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 disaccharide analogue of doxorubicin, was investigated in detail by a variety of spectroscopic techniques including spectrophotometry, fluorescence, and (1)H NMR. The pH dependent properties of MEN 10755 were also analysed by spectrophotometry and potentiometry within the pH range 5--11. It is found that MEN 10755 behaves very similarly to doxorubicin and reproduces closely its pH dependent pattern. Like doxorubicin, MEN 10755 undergoes dimerization with a significantly smaller association constant. The interaction of MEN 10755 with calf thymus DNA was studied in detail. Spectrophotometric and fluorescence titrations of MEN 10755 with calf thymus DNA show spectral patterns almost identical to those obtained with doxorubicin implying that the binding mechanism and the stability of the resulting adducts are very similar. An apparent 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 both anthracyclines on the thermal denaturation profiles of calf thymus DNA were also analyzed; both compounds turned out to stabilize to a similar extent the DNA double helix and to give rise to a characteristic two-step melting 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.
Messori
L
L
Department of Chemistry, University of Florence, Via Gino Capponi 7, 50121 Florence, Italy. messori@cerm.unifi.it
Temperini
C
C
Piccioli
F
F
Animati
F
F
Di Bugno
C
C
Orioli
P
P
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D002417:Cattle; D004247:DNA / Q000187:drug effects*; D004187:Disaccharides / Q000737:chemistry* / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D013050:Spectrometry, Fluorescence
D000903:Antibiotics, Antineoplastic; D004187:Disaccharides; D004317:Doxorubicin; D004247:DNA; C107602:sabarubicin