Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-03-28
1998-03-31
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
552238, 552243, 552247, 552255, 552268, 514 14, 514 16, 514 17, 514 18, 514 19, A61K 3800, C09B 116, C07C 4600, C07C 5018
Patent
active
057338809
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB94/02128 filed Sep. 30, 1994.
The present invention relates to compounds which are based on an anthraquinone nucleus, for use in medicine or as dyes. The inhibition of DNA topoisomerases, particularly topoisomerase II (topo II) is now considered to be an important component in the mechanism of action of a large number of the most clinically active anticancer drugs presently available including doxorubicin, mitoxantrone, VP16, camptothecin, topotecan, M-AMSA, VM26 and the ellipiticines. These drugs are believed to inhibit topo II by stabilising a protein/drug
ucleic acid ternary complex termed the clearable complex.
However, whilst targeting topoisomerases, these drugs also exhibit a number of other mechanisms of action, such as generation of free radicals and formation of DNA covalent adducts which contribute to their overall toxicity and poor therapeutic index. Additionally, the failure of these agents to produce long term cures in the major malignancies is probably exacerbated by the presence of de novo resistance and the development of acquired drug resistance.
U.S. Pat. No. 4,894,451 describes asymmetrically substituted anthracene-1,4-dione compounds of Formula (A): ##STR2## where B is a lower dialkyl amino group, n is 3-5 and R is hydrogen, alkanoyl or alkylsulphonyl. These compounds were proposed for use against tumours.
The co-pending WO 93/19037 describes compounds having the structural formula: ##STR3##
where Y and Y.sup.1 are independently hydrogen or hydroxyl, B and B.sup.1 are independently oxo or hydrogen, R.sup.5 is hydrogen or hydroxyl and X is the residue of an .alpha. amino acid or a derivative of an .alpha. amino acid, joined to the ring shown via the nitrogen atom of the amino acid adjacent the acid group thereof. These compounds provide clinically active drugs and coloured compounds useful as drugs.
EP-A-0 295 316 discloses symmetrically-substituted compounds for use in hydroxyaminoalkyl)-amino!-5,8 -dihydroxyanthraquinones.
A peptidic DNA-binding motif, the tetrapeptide SPKK (Ser-Pro-Lys-Lys) has been proposed (Suzuki (1989) EMBO J. 8, 797). SPKK dimers and hexamers were shown to compete with the AT-specific DNA-binding dye Hoechst 33258; nevertheless, they present a lower degree of specificity than Hoechst (Churchill & Suzuki (1989) EMBO J. 8, 4189; Suzuki (1989) EMBO J. 8, 797). Statistical studies suggested that SPKK forms a .beta.-turn stabilized by an additional hydrogen bond between the Ser side chain OH group and the main chain NH group of the third residue Lys. A model was devised for the S.sub.2 peptide, SPKKSPKK, in which the amides of Ser (the only amides to be free in the .beta.-turn/Asx-turn mixed conformation) were relatively well overlapped onto the amides of netropsin known to form three centered hydrogen bonds with DNA. Thus, a succession of SPKK motifs may bind to AT-rich sequences in the minor groove by adopting a crescent shape similar to that of netropsin and also by using the same specific hydrogen bonds.
Bailly et al (1992) Anti-Cancer Drug Design 7, 83-100 describe anilinoacridine derivatives containing the nucleic acid-binding unit SPKK. The peptide is joined to the acridine heterocyclic ring system at the position opposite the N heteroatom in the middle ring. Design 4, 37-52; ibid. (1990), 5, 291-305; (1993) J Med Chem 36, 2084-2090! disclosed various copper-chelating asymmetric peptide-anthraquinone compounds using a Gly-His-Lys moiety, or sometimes just the initial Gly, attached directly to the 4-position of the anthraquinone ring, with the 1-position being substituted by a hydroxyl group.
JP,A,82, 141456 describes lanine as a dyestuff.
Morier-Teissier et al (1993) J. Med. Chem. 36, 2084-2090 describes the synthesis of anthraquinone bisubstituted by the copper chelating peptide Gly-Gly-His.
It is an object of this invention to provide improved clinically active drugs. It is a further object of the invention to provide coloured compounds useful as dyestuffs.
In one aspect the invention provides a compound having the structu
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Badio Barbara
Dees Jos,e G.
Napier University Ventures Limited
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