1. Effect of mono- and dinuclear thiosemicarbazone platinacycles in the proliferation of a colorectal carcinoma cell line.
- Author
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Reigosa-Chamorro F, Cordeiro S, Pereira MT, Filipe B, Baptista PV, Fernandes AR, and Vila JM
- Subjects
- Humans, Animals, Membrane Potential, Mitochondrial drug effects, Organoplatinum Compounds pharmacology, Organoplatinum Compounds chemistry, Organoplatinum Compounds chemical synthesis, HCT116 Cells, Drug Screening Assays, Antitumor, Cell Line, Tumor, Molecular Structure, Structure-Activity Relationship, Coordination Complexes pharmacology, Coordination Complexes chemistry, Coordination Complexes chemical synthesis, Thiosemicarbazones chemistry, Thiosemicarbazones pharmacology, Thiosemicarbazones chemical synthesis, Cell Proliferation drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Colorectal Neoplasms pathology, Colorectal Neoplasms drug therapy, Colorectal Neoplasms metabolism, Apoptosis drug effects, Reactive Oxygen Species metabolism
- 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 {Ph the induction of reactive oxygen species (ROS). The three compounds were not toxic to a chicken embryo2 P(CH2 )4 PPh2 }] , and phosphine derivatives, were deemed unpromising owing to their lack of activity. However, mono-coordinated diphosphine complexes [Pt( L1-L3 )(Ph2 PCH2 PPh2 - 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.- Published
- 2024
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