In vitro and in vivo cytotoxic activity and human serum albumin interaction for a methoxy-styryl-thiosemicarbazone
Thiosemicarbazone is a class of compounds with potential applications in medicine, presenting high capacity to inhibit the growth of cancer cells as well as low toxicity. Because of high interest in anticancer studies involving thiosemicarbazones as new chemotherapeutic agents, a synthetic thiosemicarbazone derivative, 4-N-(2′-methoxy-styryl)-thiosemicarbazone (MTSC) was evaluated in vivo against Ehrlich carcinoma in an animal model. In vivo results demonstrated that MTSC treatment induced the survival of mice and altered significantly the body weight of the surviving mice 12 days after tumor inoculation. Treatment with 30 mg/kg of MTSC exhibited effective cytotoxic activity with T/C values of 150.49% (1 dose) and 278% (2 doses). Its interaction with human serum albumin (HSA), which plays a crucial role in the biodistribution of a wide variety of ligands, was investigated by multiple spectroscopic techniques at 296 K, 303 K, and 310 K, as well as by theoretical calculations. The interaction between HSA and MTSC occurs via ground-state association in the subdomain IIA (Sudlow’s site I). The binding is moderate (Ka ≈ 104 M–1), spontaneous, entropically, and enthalpically driven. Molecular docking results suggested hydrogen bonding and hydrophobic interactions as the main binding forces. Overall, the interaction HSA:MTSC could provide therapeutic benefits, improving its cytotoxic efficacy and tolerability.
KeywordsThiosemicarbazones Ehrlich carcinoma Human serum albumin Spectroscopy Molecular docking
The authors gratefully acknowledge the financial support from the Brazilian agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico, Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Programa de Oncobiologia UFRJ. The authors acknowledge Profa. Dra. Nanci Camara de Lucas Garden (UFRJ) for the time-resolved and synchronous fluorescence facilities, as well as Prof. Dr. Carlos M.R. Sant’Anna (UFRRJ) for the computational facilities. O.A.C. acknowledges Instituto Euvaldo Lodi (IEL-Brazil) for the researcher grant in the SENAI Innovation Institute for Green Chemistry (Encomenda Rhae Trainee II - 404988/2017-2 -Process: 350173/2018-4). J.C.N.-F. acknowledges INMETRO for a Visiting Professor fellowship. The authors thank Dra. Vivian M. Rumjanek from Instituto de Bioquímica Médica of UFRJ for providing cell lines.
The study was supported by Brazilian agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The in vivo assays procedures were performed in accordance to the Brazilian Guidelines (Brazilian Directive for Care and Use of Animals for Teaching and Research-DBCA) published by the Brazilian Council for Control of Animal Experimentation (Conselho Nacional de Controle de Experimentação Animal – CONCEA) and Brazilian Federal Law 11.794 (October 8, 2008). The local research ethics committee of the Universidade Federal Rural do Rio de Janeiro, Brazil, approved the protocols used in the present study (Number 6985210617).
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