Abstract
Copper complex of a novel estrone–thiosemicarbazone hybrid with significant cytotoxicity, lipophilicity and solution stability in addition to its structurally related bicyclic analogue.
Highlights
Thiosemicarbazones (TSCs) have been investigated for their versatile pharmacological activity including anticancer properties for many decades.[1,2,3] To date, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) is the most prominent representative of the compound class of a-N-heterocyclic TSCs has been already tested in more than 30 clinical phase I and II trials[4,5] and currently is involved in a Triapine–cisplatin– radiation combination therapy in a phase III trial.[6]
Novel thiosemicarbazone derivatives were prepared through molecular hybridization of salicylaldehye TSC (STSC) with estrone and th-1-n, respectively, which yielded copper(II) complexes with marked cytotoxic activity in various human cancer cell lines
The introduction of the TSC moiety to the sterane backbone resulting in estrone–TSC was performed via the condensation reaction of 2-formyl-estrone, obtained from estrone by ortho-formylation, and thiosemicarbazide in EtOH under MW-irradiation
Summary
Thiosemicarbazones (TSCs) have been investigated for their versatile pharmacological activity including anticancer properties for many decades.[1,2,3] To date, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) is the most prominent representative of the compound class of a-N-heterocyclic TSCs has been already tested in more than 30 clinical phase I and II trials[4,5] and currently is involved in a Triapine–cisplatin– radiation combination therapy in a phase III trial.[6]. Di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) and 4-(2-pyridinyl)-2(6,7-dihydro-8(5H)-quinolinylidene)-hydrazide (COTI-2) are currently undergoing phase I evaluation for treatment of advanced solid tumors and gynecologic malignancies, respectively.[9,10] The iron containing enzyme ribonucleotide reductase is considered as the main target for Triapine and related TSCs due to their prominent iron binding ability.[11] On the other hand, the role of the formation of intracellular copper(II) complexes that can be involved in redox cycling in the presence of reducing agents leading to the production of reactive oxygen species (ROS) is discussed for certain subclasses of TSCs (mainly in case of N-terminally disubstituted a-N-pyridyl TSCs).[12,13]
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