Topoisomerase II inhibitors and therapeutic uses therefor
AssigneeThe United States of America as represented by the Department of Health and Human Services
InventorsYves Pommier, Timothy L. MacDonald, Jose S. Madalengoitia
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Abstract
Azatoxin and derivatives thereof are illustrative of a new class of antitumor drugs that are topoisomerase II (top 2) inhibitors. The pharmacophore inhibits the catalytic activity of the purified enzyme but does not unwind relaxed or supercoiled DNA. It is nonintercalative and has at least two domains: a quasi-planar polycyclic ring system, which may bind between DNA base pairs, and a pendant substituent thought to interact with the enzyme, with the DNA grooves or with both. In SV40 and c-myc DNA, azatoxin induces numerous double-strand breaks according to a cleavage pattern which differs from those of known top 2 inhibitors. Azatoxin also is a potent inhibitor of tubulin polymerization.
Claims9
A compound that inhibits topoisomerase II catalytic activity and that is represented by the following formula (C):
- ##STR14## wherein (i) X denotes NH;
- (ii) R.sub.6 denotes F, Cl, Br, CN, OH, NH.sub.2 or H;
- (iii) R.sub.7 denotes H, OH, the formula ##STR15## wherein R denotes H, OH, F, Br, Cl, NO.sub.2, NH.sub.2, CN, OCH.sub.3, or CO.sub.2 CH.sub.2 CH.sub.3 ;
- R.sub.7 also denotes the formula
- --T--(CH.sub.2).sub.n Z
- wherein
- T denotes NH or O;Z denotes NH.sub.2, OH, N(CH.sub.3).sub.2, or N(CH.sub.2 CH.sub.2 Cl).sub.2 ;
- n is 2,3 or 4;
- and
- R.sub.7 may be derivatized with a 4,6 o-protected sugar;
- and
- (iv) W and W' are the same or different and denote, respectively, H or F, provided that if R.sub.6 is H, then R.sub.7 denotes the formula ##STR16## wherein R denotes H, OH, F, Br, Cl, NO.sub.2, NH.sub.2, CN, OCH.sub.3, or CO.sub.2 CH.sub.2 CH.sub.3 ;
- or
- --T--(CH.sub.2).sub.n Z
- wherein
- T denotes NH or O;
- Z denotes NH.sub.2, OH, N(CH.sub.3).sub.2, or N(CH.sub.2 CH.sub.2 Cl).sub.2 ;
- n is 2, 3 or 4.
Dependencies are inferred from the claim text.