Synthesis and DNA Cleavage Activity of a Novel Bleomycin A₅ Glycoconjugate

Abstract

[structure in text] To explore the possibility of modifying bleomycin in a fashion that could alter its physiological distribution in a therapeutic setting, a new analogue of bleomycin has been prepared. This analogue is intended to target the asialoglycoprotein receptor on liver cells. Critically, despite the large C-substituent, the bleomycin conjugate was found to degrade DNA in the same fashion as bleomycin A(5) itself, and with only modestly decreased efficiency.

Mechanistic studies on bleomycin-mediated DNA damage: multiple binding modes can result in double-stranded DNA cleavage

“…β-Cyclodextrin was chosen based on its size [6 Å (height) by 12 Å (diameter), PDB ID 3CGT] (22), its water-soluble, non-ionic nature and a facile route to its synthesis. This molecule could be characterized by NMR spectroscopy in contrast to the controlled-pore glass beads or dendrimers used for a similar purpose in previous studies (19,21). Although we argue that β-cyclodextrin is sufficiently large to prevent intercalation, we have been unable to demonstrate the mode(s) of CD-BLM binding to DNA.…”

“…In these studies, the chlorinated bithiazole tail was shown to be located in the minor groove of DNA by light-mediated DNA cleavage (18). An additional independent study by the Hecht group has also shown that BLM A5 tethered through its polyamine tail to either controlled pore glass (CPG) beads (19,20) or a dendrimer (21) can also cleave DNA. These attachments were designed to be sufficiently large to prevent binding of the bithiazole tail by partial intercalation.…”

“…The efficiency and sequence selectivity of cleavage by these tethered BLMs has been reported to be similar to that observed with the untethered BLM, demonstrating that non-intercalative modes of binding can also lead to DNA cleavage (19–21). Unfortunately, the relationship of the alternative binding mode to the mechanism of ds-DNA cleavage was not quantitatively investigated in these studies (19,21). …”

Ternary iron(ii) complex with an emissive imidazopyridine arm from Schiff base cyclizations and its oxidative DNA cleavage activity

“…distance of 1.38 Å which is similar to the C-C bond distances observed in the pyridyl rings (Table 2). Both the N (7) and N(8) atoms are planar showing a sum of three angles as 360 • . This unit is mono-cationic and aromatic with the positive charge being delocalized on N(7) or N(8), giving a resonance structure (Scheme 2).…”

“…The structural and functional aspects of the BLMs-DNA interactions have earlier been studied using various BLM analogs/conjugates to determine the specific roles of different domains. [4][5][6][7][8] In contrast, synthetic model iron complexes are rare, possibly due to the structural complexity of BLMs. [9][10][11][12][13][14][15] Scheme 1 Schematic structure of Bleomycins.…”