scaffolds of medicinal significance combined with molecular shape enhances their innovative potential and continues to attract the attention of researchers. Herein, we report the synthesis, spectroscopic characterization ((1)H and (13)C NMR, UV–vis, IR), ESI-mass...

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Autores principales: Kuznetcova, Irina, Ostojić, Marija, Gligorijević, Nevenka, Aranđelović, Sandra, Arion, Vladimir B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768754/
https://www.ncbi.nlm.nih.gov/pubmed/36473464
http://dx.doi.org/10.1021/acs.inorgchem.2c03134
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author Kuznetcova, Irina
Ostojić, Marija
Gligorijević, Nevenka
Aranđelović, Sandra
Arion, Vladimir B.
author_facet Kuznetcova, Irina
Ostojić, Marija
Gligorijević, Nevenka
Aranđelović, Sandra
Arion, Vladimir B.
author_sort Kuznetcova, Irina
collection PubMed
description [Image: see text] The search for new scaffolds of medicinal significance combined with molecular shape enhances their innovative potential and continues to attract the attention of researchers. Herein, we report the synthesis, spectroscopic characterization ((1)H and (13)C NMR, UV–vis, IR), ESI-mass spectrometry, and single-crystal X-ray diffraction analysis of a new ring system of medicinal significance, 5,6,7,9-tetrahydro-8H-indolo[3,2-e]benzazocin-8-one, and a series of derived potential ligands (HL(1)–HL(5)), as well as ruthenium(II), osmium(II), and copper(II) complexes (1a, 1b, and 2–5). The stability of compounds in 1% DMSO aqueous solutions has been confirmed by (1)H NMR and UV–vis spectroscopy measurements. The antiproliferative activity of HL(1)–HL(5) and 1a, 1b, and 2–5 was evaluated by in vitro cytotoxicity tests against four cancer cell lines (LS-174, HCT116, MDA-MB-361, and A549) and one non-cancer cell line (MRC-5). The lead compounds HL(5) and its copper(II) complex 5 were 15× and 17×, respectively, more cytotoxic than cisplatin against human colon cancer cell line HCT116. Annexin V-FITC apoptosis assay showed dominant apoptosis inducing potential of both compounds after prolonged treatment (48 h) in HCT116 cells. HL(5) and 5 were found to induce a concentration- and time-dependent arrest of cell cycle in colon cancer cell lines. Antiproliferative activity of 5 in 3D multicellular tumor spheroid model of cancer cells (HCT116, LS-174) superior to that of cisplatin was found. Moreover, HL(5) and 5 showed notable inhibition potency against glycogen synthase kinases (GSK-3α and GSK-3β), tyrosine-protein kinase (Src), lymphocyte-specific protein-tyrosine kinase (Lck), and cyclin-dependent kinases (Cdk2 and Cdk5) (IC(50) = 1.4–6.1 μM), suggesting their multitargeted mode of action as potential anticancer drugs.
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spelling pubmed-97687542022-12-22 Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs Kuznetcova, Irina Ostojić, Marija Gligorijević, Nevenka Aranđelović, Sandra Arion, Vladimir B. Inorg Chem [Image: see text] The search for new scaffolds of medicinal significance combined with molecular shape enhances their innovative potential and continues to attract the attention of researchers. Herein, we report the synthesis, spectroscopic characterization ((1)H and (13)C NMR, UV–vis, IR), ESI-mass spectrometry, and single-crystal X-ray diffraction analysis of a new ring system of medicinal significance, 5,6,7,9-tetrahydro-8H-indolo[3,2-e]benzazocin-8-one, and a series of derived potential ligands (HL(1)–HL(5)), as well as ruthenium(II), osmium(II), and copper(II) complexes (1a, 1b, and 2–5). The stability of compounds in 1% DMSO aqueous solutions has been confirmed by (1)H NMR and UV–vis spectroscopy measurements. The antiproliferative activity of HL(1)–HL(5) and 1a, 1b, and 2–5 was evaluated by in vitro cytotoxicity tests against four cancer cell lines (LS-174, HCT116, MDA-MB-361, and A549) and one non-cancer cell line (MRC-5). The lead compounds HL(5) and its copper(II) complex 5 were 15× and 17×, respectively, more cytotoxic than cisplatin against human colon cancer cell line HCT116. Annexin V-FITC apoptosis assay showed dominant apoptosis inducing potential of both compounds after prolonged treatment (48 h) in HCT116 cells. HL(5) and 5 were found to induce a concentration- and time-dependent arrest of cell cycle in colon cancer cell lines. Antiproliferative activity of 5 in 3D multicellular tumor spheroid model of cancer cells (HCT116, LS-174) superior to that of cisplatin was found. Moreover, HL(5) and 5 showed notable inhibition potency against glycogen synthase kinases (GSK-3α and GSK-3β), tyrosine-protein kinase (Src), lymphocyte-specific protein-tyrosine kinase (Lck), and cyclin-dependent kinases (Cdk2 and Cdk5) (IC(50) = 1.4–6.1 μM), suggesting their multitargeted mode of action as potential anticancer drugs. American Chemical Society 2022-12-06 2022-12-19 /pmc/articles/PMC9768754/ /pubmed/36473464 http://dx.doi.org/10.1021/acs.inorgchem.2c03134 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Kuznetcova, Irina
Ostojić, Marija
Gligorijević, Nevenka
Aranđelović, Sandra
Arion, Vladimir B.
Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs
title Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs
title_full Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs
title_fullStr Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs
title_full_unstemmed Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs
title_short Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs
title_sort enriching chemical space of bioactive scaffolds by new ring systems: benzazocines and their metal complexes as potential anticancer drugs
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768754/
https://www.ncbi.nlm.nih.gov/pubmed/36473464
http://dx.doi.org/10.1021/acs.inorgchem.2c03134
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