Binding affinity and site selectivity of daunomycin analogs

Abstract

We have tested a series of daunomycin analogues for binding affinity to a group of oligonucleotides that contain binding sites specific for daunomycin and that were previously screened for relative binding affinity for daunomycin. The series of drugs differed from daunomycin in the sugar moiety, including substitution of a hydroxyl group for the charged amino group and replacement of the 2'-OH by an iodo substituent. Data were analyzed by Scatchard plots and association constants were estimated from the gamma-intercept at saturating levels of oligonucleotide. Because of the solubility problems associated with these compounds, Scatchard plots could not be extended to high levels of binding. A second method of analysis of the fluorescence data confirmed the semiquantitative association constants obtained from the intercepts of the Scatchard plots. The association constants were in the range of 10(5)-10(7) M-1. When compared with daunomycin, the compounds with hydroxyl substituted for the amino group in the sugar ring generally bound less well to the oligonucleotides, by factors of up to several hundred. Much of the binding lost upon removal of the charged amino group was restored, however, with compounds containing an iodo substituent on the sugar ring. Changing the iodo-substituted sugar from the natural L-form to the D-form diminished binding by 6-50-fold, depending on sequence. This result implies a stereospecific interaction of the natural sugar with the DNA chain. A positively cooperative curve was observed in the Scatchard plot for the D-form sugar.(ABSTRACT TRUNCATED AT 250 WORDS)

First Glycosylation of Decarestrictine B and D: A Route to Hybrid Antibiotics

“…The DNA binding of the substance is expressed as the quotient of the R f in the presence of DNA (R f1 ) and without DNA (R f2 ); this results in R f1 /R f2 0.1 for 5 and In this context, it is worth noting that Schreiber et al [27] proposed that the iodine group in the calicheamycin g I 1 oligosaccharide binds to the exocyclic amino group of guanine residues in duplex DNA; this was confirmed recently. [29] Further investigations on the DNA binding properties of decarestrictine D glycosides with a biosensor system [30] are in progress. Their data showed that much of the activity lost upon removing the charged amino group from the carbodrate framework can be compensated by an iodo substituent at C-2.…”

Anthracyclines as effective anticancer drugs

“…Chemical modifications on the sugars of anthracyclines have been shown to markedly alter their anticancer activity, target selectivity and the sequence specificity of DNA break sites [73]. Three major trends have surfaced in regards to sugar modifications: first, α-glycosides of anthracyclines show higher anticancer activities than the β-anomers [74]; second, configurational changes at the 3′ and 4′ positions of the sugar dramatically affect activity and the sequence specificity [75], and third, increasing the length of the carbohydrate chain is associated with increasing antitumour potency, for example, pyrromycin to musettamycin and marcellomycin (Figure 6) [72,76,77].…”

Fluorinated Anthracyclines: Synthesis and Biological Activity

“…Evidence is available that cell DNA is the main biological target of antitumor anthracyclines, in agreement with the high-affinity constant of DOXO useful congeners for native double-stranded DNA [8,9]. Different X-ray diffraction studies of anthracycline-DNA complexes are now available.…”

“…All four possible monosubstitution topologies at position 8 Conversely (Scheme 6), another approach for the synthesis of the (8R)-fluoroepimer (25) involved the fluorobromination of the C(8)-C(9) olefinic bond of the common intermediate (20), formation of the C(9)-C(13) epoxide (24) which, after regioselective hydrolysis and oxidation of the resulting fluorodiol to the epimeric fluorohydroxyketone (25), similarly gave the desired fluoroaglycone and, hence, the corresponding glycoside. Some different approaches for the synthesis of (8R)-fluoroepimer have been reported [46].…”