New daunomycin–oligoarginine conjugates: Synthesis, characterization, and effect on human leukemia and human hepatoma cells

Abstract

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.

Novel Peptide–Doxorubucin Conjugates for Targeting Breast Cancer Cells Including the Multidrug Resistant Cells

“…Similar decreases in potency have been observed for other amide peptide-Dox conjugates. 9,20,43 Other studies highlight the significance of such conjugates in the slow release of drug on longer exposure times, for instance, amide conjugates of Dox showed high cytotoxicity comparable to free Dox on longer incubation times reaching 120 h. 44 Different studies have shown that coupling peptides to free Dox can overcome P-gp resistance pathway, as the conjugates bypass the P-gp pump 9,10,15 Verapamil is a calcium channel blocker that inhibits anthracycline efflux by direct interference with P-gp, thus increasing the intracellular accumulation of the drugs. 45 …”

Biokonjugátumok – összefogni érdemes

“…Guy Serre professzorral és munkatársaival (CNRS -Université Toulouse 3) folytatott közös kutatá-saink során három immundomináns fehérje epitóprégiót azonosítottunk. A fibrin a-és b-láncából származó Arg/Cit tartalmú 34 …”

“…33,34 (10. ábra) Eredményeink arra utaltak, hogy a szabad hatóanyag és fehérjével, elágazó láncú polipeptiddel vagy oktaargininnel konjugált származékok hatása és sejtekbe történõ bejutása egymástól eltérõ mechanizmus szerint valósul meg. 10.…”

“…34,35,36,37 Új kísérleteinkben, az ErbB2 receptor ligandumát az LTVSPWY oligopeptidet és Dau-t tartalmazó konjugátum állítottunk elõ. 38 Az ErbB2 receptor fokozott expresszióját figyelték meg bizonyos (pl.…”

pH-Responsive Triblock Copolymeric Micelles Decorated with a Cell-Penetrating Peptide Provide Efficient Doxorubicin Delivery

“…pArg has therefore been utilized in gene therapy [16], protein/vaccine delivery [17], and cancer treatment [18]. Recent studies reported that poly(amino acid)-based nanoparticles could also effectively translocate through cell membranes [19–22].…”