Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives.
The cytotoxic activity of mitoxantrone and related anthracenediones has been ascribed to the ability of these compounds to interfere with DNA topoisomerase II function, resulting in DNA cleavage stimulation. The molecular details of enzyme inhibition by these intercalating agents remain to be defined. In an attempt to identify the structural determinants for optimal activity, the molecular and cellular effects of a series of heteroanalogues bearing different side-chains were examined in relation to the physico-chemical and DNA binding properties of these compounds. The results indicated that substitution of a pyridine ring for the dihydroxyphenylene ring in the planar chromophore caused a marked reduction of cytotoxic activity and of the ability to stimulate topoisomerase II-mediated DNA damage in intact cells and with simian virus 40 DNA in vitro. Although all tested derivatives were shown to intercalate into DNA, their DNA binding affinities were appreciably lower than that of mitoxantrone. The behavior of 2-aza derivatives more closely resembled that of ametantrone, suggesting that the potency of agents of this class is influenced more by the presence of hydroxyl groups than by the phenylene ring. The observation that a dramatic reduction (or loss) of the ability of aza derivatives to stimulate DNA cleavage is associated with a marked reduction of cytotoxic potency supports a primary role of topoisomerase II-mediated effects in the mechanism of action of the effective agents of this class. Because appreciable cytotoxic activity and significant in vivo antitumor efficacy are retained by compounds inactive (or poorly active) in inhibition of topoisomerase II, these results are consistent with multiple effects of anthracenediones at the cellular level.
De Isabella
P
P
Division of Experimental Oncology B, Istituto Nazionale Tumori, Milan, Italy.
Palumbo
M
M
Sissi
C
C
Capranico
G
G
Carenini
N
N
Menta
E
E
Oliva
A
A
Spinelli
S
S
Krapcho
A P
AP
Giuliani
F C
FC
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000187:drug effects; D004279:DNA, Viral / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011485:Protein Binding; D013539:Simian virus 40 / Q000235:genetics; D013237:Stereoisomerism; D013816:Thermodynamics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D004277:DNA, Single-Stranded; D004279:DNA, Viral; D007546:Isoquinolines; D004247:DNA; D004250:DNA Topoisomerases, Type II; C086548:pixantrone