Solid phase synthesis method and reagent

Details Solid phase synthesis method and reagent Solid phase synthesis method and reagent

2000-03-09

2002-06-25

Nutter, Nathan M. (Department: 1711)

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

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C536S025300, C536S126000, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500

Reexamination Certificate

active

06410643

ABSTRACT:

TECHNICAL FIELD
In one aspect, the present invention relates to methods, reagents and support surfaces for use in solid phase (e.g., repetitive or combinatorial) synthesis. In another aspect, the invention relates to substituted polyacrylamide reagents. In yet another aspect, the invention relates to reagents for use in modifying support surfaces, and in particular, the use of photochemical means to attach such reagents to such surfaces.
BACKGROUND OF THE INVENTION
Solid phase synthesis has evolved tremendously since the seminal work of R. B. Merrifield in 1963. Typically, the reactions used are the same as ordinary synthesis, with one of the reactants being anchored onto a solid support. Solid phase synthesis can be used, for instance, for the synthesis of polynucleotides, polysaccharides, and polypeptides, as well as other applications in repetitive syntheses and combinatorial chemistry.
The basic advantage of the solid phase technique is that the support (including all reagents attached to it) remains insoluble and is therefore easily separated from all other reagents. Excess reagents, other reaction products and side products, are quickly and efficiently removed upon removal of the solvents. Purification of the solid phase species is rapid and complete as well, and the entire process can be automated.
In recent years, the principles of solid phase synthesis have been applied to a new methodology known as “combinatorial chemistry”. Scientists use combinatorial chemistry to create large populations of molecules, or libraries, that can be screened efficiently en masse. By producing larger, more diverse compound libraries, companies increase the probability that they will find novel compounds of significant therapeutic and commercial value. The field represents a convergence of chemistry and biology, made possible by fundamental advances in miniaturization, robotics, and receptor development.
As with traditional drug design, combinatorial chemistry relies on organic synthesis methodologies. The difference is the scope—instead of synthesizing a single compound, combinatorial chemistry exploits automation and miniaturization to synthesize large libraries of compounds. But because large libraries do not produce active compounds independently, scientists also need to find the active components within these enormous populations. Thus, combinatorial organic synthesis is not random, but systematic and repetitive, using sets of chemical “building blocks” to form a diverse set of molecular entities.
There are at least three common approaches to combinatorial organic synthesis. During arrayed, spatially addressable synthesis, building blocks are reacted systematically in individual reaction wells or positions to form separate “discrete molecules.” Active compounds are identified by their location on the grid. This method has been applied in scale (as in the Parke-Davis Pharmaceutical “DIVERSOMER” technique), as well as in miniature (as in the Affymax “VLSIPS” technique). The second technique, known as encoded mixture synthesis, uses nucleotide, peptide, or other types of more inert chemical tags to identify each compound.
During deconvolution, the third approach, a series of compound mixtures is synthesized combinatorially, each time fixing some specific structural feature. Each mixture is assayed as a mixture and the most active combination is pursued. Further rounds systematically fix other structural features until a manageable number of discrete structures can be synthesized and screened. Scientists working with peptides, for example, can use deconvolution to optimize, or locate, the most active peptide sequence from millions of possibilities.
On a related subject, surfaces modified to provide reactive groups or other desired functionalities have long been used for performing solid phase syntheses of both polymeric and nonpolymeric molecules. A variety of solid phase resins are commercially available, e.g., those available from Argonaut Technologies, including their line of Polystyrene, ArgoGel™, and ArgoPore™ resins. Along similar lines, published International Patent Application No. WO9727226 (“Highly Functionalized Polyethylene Glycol Grafted Polystyrene Supports”), assigned to Argonaut Technologies, describes polymers and graft copolymers having a backbone of poly(methylsytrene) and side chain polymers of poly(ethylene oxide).
Such supports are also described in JW Labadie (“Polymeric Supports for Solid Phase Synthesis”),
Current Opinions in Chemical Biology
2:346 (1998). This article describes, for instance, the manner in which functional groups can be introduced into lightly cross-linked polystyrene, using either functional styrene monomers or in a post-functionalization step. In both approaches, however, the functional groups are apparently attached to the polystyrene polymers used to form the support (e.g., bead) itself, e.g., as opposed to being added as a separate coating to a pre-existing support.
The Labadie article also describes the use of PEG-grafted polystyrene, e.g., in the form of the “TentaGel” product prepared by grafting ethylene oxide to hydroxyl-functional polystyrene. The article further describes the manner in which various “shortcomings” associated with PEG grafts resins have been overcome by a graft resin identified as “ArgoGel™” which is designed with a bifurcation at the polystyrene-graft linkage through the use of a polystyrene diol as the base resin. With each of these approaches, the resultant polymers appear to be limited to functional groups at their terminal ends, as opposed to having functional groups in multiple positions along the length of the polymers.
On yet another subject, a variety of polymeric compositions have been described for use as electrophoretic gels. See generally, Righetti, et al.,
J. Chromatog. B. Biomed. Sci.
10;699(1-2):63-75 (1997) which describes recent advances in polyacrylamide gel electrophoresis.
See, for instance, U.S. Pat. No. 5,470,916, for “Formulations for Polyacrylamide Matrices in Electrokinetic and Chromatographic Methodologies”. The '916 patent describes formulations obtained via polymerization or co-polymerization of a unique class of monomers.
See also, U.S. Pat. No. 5,785,832, for “Covalently Cross-linked, Mixed-bed Agarose-polyacrylamide Matrices for Electrophoresis and Chromatography”, which describes polyacrylamide matrices based on a novel class of N-mono- and di-substituted acrylamide monomers. The '832 patent describes the manner in which mixed-bed matrices of the type polyacrylamide-agarose, covalently linked (cross-linked), are useful in the separation of fragments of nucleic acid, particular DNA, of intermediate size (from 50 to 5,000 base pairs) and of high molecular mass proteins (>500,000 Da). The '832 patent provides covalently-linked polyacrylamide-agarose mixed-bed matrices suitable for use in the separation of fragments of nucleic acids of intermediate size.
Substituted polyacrylamides such as those described above have been restricted to use in preparing electrophoretic gels, and, to the best of Applicant's awareness, have not previously been attached to surfaces, let alone attached for the purpose of providing a solid phase synthetic surface, or by photochemical means.
On a separate subject, the assignee of the present invention has previously described the modification of surfaces for a variety of purposes, and using a variety of reagents. In particular, these reagents generally involve the use of photochemistry, and in particular, photoreactive groups, e.g., for attaching polymers and other molecules to support surfaces. See, for instance, U.S. Pat. Nos. 4,722,906, 4,979,959, 5,217,492, 5,512,329, 5,563,056, 5,637,460, 5,714,360, 5,741,551, 5,744,515, 5,783,502, 5,858,653, and 5,942,555.
SUMMARY OF THE INVENTION
The present invention provides a method for performing solid phase synthesis, the method comprising the steps of:
a) providing a support material providing a surface adapted for use in solid phase synthesis,
b) providing a polymeric reagent formed by the

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