In vitro characterization of arylhydrazones of active methylene derivatives

Suresh Palanivel; Anastasia Zhurina; Phuong Doan; Jerome G. Chandraseelan; Vinoth Kumar Megraj Khandelwal; Fedor I. Zubkov; Kamran T. Mahmudov; Armando J.L. Pombeiro; Olli Yli-Harja; Meenakshisundaram Kandhavelu

doi:10.1016/j.jsps.2017.12.018

Saudi Pharmaceutical Journal (Mar 2018)

In vitro characterization of arylhydrazones of active methylene derivatives

Suresh Palanivel,
Anastasia Zhurina,
Phuong Doan,
Jerome G. Chandraseelan,
Vinoth Kumar Megraj Khandelwal,
Fedor I. Zubkov,
Kamran T. Mahmudov,
Armando J.L. Pombeiro,
Olli Yli-Harja,
Meenakshisundaram Kandhavelu

Affiliations

Suresh Palanivel: Molecular Signaling Lab, CSB, BioMediTech Institute and Faculty of Biomedical Sciences and Engineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland
Anastasia Zhurina: Molecular Signaling Lab, CSB, BioMediTech Institute and Faculty of Biomedical Sciences and Engineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland
Phuong Doan: Molecular Signaling Lab, CSB, BioMediTech Institute and Faculty of Biomedical Sciences and Engineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland
Jerome G. Chandraseelan: Molecular Signaling Lab, CSB, BioMediTech Institute and Faculty of Biomedical Sciences and Engineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland
Vinoth Kumar Megraj Khandelwal: Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy
Fedor I. Zubkov: Organic Chemistry Department, RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
Kamran T. Mahmudov: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal; Department of Ecology and Soil Sciences, Baku State University, Z. Xalilov Str. 23, Az 1148 Baku, Azerbaijan
Armando J.L. Pombeiro: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
Olli Yli-Harja: Computational Systems Biology Group, BioMediTech Institute and Faculty of Biomedical Sciences and Engineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland
Meenakshisundaram Kandhavelu: Molecular Signaling Lab, CSB, BioMediTech Institute and Faculty of Biomedical Sciences and Engineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland; Corresponding author.

DOI: https://doi.org/10.1016/j.jsps.2017.12.018
Journal volume & issue: Vol. 26, no. 3
pp. 430 – 436

Abstract

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Arylhydrazones of active methylene compounds (AHAMCs) are potent chemotherapy agents for the cancer treatment. AHAMCs enhance the apoptotic cell death and antiproliferation properties in cancer cells. In this study, a series of AHAMCs, 13 compounds, was assayed for cytotoxicity, apoptosis, externalization of phosphatidylserine, heterogeneity and cellular calcium level changes. The in vitro cytotoxicity study against HEK293T cells suggests that AHAMCs have significant cytotoxic effect over the concentrations. Top 5 compounds, 5-(2-(2-hydroxyphenyl) hydrazono)pyrimidine-2,4,6(1H,3H,5H)-trione (5), 4-hydroxy-5-(2-(2,4,6-trioxo-tetrahydro-pyrimidin-5(6H) ylidene)hydrazinyl)benzene-1,3-disulfonic acid (6), 5-chloro-3-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-2-hydroxybenzenesulfonic acid (8), 5-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-4-hydroxybenzene-1,3-disulfonic acid (9) and 2-(2-sulfophenylhydrazo)malononitrile (10) were chosen for the pharmacodynamics study. Among these, compound 5 exhibited the better cytotoxic effect with the IC50 of 50.86 ± 2.5 mM. DNA cleavage study revealed that 5 induces cell death through apoptosis and shows more effects after 24 and/or 48 h. Independent validation of apoptosis by following the externalization of phosphatidylserine using Annexin-V is also in agreement with the potential activity of 5. Single cell image analysis of Annexin-V bound cells confirms the presence of mixture of early, mid and late apoptotic cells in the population of the cells treated with 5 and a decreased trend in cell-to-cell variation over the phase was also identified. Additionally, intracellular calcium level measurements identified the Ca2+ up-regulation in compound treated cells. A brief inspection of the effect of the compound 5 against multiple human brain astrocytoma cells showed a better cell growth inhibitory effect at micro molar level. These systematic studies provide insights in the development of novel AHAMACs compounds as potential cell growth inhibitors for cancer treatment.

Published in Saudi Pharmaceutical Journal

ISSN: 1319-0164 (Print)
Publisher: Elsevier
Country of publisher: Saudi Arabia
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/saudi-pharmaceutical-journal/

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