Daunomycin shifts

These phenolic hydroxyls have been observed in the proton NMR spectrum of N-acetyldaunomycin in chloroform solution (83) though they are broadened out due to rapid exchange with solvent in the spectrum of daunomycin in H2O solution. We can therefore compare the H-6 and H-ll ring B hydroxyl chemical shifts of 12.3 and 11.5 ppm for the Nuc/D = 5.9 daunomycin poly(dA-dT) complex in aqueous solution (Figure 25) with the values of 13.86 and 13.15 ppm observed for N-acetyldaunomycin in nonpolar solution (83). 

Chemical Shift of the Thymidine H-3 Proton In Poly(dA-dT) and Its Daunomycin Complex rnlMNaCl Solution... 

Chemical Shifts of Anthracycline Ring B OH Groups at Positions 6 and 11 in the Daunomycin Poly(dA-dT) Complex3... 

Base Proton Complexation Shifts The complexation shifts of certain nucleic acid base resonances of poly(dA-dT) on formation of the daunomycin neighbor exclusion complex reflect the shielding contribution due to the anthracycline ring less the contribution from one neighboring base pair which is displaced following intercalation. Thus, the adenosine H-2 resonance remains unperturbed (Figure 27) while the thymidine exchangeable H-3 proton... 

Experimental Upfield Anthracycline Complexation Shifts on Formation of The Daunomycin-Poly(dA-dT) Complex... 

The experimental upfield complexation shift is the difference between the values for the intact complex at 80°C relative to free daunomycin at 90°C. 

Phosphodiester Linkages The proton noise decoupled lp nmr spectra of the daunomycin poly(dA-dT) complex in 1 M NaCl solution at 67°C have been recorded at 1 antibiotic per 6 base pairs (Nuc/D = 11.8) and 1 antibiotic per A,3 base pairs (Nuc/D = 5.9). Resolved resonances are observed for the complex at both Nuc/D ratios (Figure 32). One of the resonances in the complex exhibits a chemical shift similar to that observed for poly(dA-dT) in 1 M NaCl alone ( 4.1 ppm) at this temperature while the other resonance is shifted downfield by 0.3 ppm in the Nuc/D = 11.8 complex and by 0.45 ppm in the NucD = 5.8 complex (Table XI). The results suggest that daunomycin intercalates at either the dTgdA or dApdT sites, resulting in a downfield shift of the 31p resonance of the corresponding phosphodiester grouping at the intercalation site. 

Overlap Geometry at the Intercalation Site We shall attempt to utilize the nucleic acid base and anthracycline ring proton com-plexation shifts to deduce which anthracycline aromatic ring(s) overlap with nearest neighbor base pairs in the daunomycin poly-(dA-dT) intercalation complex. It should be noted that the nonplanarity of ring A in the antibiotic requires that the aromatic portion of the anthracycline chromophore cannot intercalate with its long axis colinear to the direction of the Watson-Crick hydrogen bonds at the intercalation site as was demonstrated for proflavine-nucleic acid complexes. 

Figure 32. The proton noise decoupled 145.7-MHz 3,P NMR spectra of the daunomycin poly(dA-dT) complex in IM NaCl, 10/nM cacodylate, WmM EDTA, 80% H/O-20% D O. Spectrum A corresponds to the Nuc/D = 11.8 complex, pH 6.0 at 67°C and Spectrum B corresponds to the Nuc/D — 5.9 complex, pH 6.05 at 67°C. The chemical shifts are upfield from standard trimethyl-...

The purine(3 -5 Ipyrimidine and the pyrimidine(3 -5 )purine phosphodiester linkages are partially resolved in the proflavine and daunomycin intercalation complexes with poly(dA-dT) with the phosphodiester at the intercalation site shifting to low field. This suggests that these intercalating agents exhibit a sequence specificity in their complexes with alternating purine-pyrimidine polynucleotides. 

Anthracyclines, doxorubicin, daunomycin and idarubicin, belong to the most widely used anticancer agents and many efforts have been made in order to remove their undesirable side effects. Recently, convenient syntheses of daunomycinone-7-D-glucuronides and doxorubicinone-7-D-glucuronides have been reported by Rho et who fully characterised their anomeric configuration and conformation by the assignment of H NMR chemical shifts and H-H couplings. 

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