Enhanced cellular uptake and in vitro antitumor activity of short-chain fatty acid acylated daunorubicin-GnRH-III bioconjugates

Rózsa Hegedüs, Marilena Manea, Erika Orbán, Ildikó Szabó, Éva Kiss, Éva Sipos, Gábor Halmos, Gábor Mez

Research output: Article

24 Citations (Scopus)

Abstract

Here we report on the synthesis and biochemical characterization (enzymatic stability, cellular uptake, in vitro antitumor activity, membrane interaction and GnRH-receptor binding affinity) of novel short-chain fatty acid (SCFA) acylated daunorubicin-GnRH-III bioconjugates, which may serve as drug delivery systems for targeted cancer chemotherapy. Ser in position 4 of GnRH-III was replaced by Lys, followed by the acylation of its ε-amino group with various fatty acids. SCFAs are potentially chemoprotective agents by suppressing the growth of cancer cells and therefore may enhance the antitumor activity of the bioconjugates. We found that all synthesized bioconjugates had high cytostatic effect in vitro, were stable in cell culture medium for 6 h and degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked daunorubicin-Lys as the smallest active metabolite. In the presence of α-chymotrypsin, all compounds were digested, the degradation rate strongly depending on the type of fatty acid. The bioconjugate containing Lys(nBu) in position 4 was taken up most efficiently by the cancer cells and exerted higher in vitro cytostatic effect than the previously developed GnRH-III(4Lys(Ac), 8Lys(Dau = Aoa)) or the parent GnRH-III(Dau = Aoa) bioconjugate. Our results could be explained by the increased binding affinity of the newly developed compound containing Lys(nBu) to the GnRH receptors.

Original languageEnglish
Pages (from-to)155-165
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume56
DOIs
Publication statusPublished - okt. 2012

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Daunorubicin
Volatile Fatty Acids
LHRH Receptors
Cytostatic Agents
Fatty Acids
Cells
Aminoacylation
Acylation
Neoplasms
Oximes
Chemotherapy
Chymotrypsin
Drug Delivery Systems
Metabolites
Cell culture
Liver
Culture Media
Rats
Cell Culture Techniques
Membranes

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Enhanced cellular uptake and in vitro antitumor activity of short-chain fatty acid acylated daunorubicin-GnRH-III bioconjugates. / Hegedüs, Rózsa; Manea, Marilena; Orbán, Erika; Szabó, Ildikó; Kiss, Éva; Sipos, Éva; Halmos, Gábor; Mez, Gábor.

In: European Journal of Medicinal Chemistry, Vol. 56, 10.2012, p. 155-165.

Research output: Article

Hegedüs, Rózsa ; Manea, Marilena ; Orbán, Erika ; Szabó, Ildikó ; Kiss, Éva ; Sipos, Éva ; Halmos, Gábor ; Mez, Gábor. / Enhanced cellular uptake and in vitro antitumor activity of short-chain fatty acid acylated daunorubicin-GnRH-III bioconjugates. In: European Journal of Medicinal Chemistry. 2012 ; Vol. 56. pp. 155-165.
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AU - Orbán, Erika

AU - Szabó, Ildikó

AU - Kiss, Éva

AU - Sipos, Éva

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