Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-10-29
1996-12-03
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
556137, 435 5, 435 6, 424 936, C07D31120, C07F 1500, C12Q 170, C12Q 168
Patent
active
055809901
DESCRIPTION:
BRIEF SUMMARY
Such Pt-containing compounds are known from Reedijk, J. Struct. Bonding (Berlin), 67: 53-72.
This article describes the anti-tumor compound cis-Pt(NH.sub.3).sub.2 Cl.sub.2, which compound has a high affinity for (amongst others) proteins and DNA molecules and particularly it appears that such a compound has a marked affinity for the N7-nitrogen atom in the purine bases Guanine and Adenine, as well as for sulphur groups in macromolecules.
By dissociation of the two chlorine ligands two reactive sites arise, with which such platinum compounds can cross-link between two neighbouring Guanine and/or Adenine bases in the same or in opposite DNA strands. The application of cis-platinum as anti-tumor drug (cytostaticum) is based on this mechanism.
Besides this related carbo-platinum compounds are known from the same literature, which also have a high affinity for amongst others proteins and DNA molecules in a similar way as cis-platinum compounds.
On the contrary monochlorinated platinum compounds like Pt(diene)Cl appear to keep their DNA affinity but they do not form cross-links and interfere only slightly with the base pairing of complementary DNA strands, and are as such not anti-tumor active.
According to U.S. Pat. No. 4,711,955 it is preferred to apply DNA/RNA technology in the present medical-biological practice, especially the diagnostical practice, when non-radioactive nucleic acid labelling techniques are available. The presently applied known non-radioactive labelling techniques for DNA and RNA are globally to be divided in two categories.
1. Labelling which proceeds via enzymatic or organic synthetic routes; for instance biotin, bromodeoxyuridine (BrdU), digoxygenin, fluorescein and peroxidase.
2. Labelling by direct chemical coupling, like photobiotin, AAF, mercury, sulfone groups.
Application of such labels brings along a number of problems, which are particularly related to the complexity of the labelling procedure, the sometimes limited length of the synthetic oligonucleotides which are to be labelled, to use of health-injuring compounds and the stability of the label, when it is bound to the nucleic acid.
The invention now contemplates providing platinum-containing compounds, in the application of which the above-mentioned disadvantages are effectively removed.
To this end the invention provides a compound with the formula {Pt.sup.II (w)(x)(y)(z)} or {Pt.sup.IV (u)(v)(w)(x)(y)(z)} with the structural formula 1 or 2 respectively ##STR1## in which u, v, w, x, y and z represent whether or not the same whether or not interconnected ligands, from which at least one is a leaving ligand and at least one of the remaining ligands represents a detectable marker group.
Such a compound which is novel per se, and on the one side is provided with a directly or indirectly detectable marker group, as for instance a hapten, fluorescein or rhodamine and on the other side is provided with a suitable leaving group, is an especially suitable and novel DNA label with the general indication PtM (Pt stands for platinum and M stands for marker group) with unique properties.
For it appeared, that such a compound adheres spontaneously and irreversibly to DNA in aqueous medium. Further, the thus labelled DNA may be separated from the redundant compound with the formula 1 or 2 by alcohol precipitation. An important advantage is, that the thus labelled DNA may be detected immediately after hybridization by means of a fluorescence microscope or indirectly with one of the known immunohistochemical staining techniques.
The advantages of the present platinum-containing compounds are shortly summarized:
1. Direct--almost instantaneous--labelling of macromolecules without necessity of enzymatic or organosynthetic procedures.
2. One-step purification of labelled molecules by means of a simple routine technique.
3. Direct and/or indirect detection of labelled molecules by way of almost all known (microscopic) techniques.
As further advantage may be mentioned, that for specific purposes (for instance extra sensitive in situ hybridizatio
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Bloemink Marieke J.
Lempers Edwin L. M.
Reedijk Jan
van den Berg Franciscus M.
Rijksuniversiteit Leiden
Shah Mukund J.
Stichting Klinische Research Academisch Medisch Centrum
Wong King Lit
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