Molecular basis for potentiation of bleomycin‐mediated degradation of DNA by polyamines. Experimental and molecular mechanical studies

Abstract

The bleomycin-mediated degradation of DNA is stimulated (amplified) by certain DNA binding compounds, such as polyamines, that distort the double helix. Computer modelling studies suggest that putrescine (1), spermidine (2), and spermine (3) bind preferentially on the floor of the major groove of (dGdC)5.(dGdC)5. This interaction results in a bend of the oligomer helix toward the major groove and enlargement of the minor groove, both effects being in the order 1 less than 2 less than 3. These polyamine-induced distortions, as obtained from theoretical studies, parallel the experimental values of the amplification activities of 1-3 in the bleomycin-mediated degradation of poly(dGdC).poly(dGdC). The amplification mechanism of non-competitive binding of amplifier molecules in the major groove, and bleomycin in the minor groove, is proposed. It is suggested that the amplifier-induced conformational changes of the DNA helix increase affinity of the activated bleomycin complex toward the DNA minor groove and, consequently, result in an increased efficiency of the bleomycin-mediated degradation of the helix.

Synthesis, DNA-Binding and Antibacterial Activity of the Cell-Penetrating Peptide HIV-1 Tat (49-57)

“…According to this line, binding constant K was determined to be 2.63×10 5 l×mol -1 , and n was 1.12. K was similar to the value that had been well-established among groove binding agents [30] .…”

“…The intercalative binding mode generally causes DNA viscosity to increase significantly because [26,30] . As shown in fig.…”

Structure–activity analysis of the potentiation by aminothiols of the chromosome‐damaging effect of bleomycin in G0 human lymphocytes

“…Protective effects have also been ascribed to CSM , cysteine [Chatterjee and Jacob-Raman, 1993], and WR-1065 [Nagy and Grdina, 1986;Hoffmann et al, , 1999. Of the other amines and thiols that we have studied, putrescine, spermidine, and spermine have been shown to potentiate the degradation of DNA by BLM [Strekowski et al, 1989]. The reducing agents 2-ME and dithiothreitol (a diastereomer of DTE with similar chemical properties) enhance the induction of DNA strand breakage by BLM in vitro [Sausville et al, 1978].…”

“…WR-1065 and CSM bind to DNA [Liquier et al, 1983;Smoluk et al, 1986Smoluk et al, , 1988a. This binding, like that of polyamines [Feuerstein et al, 1986], may cause widening of the minor groove [Strekowski et al, 1989;Sy et al, 1999], thereby increasing the access of BLM to the site where it abstracts the 4Ј-hydrogen. Rather than being alternatives, the thiol and amine functions may also act in concert, such that the amino groups bring the thiol group to its site of action on DNA.…”

“…As a diamine, WR-1065 binds to DNA [Smoluk et al, 1988a;Sy et al, 1999] and may alter DNA conformation so as to facilitate BLM action. Widening of the minor groove of DNA, which is the likely site of BLM binding [Strekowski et al, 1989;Stubbe et al, 1996;Burger, 1998] and the location of the 4Ј position of deoxyribose [Burger, 1998], may give BLM better access to its target.…”