Physicochemical properties, cytotoxic activity and topoisomerase II inhibition of 2,3-diaza-anthracenediones.
The physicochemical, cytotoxic and pharmacological properties of 2,3-diaza-anthracenedione derivatives were examined to gain insight into the structure-activity relationships in this class of compounds. Spectrophotometric, chiroptical and voltammetric measurements were performed, along with cell cytotoxicity, alkaline elution, topoisomerase II-mediated DNA cleavage and cellular drug-uptake determination. In comparison with classic anthracenediones such as mitoxantrone and ametantrone, the aza derivatives were characterized by less negative reduction potentials, lower affinity for DNA and modified geometry of intercalation. The biological effects of the new compounds were also profoundly affected by bioisosteric N for C replacement. Stimulation of topoisomerase II-mediated DNA cleavage was not observed, whereas other mechanisms of cell cytotoxicity, possibly involving oxidative DNA damage appeared to be operative. The inability to generate protein-associated strand breaks could be explained by an unfavorable orientation of the drug in the intercalation complex rather than by a reduced binding to DNA. Geometry of drug intercalation may have a critical influence on the formation of the ternary complex. In turn, the onset of a different DNA-damaging pathway is likely to be related to easy redox cycling of the 2,3-diaza-substituted anthracenedione derivatives, which could produce radical species to a remarkably greater extent than could the carbocyclic parent drugs.
de Isabella
P
P
Division of Experimental Oncology B, Istituto Nazionale per Lo Studio e la Cura dei Tumori, Milan, Italy.
Palumbo
M
M
Sissi
C
C
Carenini
N
N
Capranico
G
G
Menta
E
E
Oliva
A
A
Spinelli
S
S
Krapcho
A P
AP
Giuliani
F C
FC
Zunino
F
F
D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA