Self-Association of Doxorubicin and Related Compounds in Aqueous Solution

The dimerization of doxorubicin, daunorubicin, and their 4-demethoxy, 4′-epi, and 4′-deoxy analogues was studied spectrophotometrically. Self-association was found to be influenced by buffer composition and ionic strength. Kd values were 1.3 × 104 and 2.3 × 104 M−1 for doxorubicin and daunorubicin, respectively, and ranged from 3.8 × 103 to 6.1 × 103 M−1 for the 4-demethoxy analogues. For 4′-epi- and 4′-deoxydoxorubicin, tetramerization has also been considered. On this basis, values of 2.0 × 104 and 2.2 × 104 M−1 were found, respectively, for the formation constant of the dimerization process. Stability of the dimeric species appears to be strongly influenced by substitution of the chromophore moiety.