Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-03-12
2001-03-27
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S283000, C514S285000, C514S297000, C514S463000, C546S048000, C546S105000, C546S106000, C546S070000, C549S298000, C549S432000
Reexamination Certificate
active
06207673
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns covalent conjugates of topoisomerase I inhibitors (e.g., camptothecins) and topoisomerase II inhibitors (e.g., amsacrine, ellipticines, anthracycline antibiotics, epipodophyllotoxins).
BACKGROUND OF THE INVENTION
Etoposide is a widely-used antineoplastic agent which inhibits mammalian DNA topoisomerase II isoenzymes. See, F. Drake et al.,
Biochem.
28:8154 (1989); P. Watt and I. Hickson,
Biochem. J.
303:681 (1994); and Y. Pommier,
Cancer Chemo. & Pharmac.
32:103 (1993). Various etoposide derivatives have been developed in order to improve antitumor activity, cytotoxicity against drug resistant cells and drug-formulation characteristics including the 4′-O-demethylepipodophyllotoxins bearing C-4&bgr;-N-linked substituents. See, Y. Zhang and K. H. Lee,
Chin. Pharm. J.
46:319 (1994). The other mammalian DNA topoisomerase, a type I enzyme, is also considered to be a useful therapeutic target. Several selective inhibitors have been identified to date including the antitumor alkaloid, camptothecin, (CPT) and two analogs are currently approved for clinical use in the United States. See, P. Watt and I. Hickson,
Biochem. J
303:681 (1994); and A. Chen and L. Liu,
Annu. Rev. Pharmacol. Toxicol.
34:191 (1994). However, not all topoisomerase inhibitors of potential clinical value are topoisomerase-type specific. For example, a 7-H-benzopyrido (4,3-b) indole-derivative (inotoplicine), inhibits topoisomerases I and II simultaneously and can circumvent topoisomerase-mediated mechanisms of drug-resistance. See, B. Podderin et al.,
Mol. Pharmacol.
44:767 (1993).
All of the above-mentioned compounds share a common inhibitory mechanism which is understood in some depth at the biochemical level. Enzyme inhibition involves the trapping of a putative covalent reaction intermediate called a reversible “cleavable complex”. The intracellular lesion, presumably a topoisomerase-DNA-drug ternary complex, ultimately leads to cell death. Although the cytotoxic events depend on the particular type of topoisomerase involved, the precise biochemical pathway(s) to cell killing remains to be defined. See, P. Watt and I. Hickson,
Biochem. J.
303:681 (1994); A. Chen and L. Liu,
Annu. Rev. Pharmacol. Toxicol.
34:191 (1994); and P. Darpa et al.,
Cancer Res.
50:6919 (1990).
SUMMARY OF THE INVENTION
A first aspect of the present invention is covalent conjugates of topoisomerase I and topoisomerase II inhibitors. Such compounds have a structure according to formula I:
T
I
—L—T
II
(I)
wherein:
T
I
is a topoisomerase I inhibitor such as a camptothecin group;
T
II
is a topoisomerase II inhibitor such as an amsacrine, ellipticine, epipodophyllotoxin, anthracycline antibiotic group, or mitoxantrone group; and
L is a linking group.
The compounds of formula I are useful as, among other things, inhibitors of topoisomerase I and topoisomerase II.
The present invention is explained in greater detail in the drawings herein and the specification set forth below.
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L. F. Liu, “DNA Topoisomerase Poisons as Antitumor Drugs,”Annu. Rev. Biochem., vol. 58, p. 351-375 (1989).
Bastow, K.F. et al., Antitumor agents—CLXXIII. Synthesis and evaluation of camptothecin-4 beta-amino-4′-0-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents, Bioorg Med. Chem., vol. 5 (8), 1481-8 (Aug. 1997) (Abstract).
Poddevin B. et al., Dual Topoisomerase I and II Inhibition by Intoplicine (RP-60475), a New Antitumor Agent in Early Clinical Trials, Molecular Pharmacology, 44 (4) pp. 767-774 (1993).
Guo, X. et al., Novel Biochemical and antitumor activity of the camptothecin-4beta-amino-4′-0-demethyl epipodophyllotoxin conjugates (meeting abstract), Proc.Annu. Meet., Am. Assoc. Cancer Res., 38, A4108 (1997).
CA 127:326521, 1997, Teicher, 1997.*
CA 122:306028, Petersen,, 1994.*
Registry search report of RN 204133-84-6, 204133-83-5, and 204133-81-3, 1999.
Bastow Kenneth F.
Cheng Yung-Chi
Guo Xin
Lee Kuo-Hsiung
Wang Hui-Kang
Myers Bigel & Sibley & Sajovec
Seaman D. Margaret
The University of North Carolina at Chapel Hill
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