title: Cholic acid-carboplatin compounds (CarboChAPt) as models for specific drug delivery: synthesis of novel carboplatin analogous derivatives and comparison of the cytotoxic properties with corresponding cisplatin compounds.
abstract: This report continues our work on new compounds which consist of three functional parts--a transport fragment, a spacer and a biologically active 'drug' component. Here cholic acid functions as the transport fragment, linked via an alkyl spacer to a carboplatin analog, representing the drug (carbo-ChAPt-Fig. 1). We describe the synthesis and characterization of the series of complexes [Pt(Cyclobutane-1,1-dicarboxylato)(diamine)], [diamine=CholCOO(CH(2))(n)CH(CH(2)NH(2))(2) and THP(CH(2))(n)CH-(CH(2)NH(2))(2), n=4, 6, 8, 11]. The compounds were characterized by elemental analysis and NMR-measurements. Cytostatic activity data are given. In general, the cytostatic activity is similar to that of the parent compound and is strongly influenced by the length of the alkyl chain spacer separating the drug and transport fragments, the ones with long chain spacers being more toxic than the parent complexes. Preliminary investigations indicate the ability of the ChAPt to break resistance of tumor cells against common platinum tumor drugs, e.g. cisplatin. They are effective even on cell lines that have developed resistance to other drugs such as cis- and carboplatin. They are more cytotoxic so they are potentially effective at lower dose concentrations. The mode of cell death was examined by trypan-blue exclusion test and DNA gelelectrophoresis. Typical fragmentation of DNA was observed and the cells were still able to exclude trypan-blue.
authors.affiliation: Biocenter of the Martin-Luther-University Halle-Wittenberg, D-06099 Halle, Germany. paschke@biozentrum.uni-halle.de
authors.forename: Reinhard
authors.initials: R
authors.lastname: Paschke
authors.forename: Jutta
authors.initials: J
authors.lastname: Kalbitz
authors.forename: Christian
authors.initials: C
authors.lastname: Paetz
authors.forename: Martin
authors.initials: M
authors.lastname: Luckner
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
authors.forename: Helmut
authors.initials: H
authors.lastname: Mueller
authors.forename: Eduard
authors.initials: E
authors.lastname: Sorkau
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Sinn
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D019826:Cholic Acid / Q000737:chemistry* / Q000494:pharmacology; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004586:Electrophoresis / Q000379:methods; D006801:Humans; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014343:Trypan Blue / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004337:Drug Carriers; D009944:Organoplatinum Compounds; D016190:Carboplatin; D019826:Cholic Acid; D014343:Trypan Blue; D002945:Cisplatin