title: Butyltin(IV) benzoates: inhibition of thioredoxin reductase, tumor cell growth inhibition, and interactions with proteins.
abstract: Thioredoxin reductase (TrxR) is overexpressed in cancer cells and is therefore a putative cancer target. Inhibition of this enzyme is considered an important strategy for the development of new chemotherapeutic agents with a specific mechanism of action. Organotin compounds have been described as experimental antitumor agents, yet their mechanism of action remains largely unknown. Based on the outcome of a virtual screening study, various di- and tri-n-butyltin(IV) carboxylates were synthesized, and their biological properties were evaluated. All synthesized compounds were able to inhibit TrxR selectively within the micromolar range and showed potent antitumor activity against HT-29 and MCF-7 cancer cell lines. Moreover, tin(IV) organometallics were found to strongly induce apoptosis in the BJAB lymphoma cell line. Mass spectrometry and atomic absorption spectroscopy experiments revealed metal binding to proteins, and efficient cellular uptake was observed using a di-n-butyltin(IV) complex as an example.
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 38106 Braunschweig, Germany.
authors.forename: Kely
authors.initials: K
authors.lastname: Navakoski de Oliveira
authors.forename: Vincent
authors.initials: V
authors.lastname: Andermark
authors.forename: Susanne
authors.initials: S
authors.lastname: von Grafenstein
authors.forename: Liliane A
authors.initials: LA
authors.lastname: Onambele
authors.forename: Gregor
authors.initials: G
authors.lastname: Dahl
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rubbiani
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabbiani
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009947:Organotin Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D009947:Organotin Compounds; D014220:Trialkyltin Compounds; C056189:di-n-butyltin; D012710:Serum Albumin, Bovine; C011559:tributyltin; D013880:Thioredoxin-Disulfide Reductase