Azatoxin derivatives with potent and selective action on topoisomerase II.
Azatoxin was rationally designed as a DNA topoisomerase II (top2) inhibitor [Leteurtre et al., Cancer Res 52: 4478-4483, 1992] and was also found to inhibit tubulin polymerization. Its cytotoxicity is due to action on tubulin at lower concentrations and on top2 at higher concentrations. At intermediate concentrations, the combination of the two mechanisms appears antagonistic [Solary et al., Biochem Pharmacol 45: 2449-2456, 1993]. The aim of this study was to design azatoxin derivatives that would act only on tubulin or on top2. Selective targeting of top2 or tubulin was tested using top2-mediated DNA cleavage assays, and tubulin polymerization and tubulin proteolysis assays, as well as COMPARE analyses of cytotoxicity assays in the National Cancer Institute in vitro Drug Screening Program. Selective inhibitors of top2 and tubulin polymerization have been obtained. Top2 inhibition, abolished by methylation at position 4', was enhanced by the addition of a bulky group at position 11. Bulky substitution at position 11 determined different patterns of top2 cleavage sites and suppressed the action on tubulin. Selective inhibition of tubulin was obtained with 4'-methylazatoxin that was found to bind to the colchicine site. These results are consistent with those obtained in the podophyllotoxin family to which azatoxin is structurally related. Some azatoxin derivatives are under consideration for further preclinical development.
Leteurtre
F
F
Laboratory of Molecular Pharmacology, DTP, DCT, NCI, NIH, Bethesda, Maryland 20892, USA.
Sackett
D L
DL
Madalengoitia
J
J
Kohlhagen
G
G
MacDonald
T
T
Hamel
E
E
Paull
K D
KD
Pommier
Y
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D004354:Drug Screening Assays, Antitumor; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D050257:Tubulin Modulators
C093730:4'-methylazatoxin; D000970:Antineoplastic Agents; D007211:Indoles; D059005:Topoisomerase II Inhibitors; D050257:Tubulin Modulators; C093728:fluoroanilinoazatoxin; C075996:azatoxin