Pt() complexes based on cyclohexanediamines and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid: synthesis, characterization, cell penetration properties and antitumor activity

The Pt( iv ) complexes based on ( SP -4-2)-dichlorido(cyclohexane-1,4-diamine)platinum( ii ) (kiteplatin) and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid ( POA ) were investigated. Since POA contains a chiral carbon, all the possible Pt( iv ) isomers were prepared and characterized...

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Published in:Dalton transactions : an international journal of inorganic chemistry 2021-04, Vol.5 (13), p.4663-4672
Main Authors: Gabano, Elisabetta, Rangone, Beatrice, Perin, Elena, Caron, Giulia, Ermondi, Giuseppe, Vallaro, Maura, Gandin, Valentina, Marzano, Cristina, Barbanente, Alessandra, Margiotta, Nicola, Ravera, Mauro
Format: Article
Language:English
Subjects:
Anticancer properties
Body weight
Cancer
Cyclohexane
Diamines
Histones
Inhibitors
Isomers
NMR
Nuclear magnetic resonance
Octanoic acid
Penetration
Platinum
Weight loss
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Summary:The Pt( iv ) complexes based on ( SP -4-2)-dichlorido(cyclohexane-1,4-diamine)platinum( ii ) (kiteplatin) and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid ( POA ) were investigated. Since POA contains a chiral carbon, all the possible Pt( iv ) isomers were prepared and characterized, and their antiproliferative activity on six cancer cell lines was compared with that of the corresponding Pt( iv ) complexes containing the cyclohexane-1 R ,2 R -diamine equatorial ligand. To justify the very good antiproliferative activity (nanomolar IC 50 ), the polarity, lipophilicity, permeability, and cell accumulation of the complexes were studied. Overall, the two series of Pt( iv ) complexes showed similar cell penetration properties, being significantly better than that of the Pt( ii ) reference compounds. Finally, a representative compound of the whole set of complexes ( i.e. , that based on cyclohexane-1 R ,2 R -diamine and racemic POA ) was tested in vivo on mice bearing Lewis lung carcinoma, showing good tumor growth inhibition with negligible body weight loss. Combinations of different cyclohexanediamines and 2-(2-propynyl)octanoate in Pt( iv ) complexes resulted in prodrug candidates with promising antiproliferative and in vivo antitumor activity.
ISSN:1477-9226
1477-9234
DOI:10.1039/d0dt04135a