New daunomycin-oligoarginine conjugates: synthesis, characterization, and effect on human leukemia and human hepatoma cells.
In this article, the synthesis, a novel chromatographic procedure and characteristics of a new class of daunomycin (Dau)-oligoarginine conjugates are described. In these compounds oligoarginine with 6 or 8 residues (Arg(n), n = 6, 8) is attached to Dau by different covalent bond: squaric amide (Dau- square-Arg(n)), oxime (Dau=N-O-CH2-CO-Arg(n)), or hydrazone (H-Glu(Arg(n))-NH-N=Dau). Conjugates were characterized by RP-HPLC and mass spectrometry. We report also on our findings concerning chemical and biological properties of Dau-conjugates as a function of covalent linkage, site of conjugation and length of the oligoarginine moiety. Stability, fluorescent properties as well as cytostatic effect and cellular uptake of these compounds were studied. Dau-conjugates with squaric amide or oxime linkage were stable, but continuous release of free Dau was observed from the hydrazone conjugate in solution. We found that some spectral characteristics (e.g., the amplitude of the emission spectrum) of conjugates could be sensitive for the site of coupling (amino vs. oxo function). Cytostasis and cellular uptake of conjugates were investigated both on human leukemia (HL-60) and human hepatoma (HepG2) cell lines by MTT assay and flow cytometry We found that cytostatic effect and uptake properties of Dau-conjugates were dependent on the acid stability of the linkage (hydrazone vs. oxime/amide) applied and more markedly on the cell line studied.
Miklán
Zsanett
Z
Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Budapest, Hungary.
Orbán
Erika
E
Csík
Gabriella
G
Schlosser
Gitta
G
Magyar
Anna
A
Hudecz
Ferenc
F
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D003630:Daunorubicin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D056945:Hep G2 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D010455:Peptides; C015462:polyarginine; D003630:Daunorubicin