Amide containing molecular imprinted polymers

Details Amide containing molecular imprinted polymers Amide containing molecular imprinted polymers

1997-05-30

2001-08-14

Zitomer, Fred (Department: 1713)

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

Synthetic resins

Polymers from only ethylenic monomers or processes of...

C210S656000, C210S660000, C526S213000, C526S215000, C526S217000, C526S220000, C526S236000, C526S307700, C526S335000

Reexamination Certificate

active

06274686

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to synthetic molecular imprinted polymers (MIPs), methods of making them and their use as specific binding surfaces. The MIPs of this invention possess amide functional groups which participate in hydrogen bonding during recognition and binding of molecules to the MIP. Accordingly, the improved recognition and binding properties associated with the MIPs of this invention makes them useful, for example, as affinity reagents in separation chemistry, artificial enzymes and artificial receptors.
BACKGROUND OF THE INVENTION
The fabrication of artificial receptors that can achieve recognition at the molecular level is one of the major goals of organic and bio-organic chemistry. Based on the increasing understanding of the basic interactions (hydrogen bonding, ionic interaction, hydrophobic effect, metal chelating, etc.) between molecules and the recognition between substrate-enzyme, antigen-antibody and ligand-receptor, several well known synthetic recognition systems have been developed
1
, and newly synthesized receptors are rapidly emerging
2
.
Molecular imprinting is a technique for the preparation of such artificial receptors, separation materials of high specificity, artificial enzymes and other synthetic members of a ligand binding pair
3-6
. Molecular imprinted polymer (MIP) materials prepared by molecular imprinting have been successfully used for chiral separation of amino acid derivatives
7
, drugs
8
, sugar derivatives
9
, specific recognition of steroids
10
, proteins and protein analogues
11
, as antibody and receptor mimics
12
, as ion selective absorbents
13
and as enzyme mimics to direct organic reactions
14-17
.
Generally, MIPs are prepared by polymerization in a relatively non-polar solvent exhibiting better recognition sites than those prepared using a polar solvent. Better recognition sites are also expected using templates having more noncovalent interacting groups. However, one common problem is that many such compounds are normally not very soluble in nonpolar organic solvents. Because of this, the development of a method for making good MIPs in polar organic solvents is of general interest.
Currently, the carboxyl group is the most commonly used hydrogen bonding functional group. Although it can form strong ionic interactions with basic functional groups, the hydrogen bonding ability of this functional group is not very strong in polar solvents. Often MIPs made in a polar solvent containing carboxyl groups which can only form hydrogen bond interactions with the print molecule exhibit weak recognition, and in some cases no recognition at all
7c,d,18
.
Although amide monomers have not been reported as components of MIPs, previous results reported that a polymer imprinted against a template having an amide group instead of an ester group normally gave much better enantiomeric resolution
7a,b.19,20
. In addition, amide monomers have also been used in templates in combination with different functional monomers. For templates having both hydrogen bonding and acidic functional groups, the combination of methyacrylic acid and a basic functional monomer (vinyl pyridine) was shown to give MIPs improved enantiomeric recognition
7d
. One obvious problem with this combination is that the ionic interaction between these two functional monomers might decrease the imprinting efficiency.
U.S. Pat. No. 5,541,342 refers to the preparation of molecular imprints using polymers of L-proline and methacrylic acid amide. The amide group, however, becomes part of the linking group to the proline and is not available to participate in bonding to the print molecule. Rather, as in other prior art MIPS, non-covalent bonding of the print molecule occurs through carboxyl groups, in this case provided by the prolines.
SUMMARY OF THE INVENTION
This invention relates to synthetic amide containing synthetic molecular imprinted co-polymers (MIPs), methods of making them and their use as members of a ligand binding pair. The MIPs of the invention comprise a monomer possessing a free amide group and a cross-linking component. Monomer subunits containing at least one free amide group provide for reversible binding with print molecules to which the MIPs are formed. Following formation of the MIPs, and separation of the print molecules, the MIPs of the invention are capable of specifically binding to certain molecules structurally similar to the print molecules.
The MIPs of the invention are useful as specific binding reagents as a result of their ability to participate in strong non-covalent binding interactions with ligands which fit into the binding site created by the print molecule. The MIPs of the invention are therefore useful in any system dependent on specific molecular recognition such as, for example, separation materials, artificial enzymes, artificial receptors or antibodies.
Another aspect of this invention are MIPs without carboxylic acid groups and the subsequent reduction of nonspecific binding.
An object of this invention is to provide MIPs containing free amide groups which are capable of non-covalently binding to print molecules and other structures capable of binding to the binding site created by the print molecule and thus have improved specificity for such ligands.
Another object of this invention is to provide methods of making the MIPs of the invention by using monomers possessing amide rather than carboxyl groups.
Another object of this invention is provide reagents and methods for effecting the separation of enantiomers from racemic mixtures.
Another object of the invention are methods of preparing the MIPs of the this invention.
A still further object of the present invention are MIPs containing a plurality of molecular subunits geometrically configured for selective absorption of a print molecule of interest, and wherein at least one of the subunits contains a free amide group.
A further object of the present invention is providing a print molecule configured copolymer containing free amide groups for reversibly binding.
These and other objects will become more apparent when considered inconjunction with the following detailed description, non-limiting examples, drawing figures and appended claims.


REFERENCES:
patent: 5541342 (1996-07-01), Korhonen et al.
patent: 5630978 (1997-05-01), Domb
patent: 5728296 (1998-03-01), Hjerten et al.
C. Yu, K. Mosbach: “Molecular Imprinting Utilizing an Amide Functional Group for Hydrogen Bonding Leading to Highly Efficient Polymers” J. of Organic Chemistry, vol. 62, No. 12, 1997, pp. 4057-4064.
M. Burow, N. Minoura: “Molecular Imprinting: Synthesis of Polymer Particles with Antibody-like Binding Characteristic for Glucose Oxidase:” Biochemical and Biophysical Research Comm., vol. 227, No. 2, 1996, pp. 419-422.
K. Ohkubo, Y. Urata, S. Hirota, Y. Funakoshi, t. Sagawa, S. Usui, K. Yoshinaga: “Catalytic activities of novel L-histidyl group-introduced polymers imprinted by a transition state analogue in the hydrolysis of amino acid esters” J. of Molecular Catalysis A: Chemical, vol. 101, No. 2, Aug. 11, 1995, pp. L111-L114.
K. Ohkubo, Y. Funakoshi, t. Sagawa: “Catalytic activity of a novel water-soluble cross-linked polymer imprinted by a transition-state analogue for the stereoselective hydrolysis of enantiomeric amino acid esters” Polymer, vol. 31, No. 17, 1996, pp. 3993-3995.
O. Ramstrom, L. I. Andersson, K. Mosbach: “Recognition Sites Incorporating Both Pyridinyl and Carboxy Functionalities Prepared by Molecular Imprinting” J. of Organic Chem., vol. 58, No. 26, 1993, pp. 7562-7564.
L. Andersson, B. Sellergren, K. Mosbach: Imprinting of Amino Acid Derivatives in macroporous Polymers: Tetrahedron Letters, vol. 25, No. 45, 1984, pp. 5211-5214.
Beach, J. V. et al: Designed Catalysts. A Synthetic Network Polymer that Catalyzes the Dehydrofluorination of 4-Fluoro-4-(P-Nitrophyenyl)Butan-2-One: J. of Amer Chem Soc., vol. 115, No. 1, Jan. 12, 1994, pp. 379/380.
Shea K. J. et al: Synthesis and Characterization of Highly Cross-Linked Polyacrylamides and Polymethacrylamides. A New class of macropo

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