Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1985-01-16
1987-03-03
Schain, Howard E.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
424 85, 435188, 530345, 530404, 530408, 530388, 546193, 546261, 546270, 546281, 546291, 546294, A61K 39395, C07K 1500, C12N 996
Patent
active
046476555
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method for splitting at least one disulphide bond, --S--S--, in which each of the sulphur atoms is bonded covalently directly to a respective aliphatic carbon atom in an organic substance containing at least one such disulphide bond, each bond --S--S--, which is split, being substantially converted to two reactive groups of the formulae --S--S--R.sub.1 and R.sub.2 --S--S--, where R.sub.1 and R.sub.2 are the same or different and each is an organic residue. The invention also relates to an organic compound which exhibits at least one group --S--S--R.sub.1 and/or R.sub.2 --S--S-- bound covalently to an aliphatic carbon atom, in which groups R.sub.1 and R.sub.2 have the aforesaid significance.
Aliphatic thiol groups (i.e. the thiol group is bound to an aliphatic carbon atom) and disulphide groups derived therefrom have an important part to play in biochemical contexts. Thiol groups react under physiological conditions with a multiplicity of other functional structures, such as active thioesters for example. Thiol groups are often found in the active sites of enzymes, in which case they play an important part in the catalytic activity of the enzyme. Disulphide groups are often present in polypeptides (which term is also considered to include proteins) and usually appear to act as fixing elements and elements which afford conformation. The part played by natural disulphides as a reagent in the context of dynamic biochemical reactions is relatively unknown, but must be considered to be of great significance, for example through the aforementioned conformational properties in connection with proteins (c.f. for example FEBS Letters 97 [1979] pages 201-10).
The type of reaction involving both thiol groups and disulphide groups at the same time is designated thiol-disulphide-exchange and can be written as: +X.sub.3 --SH aliphatic or an aromatic carbon atom which is bound to one of the sulphur atoms in --S--S--.
Although the thiol-disulphide-exchange reaction takes place rapidly under physiological conditions, the conditions of equilibrium are normally unfavourable for the preparative production of a given disulphide. For example, when a polydisulphide is mixed with a thiol component, there rapidly takes place a series of thiol-disulphide-exchange reactions which result in a complex mixture of various disulphide-containing entities. If the polydisulphide is a biologically active molecule, the activity is affected.
The intriductions of so-called reactive disulphides, e.g. of the alkyl pyridyl disulphide type, has greatly facilitated the preparation of disulphides. By reactive disulphide is normally meant a disulphide of increased electrophilicity and of such nature that departing thiols are transformed to a stabilized tautomeric thioneform or the stabilized anion thereof. This stabilization denies the departed thiols the possibility of taking part in reverse or retro-reactions, e.g. in the case of alkyl pyridyl disulphide, aliphatic thiol-structures are not split off, but thione structures are. In this way, there is obtained an equilibrium which is favourable to the preparation of desired aliphatic disulphide.
Processes which are based on thiol-disulphide-exchange reactions and involve biologically active molecule types are now used increasingly in the conjugation of biomolecules with carrier polymers or biomolecules with biomolecules, whereby in the former case the external properties of the biomolecules, such as their solubility, separability, stability, transportability, are changed to fulfil given requirements, while in the latter case a multiple of bio-activities are combined and caused to coact, e.g. immunological properties with enzymatical properties or pharmacological properties with homing properties. Such preparations have found use, or can be judged to find future use in connection with chromatography, pharmaceuticals, diagnostic analysis methods, and in process technology.
Methodology in the preparation of disulphide conjugates by means of reactive disulphides between co
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patent: 4511501 (1985-04-01), Luduena
Axen Rolf E.
Carlsson Jan P.
Drevin Hakan N.
Pharmacia Aktiebolag
Philpitt Fred
Schain Howard E.
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