title: Synthesis, enzymatic stability and in vitro cytostatic effect of Daunorubicin-GnRH-III derivative dimers.
abstract: Bioconjugates containing chemotherapeutic agents attached to peptide hormones, such as gonadotropin-releasing hormone (GnRH), are developed as drug delivery systems for targeted cancer chemotherapy. We report here the synthesis and biochemical characterization of disulfide bond-linked dimeric bioconjugates in which daunorubicin was coupled via an oxime linkage to aminooxyacetylated GnRH-III ([Glp-His-Trp-Ser-His-Asp-Trp-Lys(DauAoa-Cys)-Pro-Gly-NH2]2; where Glp is pyroglutamic acid and Aoa is aminooxyacetyl) and its derivatives modified in position four by N-Me-Ser and Lys(Ac). The in vitro stability/degradation of the bioconjugates was determined in human serum, as well as in the presence of rat liver lysosomal homogenate and digestive enzymes. All compounds were stable at least for 24h in human serum and in the presence of pepsin and trypsin, while they were degraded by lysosomal enzymes. The daunorubicin-GnRH-III derivative dimers were partly digested by α-chymotrypsin; however, they had increased stability compared to the corresponding monomers, making them potential candidates for oral administration. The in vitro cytostatic effect of the compounds was determined on MCF-7 human breast cancer cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. All daunorubicin-GnRH-III derivative dimers exerted slightly increased in vitro cytostatic effect (IC50 values in low μM range) than the corresponding monomeric bioconjugates.
authors: Laboratory of Analytical Chemistry and Biopolymer Structure Analysis, Department of Chemistry, University of Konstanz, 78457 Konstanz, Germany.
authors: Verena Natalie
authors: VN
authors: Schreier
authors: Gábor
authors: G
authors: Mező
authors: Erika
authors: E
authors: Orbán
authors: Claudia
authors: C
authors: Dürr
authors: Andreas
authors: A
authors: Marquardt
authors: Marilena
authors: M
authors: Manea
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003630:Daunorubicin / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004795:Enzyme Stability; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D054697:Cytostatic Agents; C448022:gonadotropin-releasing hormone-III; D007987:Gonadotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid; D003630:Daunorubicin