Solution chemistry and DNA binding properties of MEN 10755, a novel disaccharide analogue of doxorubicin

The behavior under physiological conditions of MEN 10755, a novel disacchar ide analogue of doxorubicin, was investigated in detail by a variety of spe ctroscopic techniques including spectrophotometry. fluorescence, and H-1 NM R. The pH dependent properties of MEN 10755 were also analysed by spectroph otometry and potentiometry within the pH range 5-11. It is found that MEN 1 0755 behaves very similarly to doxorubicin and reproduces closely its pH de pendent pattern. Like doxorubicin, MEN 10755 undergoes dimerization with a significantly smaller association constant. The interaction of MEN 10755 wi th calf thymus DNA was studied in detail. Spectrophotometric and fluorescen ce titrations of MEN 10755 with calf thymus DNA show spectral patterns almo st identical to those obtained with doxorubicin implying that the binding m echanism and the stability of the resulting adducts are very similar. An ap parent affinity constant of 1.2 x 10(6) was determined for the interaction of MEN 10755 with calf thymus DNA to be compared with the value of 3.3 x 10 (6) measured for doxorubicin, under the same conditions. The effects of bot h anthracyclines on the thermal denaturation profiles of calf thymus DNA we re also analyzed; both compounds turned out to stabilize to a similar exten t the DNA double helix and to give rise to a characteristic two-step meltin g profile. The implications of the present results for the pharmacological activity and the mechanism of action of this novel and promising antitumor compound are discussed. (C) 2001 Elsevier Science Ltd. All rights reserved.