Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents
1
Departamento de Antibióticos, Centro de Biociências, Universidade Federal de Pernambuco, Recife, PE, 50740-520, Brazil
2
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, Recife, PE, 50740-520, Brazil
3
Université de Nantes, Cibles et Médicaments des Infections et du Cancer, IICiMed, EA 1155, Nantes, F-44000, France
4
Sorbonne Université, CNRS, USR3151, « Protein phosphorylation and human diseases » Unit, Station Biologique, Roscoff, F-29688, France
5
Sorbonne Université, CNRS, FR2424, Kinase Inhibitor Specialized Screening Facility - KISSf, Station Biologique, Roscoff, F-29688, France
6
Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraiba, João Pessoa, PB, 58071-160, Brazil
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2019, 12(4), 169; https://doi.org/10.3390/ph12040169
Received: 10 October 2019 / Revised: 14 November 2019 / Accepted: 14 November 2019 / Published: 17 November 2019
(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)
Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).
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Keywords:
semicarbazones; cytotoxicity; anticancer activity; cell cycle; apoptosis; kinase inhibition
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MDPI and ACS Style
Nascimento da Cruz, A.C.; Brondani, D.J.; I´talo de Santana, T.; Oliveira da Silva, L.; da Oliveira Borba, E.F.; de Faria, A.R.; Ferreira Cavalcanti de Albuquerque, J.; Piessard, S.; Matos Ximenes, R.; Baratte, B.; Bach, S.; Ruchaud, S.; Bezerra Mendonça Junior, F.J.; Bazin, M.-A.; Montenegro Rabello, M.; Hernandes, M.Z.; Marchand, P.; Gonçalves da Silva, T. Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents. Pharmaceuticals 2019, 12, 169.
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