Process for the modification of surface

Details Process for the modification of surface Process for the modification of surface

2000-06-29

2004-08-24

Horlick, Kenneth R. (Department: 1637)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

Reexamination Certificate

active

06780980

ABSTRACT:

The present invention relates to a process for the modification of material surfaces with carbohydrates, and articles, in particular biomedical articles or biosensors comprising said modified surfaces.
Materials when in contact with biological fluids will undergo numerous phenomena such as protein adsorption, cell/material interaction or host response. In order to get a good integration of medical devices one wants to reduce non-specific adsorption and favor specific interaction of a desired cell type to achieve a controlled response [of the living medium]. This is also the case for biosensors. Since all cells are covered with a dense coating of sugars, it has long been predicted that oligosaccharides must be critical determinants of cell-cell communications. Molecules that interact with cell-attached oligosaccharides are in particular receptor proteins or carbohydrates. However, biologically relevant recognition of such proteins or carbohydrates on the surface of a biomedical article or biosensor requires an oligosaccharide modified surface in a specialized fashion; in particular the oligosaccharides should have a proper spacing and density as well as the proper three-dimensional shape on the material. Although methods to physically or chemically immobilizing carbohydrates on a material surface are already known, surfaces obtained by these processes so far have not proven satisfactory to provide effective cell-cell interactions. Accordingly, there is a demand for an improved process for the immobilization of oligosaccharides on a material surface which makes it possible to produce oligosaccharide patterns on a material surface that provide effective interactions with proteins, carbohydrates and the like.
The present invention therefore in one embodiment relates to a process for the preparation of a carbohydrate structure on a material surface comprising the steps of:
(a
1
) photochemically fixing one or more different compounds of formula
onto the material surface,
wherein X is the radical of a mono- or oligosaccharide,
R is a divalent organic radical having from 2 to 30 C-atoms which may be further substituted,
Z is —O—, —S— or a direct bond,
Y is a functional group linking R to the aromatic ring,
R
1
is an electron-withdrawing substituent and n is an integer from 0 to 4,
Q is a radical of formula
and R
2
is an electron-withdrawing substituent; or
(a
2
) photochemically fixing a compound of formula
wherein R, R
1
, n, Y, Z and Q are as defined above, onto the material surface and subsequently converting the —ZH groups to —Z—X moieties, wherein X has the above meaning; and
(b) enzymatically attaching one or more further carbohydrates to the X radicals of the modified surface obtained according to step (a
1
) or (a
2
).
The variable X is advantageously the radical of a mono-, di-, tri- or tetrasaccharide, which in case of an oligosaccharide may be linear or branched. In one embodiment of the invention X is the radical of a mono- or disaccharide and in particular the radical of a disaccharide. Examples of preferred carbohydrate radicals X are a galactose, lactose, mannose, N-acetyl glucosamine, N-acetyl galactosamine or N-acetyl lactosamine and in particular a galactose or lactose. In another embodiment of the invention X is a tetrasaccharide, in particular a branched tetrasaccharide.
Z is preferably a group —S—.
Suitable meanings of R are, for example, linear or branched C
2
-C
30
-alkylene which is unsubstituted or substituted, for example, by hydroxy, and is uninterrupted or interrupted, for example, by —O— or —NR
3
— wherein R
3
is hydrogen or C
1
-C
4
-alkyl; C
1
-C
12
-alkylene-C
8
-C
10
-arylen or C
1
-C
12
-alkylene-C
6
-C
10
-arylen-C
1
-C
12
-alkylene, for example C
1
-C
12
-alkylene-phenylene or C
1
-C
12
-alkylene-phenylene-C
1
-C
12
-alkylene; C
1
-C
12
-alkylene-C
5
-C
8
-cycloalkylene, for example C
1
-C
12
-alkylene-cyclohexylene; C
1
-C
12
-alkylene-C
5
-C
8
-cycloalkylene-C
1
-C
12
-alkylene, for example C
1
-C
12
-alkylene-cyclohexylene-C
1
-C
12
-alkylene; or C
1
-C
12
-alkylene-heterocyclene or C
1
-C
12
-alkylene-heterocyclene-C
1
-C
12
-alkylene, wherein the heterocyclyl ring is each, for example, five- or six-membered, contains at least one N—, O— or S-atom and in addition may comprise one or more carbonyl groups, for example C
1
-C
12
-alkylene-succinimidylene or N,N-di-C
1
-C
12
-alkylene-piperazinylene.
R is advantageously linear or branched C
2
-C
24
-alkylene, preferably linear or branched C
4
-C
18
-alkylene and most preferably linear C
8
-C
10
-alkylene, which in each case may be interrupted by —O— or —NR
3
—, and wherein R
3
is hydrogen or C
1
-C
4
-alkyl. R is most preferably a linear alkylene radical which is uninterrupted or interrupted by —O—.
Y is, for example, a functional group —C(O)—, —OC(O)—, —C(O)NR
4
—, —NR
4
C(O)—, —OC(O)—NH—, —NHC(S)NH— or —NHC(O)NH—, wherein R
4
is hydrogen or C
1
-C
4
-alkyl. Y is preferably a group —C(O)NR
4
— wherein R
4
is hydrogen, and the amino group is bonded to the phenyl ring.
R
1
is, for example, fluorine or trifluoromethyl, n may be an integer from 0 to 4 and is preferably 0.
Q is a group of formula (2b) or preferably of formula (2a) above.
An example of a preferred radical R
2
is trifluoromethyl.
A preferred group of compounds of formulae (1a) and (1b) corresponds to the formulae
wherein X is the radical of a mono-, di-, tri- or tetrasaccharide, R is linear or branched C
4
-C
18
-alkylene, Y is a functional group —C(O)O—, —OC(O)—, —C(O)NR
4
-, —NR
4
C(O)—, —OC(O)—NH—, —NHC(S)NH— or —NHC(O)NH—, wherein R
4
is hydrogen or C
1
-C
4
-alkyl.
The compounds of formula (1a) or (1a′) may be prepared, for example, by reacting a compound of the above formula (1b) or (1b′), for example after activating the thiol group by silylation, with a mono- or oligosaccharide corresponding to the radical X using, for example, Znl
2
as a catalyst. Another synthetic route comprises reacting a compound of the above formula (1b) or (1b′) with a mono- or oligosaccharide corresponding to the radical X, wherein the hydroxy group to be converted previously has been activated, for example, with trichloroacetimidate and the remaining hydroxy groups have been protected, for example by acetylation, at a temperature of, for example, room temperature, and finally deprotecting the hydroxy groups of the carbohydrate by a treatment in an acidic medium or preferably with a base such as an alkali alkoxide.
A further synthetic route for the preparation of the compounds of formula (1a) comprises first of all preparing a compound of formula
X′—Z—R—Y
1
  (3),
wherein Z and R are as defined above, X′ corresponds to the above mono- or oligosaccharide radical X in a form wherein the hydroxy groups are protected, for example by acetylation, and Y
1
is a functional group, for example a carboxy, hydroxy or amino group —NHR
4
, reacting said compound of formula (3) with a compound of formula
wherein Q, R
1
and n are as defined above, and Y
2
is a functional group that is coreactive with Y
1
, for example hydroxy, an amino group —NHR
4
or an isocyanato or isothiocyanato group, and finally deprotecting the hydroxy groups of the carbohydrate radical X′ by a treatment with a base as mentioned before.
The compounds of formula (3) may be obtained, for example, by reaction of a mono- or oligosaccharide corresponding to the radical X wherein some or all of the hydroxy groups have been protected, for example by acetylation, with a compound of formula
HZ—R—Y
1
  (5),
wherein, Z, R and Y
1
are as defined above, in the presence of a Lewis acid such as BF
3
etherate at a temperature of, for example, room temperature.
The compounds of formula (4) and (5) are known or may be obtained according to methods known in the art.
The compounds of formula (1b) or (1b′) may be obtained, for example, by reacting a compound of the above formula (4) with a compound of the above formula (5).
Still a further synthetic route for the preparation of the compounds of formula (1a) comprises reacting

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