title: Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents.
abstract: Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment.
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Vit
authors.initials: V
authors.lastname: Sestak
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Stariat
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Simkova, Hradec Kralove, Czech Republic.
authors.forename: Jolana
authors.initials: J
authors.lastname: Cermanova
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Eliska
authors.initials: E
authors.lastname: Potuckova
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Simkova, Hradec Kralove, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Chladek
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Roh
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Bures
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Jansova
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Prusa
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Simkova, Hradec Kralove, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Sterba
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Simkova, Hradec Kralove, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Micuda
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Simunek
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho, Hradec Kralove, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Kovarikova
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry; D013882:Thiosemicarbazones / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013882:Thiosemicarbazones; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone
keywords: Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone; anti-cancer agents; di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone; metabolism; pharmacokinetics