Polymerizable macromers and preparation thereof

Details Polymerizable macromers and preparation thereof Polymerizable macromers and preparation thereof

2003-10-29

2004-11-23

Pezzuto, Helen L. (Department: 1713)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Polymers from only ethylenic monomers or processes of...

C526S204000, C526S217000, C526S288000, C526S304000, C526S307300, C526S307700, C526S318300, C526S320000, C526S328500

Reexamination Certificate

active

06822064

ABSTRACT:

FIELD OF INVENTION
This invention relates to polymerizable macromers containing carbohydrates including with N-Acetyl Glucosamine (NAG) of molecular weight ranging between 700 Daltons to 1,00,000 Daltons having formula herein below.
wherein,
R is H, CH
3
, C
2
H
5
, C
6
H
5
,
R
1
is H, CH
3
, C
2
H
5
, C
6
H
5
X may be between 4 to 10, n is from 2 to 50
Y may be N-Acetyl Glucosamine (NAG), mannose, galactose, sialic acid, fructose, ribulose, erythrolose, xylulose, psicose, sorbose, tagatose, glucopyranose, fructofuranose, deoxyribose, galactosamine, sucrose, lactose, isomaltose, maltose, cellobiose, cellulose and amylose.
More particularly it relates to the said polymerizable macromers containing various carbohydrate ligands including with NAG and preparation thereof through the specific linkage mentioned herein. Still more particularly it relates to macromer, which bind more strongly to lysozyme than NAG itself.
The macromers of the present invention as mentioned above are prepared by coupling acryloyl-spacer conjugate of formula (2) claimed in our copending Patent Application no NF363/02 entitled “Oligomer and preparation thereof” herein below
wherein,
R is H, CH
3
, C
2
H
5
, C
6
H
5
X may be between 4 to 10.
with functional polyvalent oligomers comprising NAG, sialic acid, galactose or mannose exemplified with NAG as herein given below having Formula (3)
wherein, n=2 to 50
The polymerizable macromers may be used for inhibition of viral infections and the recoveries of biomolecules. The approach of synthesis of polymerizable macromers with ligand N-Acetyl Glucosamine (NAG) is a generic and can be used for other ligands such as sialic acid, galactose and mannose.
BACKGROUND AND PRIOR ART REFERENCES
Carbohydrates play a crucial role in biological phenomena and therefore these molecules have attracted the attention of chemists and biochemists. These biomolecules are ubiquitous, figuring prominently in various processes such as cell differentiation, cell growth, inflammation, viral and bacterial infection, tumorigenesis and metastasis (Rouhi A., M., C & EN, Sep. 23,62-66,1996).
Many infections caused by bacteria and virus are a result of host receptor interactions. The foremost step for the infection is the adhesion of the ligands present on the infectious microbe to the receptors of the host cells. Adhesion and interactions have to be strong for a successful infection. If the adhesion is not adequate then normal defense mechanism can intercept this process. Viruses and bacteria for example interact with certain saccharides of the host cell. Bacteria express a large number of lectins and are used to adhere to glycocalyx of the host cell through a multivalent interactions. Agglutination of erythrocytes is a case in point.
Carbohydrates exhibit molecular diversity and wide structural variations, which makes carbohydrates alternative ligands for competitive binding to inhibit the infections.
Many alterations and modifications of the naturally occurring O-/N-glycosidic sugars are being reported and is an area of prime interest to the chemist and biochemist.
The importance of carbohydrates in biologically relevant recognition processes has been recognized fairly recently (Feizi, T., Biochem. J. 245:1,1987). In addition, carbohydrates on cell surfaces play an important role in intercellular communication and recognition processes, which is principally based on receptor-ligand interactions.
Carbohydrates are usually attached to other moieties such as lipids or proteins. Belvilacqua et al., (Science, 243:1160,1989) have demonstrated the role of carbohydrates along with proteins and nucleic acids as a primary biological information carriers.
The inventors of the present invention have observed that it may be worthwhile to use carbohydrates in therapeutics for human, especially since they can play an important role in prevention of viral and bacterial infections. Recently few reports have been published to justify the use of carbohydrates. Krepinsky et al. (U.S. Pat. No. 6,184,368, 2001) suggested the application of carbohydrates in preventing the infections. Mandeville, et al. (U.S. Pat. No. 5,891,862,1999) reported the use of polyvalent polymers containing carbohydrates for the treatment of rotavirus infection
Polyvalent molecules bind to the receptor molecules through multiple contacts, which results in strong binding. However the synthesis of ligands is critical and involves multiple steps. The polyvalent interactions can be maximized by incorporation of ligands optimally tailored based on the understanding of the binding between the ligand and the host receptor. The enhanced interactions are important especially when the ligands are expensive e.g. sialic acid.
The inventors of the present invention have also observed that interactions of ligand with a receptor can be enhanced by 1) appropriate incorporation of the ligand 2) incorporation of spacer chain and 3) by steric stabilization/exclusion.
Spaltenstein et al., (J.Am.Chem.Soc.,113:686,1991) reported increased interaction between the receptor and ligand due to plurality of binding ligands and the receptors on the host surface. This was illustrated by the influenza virus hemagglutinin, which binds to neuraminic acid on the cell surface, which has a greater affinity for its receptor when a polyvalent structure is presented.
The early phase of infection by viral, parasitic, mycoplasmal and bacterial pathogens, is achieved by specific adhesion to cell surface carbohydrate epitopes (Dimick,et al. (J.Am.Chem.Society, 121,10286-10296,1999). Dwek, et al. (Chem. Rev., 96,693, 1996) reported the initiation of a wide range of human disease is mediated by protein-carbohydrate recognition step.
If relative density and spatial arrangement of ligands incorporated is optimized, then the binding can be substantially enhanced. The enhanced interaction between molecular conjugate with a specific binding site of biomolecule also finds applications in affinity separations, drug delivery and biotechnology.
To imitate and exploit this mechanism there is a need to devise a simple synthetic methodology, which will enhance substrate ligand interactions.
Design of high affinity protein carbohydrate binding systems can provide an alternative strategy for the treatment of infectious diseases e.g. influenza and rotavirus. This has the advantage as such agents will not have pathogen resistance to antibiotics and drugs. A new approach to treat influenza is based on the principle of inhibition of virus to the host cells. The inhibitors like sialic acid anchored to polymeric or liposomal carriers have been reported in the past.
Since monovalent interactions of natural oligosaccharides are weak, they need to be used in large quantities for an effective treatment. This problem can be overcome by synthesizing polyvalent carbohydrate molecules (Zopf, D., Roth, S. Lancet 347, 1017, 1996). The concept is attractive since it would provide a non-toxic therapeutic to a wide range of human diseases. But synthesis of such compounds is critical and requires knowledge of the host-cell binding mechanism.
Polymeric ligands that bind to the virus more powerfully than the Red Blood Cells will prevent the influenza infection. Similar binding is also involved in rotavirus infections. (Mandeville et al. U.S. Pat. No. 6,187,762, 2001)
Advantage of carbohydrate modification lies in that it may impart change in physical characteristics such as solubility, stability, activity, antibody recognition and susceptibility to enzyme. Sharon, et al., (Science,246:227-234,1989) reported carbohydrate portions of glyco-conjugate molecules to be important entity in carbohydrate biology.
Haemagglutination can be prevented by saccharides multivalent glycoconjugates, which bind to the bacterial lectins and thus inhibit bacterial adhesion. (Sigal, et al.,J.Am.Chem.Soc.118:16,3789-3800,1996).
Damschroder, et al. (U.S. Pat. No. 2,548,520,1951) reported high molecular weight preformed polymers conjugated with unsaturated monomers or proteins. Synthesis of high molecular weight materials of t

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