Synthesis, enzymatic stability and in vitro cytostatic effect of Daunorubicin-GnRH-III derivative dimers

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2013
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Schreier, Verena Natalie
Mező, Gábor
Orbán, Erika
Dürr, Claudia
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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(Dau=Aoa-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.

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ISO 690SCHREIER, Verena Natalie, Gábor MEZŐ, Erika ORBÁN, Claudia DÜRR, Andreas MARQUARDT, Marilena MANEA, 2013. Synthesis, enzymatic stability and in vitro cytostatic effect of Daunorubicin-GnRH-III derivative dimers. In: Bioorganic & Medicinal Chemistry Letters. 2013, 23(7), pp. 2145-2150. ISSN 0960-894X. eISSN 1464-3405. Available under: doi: 10.1016/j.bmcl.2013.01.114
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@article{Schreier2013-04-01Synth-22451,
  year={2013},
  doi={10.1016/j.bmcl.2013.01.114},
  title={Synthesis, enzymatic stability and in vitro cytostatic effect of Daunorubicin-GnRH-III derivative dimers},
  number={7},
  volume={23},
  issn={0960-894X},
  journal={Bioorganic & Medicinal Chemistry Letters},
  pages={2145--2150},
  author={Schreier, Verena Natalie and Mező, Gábor and Orbán, Erika and Dürr, Claudia and Marquardt, Andreas and Manea, Marilena}
}
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