Di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) is a promising analogue of the dipyridyl thiosemicarbazone class currently under development as a potential anti-cancer drug. In fact, this class of agents shows markedly greater anti-tumor activity and selectivity than the clinically investigated thiosemicarbazone, Triapine®. However, further development of DpC requires detailed data concerning its metabolism. Therefore, we focused on the identification of principal phase I and II metabolites of DpC in vitro. DpC was incubated with human liver microsomes/S9 fractions and the samples were analyzed using ultra-performance liquid chromatography (UPLC(TM)) with electrospray ionization quadrupole-time-of-flight (Q-TOF) mass spectrometry. An Acquity UPLC BEH C(18) column was implemented with 2 mM ammonium acetate and acetonitrile in gradient mode as the mobile phase. The chemical structures of metabolites were proposed based on the accurate mass measurement of the protonated molecules as well as their main product ions. Ten phase I and two phase II metabolites were detected and structurally described. The metabolism of DpC occurred via oxidation of the thiocarbonyl group, hydroxylation and N-demethylation, as well as the combination of these reactions. Conjugates of DpC and the metabolite, M10, with glucuronic acid were also observed as phase II metabolites. Neither sulfate nor glutathione conjugates were detected. This study provides the first information about the chemical structure of the principal metabolites of DpC, which supports the development of this promising anti-cancer drug and provides vital data for further pharmacokinetic and in vivo metabolism studies.

• MeSH
• jaterní mikrozomy metabolismus   MeSH
• lidé MeSH
• protinádorové látky chemie   metabolismus   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• thiosemikarbazony chemie   metabolismus   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

V tomto projektu budou vyvinuty a validovány moderní analytické a bioanalytické metody (LC/MS/MS) vhodné pro studium osudu dvou nových thiosemikarbazonových protinádorových léčiv (Dp44mT a Dpcyc) v organismu. Tyto metody budou posléze využity jako validní nástroje pro studium biotransformace (in vitro i in vivo) a farmakokinetiky těchto léčiv. Zvláštní pozornost bude věnována metabolismu i způsobu eliminace uvedených látek, ale také studiu možného vztahu mezi biotransformací a toxikologickým profilem (především kardiotoxicitou, jenž byla zaznamenána u Dp44mT). Na základě výsledků bude navržena konkrétní obměna struktury léčiva s cílem optimalizovat farmakokinetický, popřípadě toxikologický profil uvedených thiosemikarbazonů.; Novel, modern analytical and bioanalytical methods (LC/MS/MS) will be developed and validated in order to study the fate of two novel thiosemicarbazone anti-cancer drugs (Dp44mT and Dpcyc) in an organism. Thereafter, these methods will be utilized as valid tools to study biotransformation of these compounds both in vitro and in vivo and to evaluate their pharmacokinetics. Particular attention will be paid on elimination and metabolism of the thiosemicarbazones as well as the investigation of the possible involvement of particular Dp44mT metabolite in cardiotoxicity observed after administration of this compound. Based on the results of this project the rational chemical structure modification of the thiosemicarbazones will be suggested to optimize pharmacokinetic profile and potentially also toxicological profile.

• MeSH
• biotransformace účinky léků   MeSH
• cytostatické látky terapeutické užití   MeSH
• klinické laboratorní techniky metody   využití   MeSH
• medicína založená na důkazech MeSH
• nádory farmakoterapie   MeSH
• proliferace buněk účinky léků   MeSH
• thiosemikarbazony farmakokinetika   farmakologie   chemie   klasifikace   škodlivé účinky   terapeutické užití   MeSH
• vztahy mezi strukturou a aktivitou MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR