Itaconic acid hybrids as potential anticancer agents
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ORIGINAL ARTICLE
Itaconic acid hybrids as potential anticancer agents Ivana Perković1 · Maja Beus1 · Dominique Schols2 · Leentje Persoons2 · Branka Zorc1 Received: 8 July 2020 / Accepted: 28 September 2020 © Springer Nature Switzerland AG 2020
Abstract In this paper, we report the synthesis of novel hybrids 2–14 based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a naturally occurring compound with a Michael acceptor moiety, a key structural feature in several anticancer and antiviral drugs, responsible for the covalent binding of a drug to the cysteine residue of a specific protein. Aromatic parts of the hybrids also come from the substances reported as anticancer or antiviral agents. The synthetic route employed to access the amido-ester hybrids 2–13 used monomethyl itaconate or monomethyl itaconyl chloride and corresponding amines as the starting materials. Dimers 14 and 15 with two aminoindole or mefloquine moieties were prepared from itaconic acid and corresponding amino derivative, using standard coupling conditions (HATU/DIEA). All hybrids exerted anticancer effects in vitro against almost all the tumour cell lines that were evaluated (MCF-7, HCT 116, H460, LN-229, Capan-1, DND-41, HL-60, K-562, Z-138). Solid tumour cells were, in general, more responsive than the haematological cancer cells. The MCF-7 breast adenocarcinoma cell line appeared the most sensitive. Amido-ester 12 with chloroquine core and mefloquine homodimer 15 showed the highest activity with GI50 values between 0.7 and 8.6 µM. In addition, compound 15 also exerted antiviral activity against Zika virus and Coxsackievirus B4 in low micromolar concentrations. Graphic abstract
Keywords Itaconic acid · Hybrid · Michael acceptor · Anticancer activity · Antiviral activity
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-020-10147-6) contains supplementary material, which is available to authorized users. * Branka Zorc [email protected] Extended author information available on the last page of the article
Abbreviations Capan-1 Human pancreatic adenocarcinoma cell line CPE Cytopathic effect CQ Chloroquine DCC N,N′-dicyclohexylcarbodiimide DCM Dichloromethane DIEA N,N-diisopropylethylamine
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DND-41 T-acute lymphoblastic leukemia cell line DTX Docetaxel FAN Fluoroaniline FBS Foetal bovine serum HATU 1-[bis(dimethylamino)methylene]-1H1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate H460 Lung carcinoma cell line HBA Number of H-bond acceptors HBD Number of H-bond donors HCT 116 Colorectal carcinoma cell line HL-60 Acute promyelocytic leukemia cell line IA Itaconic acid IND Indole K-562 Chronic myelogenous leukemia cell line LN-229 Human glioblastoma cell line MCF-7 Breast adenocarcinoma cell line MDCK Madin-Darby Canine Kidney cell line MR Molar refractivity MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MQ Mefloquine MW Microwave irradiation PG Percentage of g
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