A New Class of Semisynthetic Anthracycline Glycoside Antibiotics Incorporating a Squaric Acid Moiety

Sztaricskai, Ferenc; Sum, Anita; Rőth, Erzsébet; Pelyvás, István F.; Sandor, Szabolcs; Batta, Gyula; Herczegh, Pál; Reményi, Judit; Miklán, Zsanett; Hudecz, Ferenc

doi:10.1038/ja.2005.96

Cited by 19 publications

(2 citation statements)

References 17 publications

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“…The reaction between Dau-&-OMe and oligoarginine peptides (Arg n , n ¼ 6, 8) was performed in methanol-water (77:23 v/v%) mixed solvent as described earlier. 47 The pH was set to 9 by DIEA. 6.5 mg (0.01 mmol) Dau-&-OMe was solved in 3.5 ml MeOH then 50 ll (0.32 mmol) DIEA and 0.03 mmol (200% molar excess) oligoarginine in 1.0 ml water were added.…”

Section: Synthesis and Purificationmentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Synthesis and Purificationmentioning

confidence: 99%

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

et al. 2009

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“…Further modifications of the amino group of daunosamine via squaric acid (Sztaricskai et al , 2005) diminished their activity against human leukemia (HL‐60) ( 22 , IC 50 =0.18 μM and 23 , IC 50 =0.22 μM) compared with daunosamine itself (IC 50 =0.12 μM) (Fig. 11).…”

Section: Anthracyclinesmentioning

confidence: 99%

Sweet antibiotics – the role of glycosidic residues in antibiotic and antitumor activity and their randomization

2008

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A large number of antibiotics are glycosides. In numerous cases the glycosidic residues are crucial to their activity; sometimes, glycosylation only improves their pharmacokinetic parameters. Recent developments in molecular glycobiology have improved our understanding of aglycone vs. glycoside activities and made it possible to develop new, more active or more effective glycodrugs based on these findings - a very illustrative recent example is vancomycin. The majority of attention has been devoted to glycosidic antibiotics including their past, present, and probably future position in antimicrobial therapy. The role of the glycosidic residue in the biological activity of glycosidic antibiotics, and the attendant targeting and antibiotic selectivity mediated by glycone and aglycone in antibiotics some antitumor agents is discussed here in detail. Chemical and enzymatic modifications of aglycones in antibiotics, including their synthesis, are demonstrated on various examples, with particular emphasis on the role of specific and mutant glycosyltransferases and glycorandomization in the preparation of these compounds. The last section of this review describes and explains the interactions of the glycone moiety of the antibiotics with DNA and especially the design and structure-activity relationship of glycosidic antibiotics, including their classification based on their aglycone and glycosidic moiety. The new enzymatic methodology 'glycorandomization' enabled the preparation of glycoside libraries and opened up new ways to prepare optimized or entirely novel glycoside antibiotics.

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