In vitro characterization of arylhydrazones of active methylene derivatives

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. © 2017 The Authors

Palanivel S.1 , Zhurina A.1 , Doan P.1 , Chandraseelan J.G.1 , Khandelwal V.K.M.3 , Zubkov F.I. 4 , Mahmudov K.T. 5, 6 , Pombeiro A.J.L.5 , Yli-Harja O.2 , Kandhavelu M.1
Elsevier B.V.
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  • 1 Molecular Signaling LabCSB, BioMediTech Institute and Faculty of Biomedical Sciences and EngineeringTampere University of Technology, P.O. Box 553, Tampere, 33101, Finland
  • 2 Computational Systems Biology GroupBioMediTech Institute and Faculty of Biomedical Sciences and EngineeringTampere University of Technology, P.O. Box 553, Tampere, 33101, Finland
  • 3 Department of Translational PharmacologyConsorzio Mario Negri Sud, Santa Maria Imbaro, Italy
  • 4 Organic Chemistry DepartmentRUDN University, 6 Miklukho-Maklaya St., Moscow, 117198, Russian Federation
  • 5 Centro de Química Estrutural, Instituto Superior TécnicoUniversidade de Lisboa, Av. Rovisco Pais, Lisbon, 1049-001, Portugal
  • 6 Department of Ecology and Soil SciencesBaku State University, Z. Xalilov Str. 23, Baku, Az 1148, Azerbaijan
Ключевые слова
Apoptosis; Arylhydrazones of active methylene compounds; Chemotherapy; Cytotoxic effect; Glioma; Immortal cells; Single cell analysis
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