Citation:

Effect of mono- and dinuclear thiosemicarbazone platinacycles in the proliferation of a colorectal carcinoma cell line, Reigosa-Chamorro, Francisco, Cordeiro Sandra, Pereira Teresa} {M., Filipe Beatriz, Baptista {Pedro V. }, Fernandes {Alexandra R. }, and Vila {José M. } , Dalton Transactions, (2024)

Abstract:

Herein, we describe the synthesis and characterization of a series of thiosemicarbazone platinacycles. Their activity towards HCT116 and A2780 cancer cell lines as well as normal fibroblasts was explored and conclusions about the influence of their structures were drawn based on the results. Ligands L1-3, tetranuclear compounds [Pt(L1-3)]4, [Pt(L1-3)(PPh3)], and [Pt(L1-L3)2{Ph2P(CH2)4PPh2}], and phosphine derivatives, were deemed unpromising owing to their lack of activity. However, mono-coordinated diphosphine complexes [Pt(L1-L3)(Ph2PCH2PPh2-P)] showed high selectivity and low IC50 values, and their antiproliferative activity was further studied. The three studied derivatives 3a, 3b and 3c showed a fast internalization of HCT116 colorectal cancer cells with similar IC50 values, which induced a depolarization of mitochondrial membrane potential, with the subsequent triggering of apoptosis and autophagy in the case of 3c. In the case of compounds 3a and 3b, cell death mechanisms (extrinsic and intrinsic apoptosis, respectively) were triggered via the induction of reactive oxygen species (ROS). The three compounds were not toxic to a chicken embryo in vivo (after 48 h), and, importantly, showed an anti-angiogenic potential after exposure to the IC50 of compounds 3a, 3b and 3c.

Notes:

Funding Information: This work is financed by national funds from FCT - Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia, I.P., in the scope of the project DOI: https://doi.org/10.54499/UIDP/04378/2020 and DOI: https://doi.org/10.54499/UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences - UCIBIO and the project DOI: https://doi.org/10.54499/LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy - i4HB and doctoral grant 2021.08629.BD (S. Cordeiro). We thank Tatiana Fernandes for her help in performing the stability spectral measurements and western blot assay. Funding Information: This work was also made possible thanks to the financial support received from the Xunta de Galicia (Galicia, Spain) under the Grupos de Referencia Competitiva Programme (project GRC2019/14). F. R. thanks the Spanish Ministry of Education (grant FPU15/07145). Publisher Copyright: © 2024 The Royal Society of Chemistry.