title: Enhanced cellular uptake and in vitro antitumor activity of short-chain fatty acid acylated daunorubicin-GnRH-III bioconjugates.
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((4)Lys(Ac), (8)Lys(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.
authors.affiliation: Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, 1117 Budapest, Hungary.
authors.forename: Rózsa
authors.initials: R
authors.lastname: Hegedüs
authors.forename: Marilena
authors.initials: M
authors.lastname: Manea
authors.forename: Erika
authors.initials: E
authors.lastname: Orbán
authors.forename: Ildikó
authors.initials: I
authors.lastname: Szabó
authors.forename: Eva
authors.initials: E
authors.lastname: Kiss
authors.forename: Eva
authors.initials: E
authors.lastname: Sipos
authors.forename: Gábor
authors.initials: G
authors.lastname: Halmos
authors.forename: Gábor
authors.initials: G
authors.lastname: Mező
mesh_terms: D000215:Acylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D003630:Daunorubicin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005227:Fatty Acids / Q000737:chemistry*; D007987:Gonadotropin-Releasing Hormone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011966:Receptors, LHRH / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005227:Fatty Acids; D011966:Receptors, LHRH; C448022:gonadotropin-releasing hormone-III; D007987:Gonadotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid; D003630:Daunorubicin