Unravelling the antitumoral potential of novel bis(thiosemicarbazonato) Zn(II) complexes: structural and cellular studies

  • Elisa Palma
  • Hugo M. Botelho
  • Goreti Ribeiro Morais
  • Inês Rodrigues
  • Isabel Cordeiro Santos
  • Maria Paula Cabral Campello
  • Paula Raposinho
  • Ana Belchior
  • Susana Sousa Gomes
  • Maria Fátima Araújo
  • Isabel Correia
  • Nadia Ribeiro
  • Sofia Gama
  • Filipa MendesEmail author
  • António PauloEmail author
Original Paper


The development of pharmacologically active compounds based on bis(thiosemicarbazones) (BTSC) and on their coordination to metal centers constitutes a promising field of research. We have recently explored this class of ligands and their Cu(II) complexes for the design of cancer theranostics agents with enhanced uptake by tumoral cells. In the present work, we expand our focus to aliphatic and aromatic BTSC Zn(II) complexes bearing piperidine/morpholine pendant arms. The new complexes ZnL1ZnL4 were characterized by a variety of analytical techniques, which included single-crystal X-ray crystallography for ZnL2 and ZnL3. Taking advantage of the fluorescent properties of the aromatic complexes, we investigated their cellular uptake kinetics and subcellular localization. Furthermore, we tried to elucidate the mechanism of action of the cytotoxic effect observed in human cancer cell line models. The results show that the aliphatic complexes (ZnL1 and ZnL2) have a symmetrical structure, while the aromatic counterparts (ZnL3 and ZnL4) have an asymmetrical nature. The cytotoxic activity was higher for the aromatic BTSC complexes, as well as the cellular uptake, evaluated by measurement of intracellular Zn accumulation. Among the most active complexes, ZnL3 presented the fastest uptake kinetics and lysosomal localization assessed by live-cell microscopy. Detailed studies of its impact on cellular production of reactive oxygen species and impairment of lysosomal membrane integrity reinforced the influence of the pendant piperidine in the biological performance of aromatic BTSC Zn(II) complexes.


Zinc Bis(thiosemicarbazones) X-ray diffraction Fluorescence imaging Cellular studies 



This work was supported by Fundação para a Ciência e Tecnologia (projects PTDC/QUI–QUI/114139/2009, RECI/QEQ-QIN/0189/2012, EXCL/QEQ-MED/0233/2012, UID/Multi/04349/2013 (to C2TN) and UID/Multi/04046/2013 (to BioISI); fellowships SFRH/BPD/29564/2006, SFRH/BPD/80758/2011, SFRH/BPD/93017/2013 and SFRH/BPD/112654/2015 to S. Gama, E. Palma and H.M: Botelho, respectively, and Grants Ciência 2008 to G. Ribeiro Morais and FCT Investigator to F. Mendes and I. Correia) and Collaborative Research Centre ChemBioSys (CRC 1127) funded by the Deutsche Forschungsgemeinschaft (DFG). The authors would also like to thank Pedro Reis for the elemental analyses measurements. We also thank the Fundação para a Ciência e a Tecnologia for financial support through RNEM—Portuguese Mass Spectrometry Network. The authors declare no competing financial interest.

Supplementary material

775_2018_1629_MOESM1_ESM.docx (32 kb)
Summary of crystallographic data NMR and fluorescence spectra See DOI: (DOCX 31 kb)


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Copyright information

© SBIC 2018

Authors and Affiliations

  • Elisa Palma
    • 1
    • 2
  • Hugo M. Botelho
    • 3
  • Goreti Ribeiro Morais
    • 1
    • 4
  • Inês Rodrigues
    • 1
  • Isabel Cordeiro Santos
    • 1
  • Maria Paula Cabral Campello
    • 1
  • Paula Raposinho
    • 1
  • Ana Belchior
    • 1
  • Susana Sousa Gomes
    • 1
  • Maria Fátima Araújo
    • 1
  • Isabel Correia
    • 2
  • Nadia Ribeiro
    • 2
  • Sofia Gama
    • 1
    • 5
  • Filipa Mendes
    • 1
    Email author
  • António Paulo
    • 1
    Email author
  1. 1.Centro de Ciências e Tecnologias Nucleares, Instituto Superior TécnicoUniversidade de LisboaBobadela LRSPortugal
  2. 2.Centro Química Estrutural, Instituto Superior TécnicoUniversidade de LisboaLisbonPortugal
  3. 3.BioISI—Biosystems and Integrative Sciences InstituteUniversity of Lisboa, Faculty of SciencesLisbonPortugal
  4. 4.Institute of Cancer Therapeutics, Faculty of Life SciencesUniversity of BradfordBradfordUK
  5. 5.Institut für Anorganische und Analytische Chemie, Friedrich-Schiller-Universität JenaJenaGermany

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