Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-11-20
2001-03-20
Lee, Howard C. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018500, C536S117000, C536S123000, C536S123100
Reexamination Certificate
active
06204376
ABSTRACT:
SPECIFICATION
1. Field of the Invention
The invention relates to oligosaccharides and libraries incorporating oligosaccharide. More particularly, the invention relates to oligosaccharides and libraries of oligosaccharides which employ amide and/or phosphodiester linkages for joining adjacent carbohydrate subunits.
2. Background
Carbohydrates are known to mediate many cellular recognition processes. Carbohydrates can serve directly as binding molecules and, in such instances, are essential to the recognition process. A review of the biological role of carbohydrates with respect to cellular recognition phenomena is provided by Sharon et al. (
Scientific American
, January 1993, 82). The emerging importance to glycobiology is further characterized by Mekelburger et al. (
Angew. Chem. Int. Ed. Engl.
1992, 31, 1571) and by Dagani et al. (
Chem. Eng. News
, Feb. 1, 1993, 28).
Dysfunctional mediation of cellular recognition processes can lead to disease states. If a cellular recognition process is mediated by an oligosaccharide, then an absence or excess of such oligosaccharide can lead to a dysfunctional mediation of such process. The mediating oligosaccharide may be deficient or absent due to a deficiency of production or due to a high rate of catabolism. If rate of catabolism is excessive, then catabolically resistant analogs of the bioactive oligosaccharide may be preferred as drug candidates as compared to the native bioactive oligosaccharide.
Accordingly, what is needed is a library which includes analogs of known bioactive oligosaccharides. Such a library may be usefully employed for screening drug candidates.
Central requirements for the design of libraries of oligosaccharide analogs include the following:
(a) A need to maximize the potential of the designed oligosaccharides as ligand and drug candidates;
(b) A need to capitalize on existing highly sophisticated technology directed to the synthesis of oligopeptides and oligonucleotides in order to facilitate the rapid and efficient design and construction of oligosaccharides; and
(c) A need for flexibility with respect to synthesizing either single target molecules or large libraries of target molecules simultaneously.
Methodologies for synthesizing biopolymers are well developed for peptides, nucleic acids, and saccharides. Segments of oligopeptides and of oligonucleotides can now be routinely synthesized both in solution and in the solid phase, manually and/or on automated systems. The synthesis of such structures is facilitated by the availability of efficient techniques and sophisticated instrumentation for synthesizing peptide and phosphate bonds with high yields. The synthesis of oligopeptides and oligonucleotides is also facilitated by the absence of stereocenters in these linkages. In contrast, technology for the construction of oligosaccharides is comparatively less sophisticated and efficient. Synthetic methods for constructing oligosaccharides give comparatively lower yields and are complicated by the two isomer possibilities (&agr; and &bgr;) in glycoside bond formation.
Techniques and chemical methods for simultaneously synthesizing multiple oligopeptides, e.g. 100-150 completely different peptides having lengths of up to 20 amino acid residues, are reviewed by Jung, G. et al. (
Angew. Chem, Int. Ed. Engl.
1992, 31, 367-383—incorporated therein by reference). Such techniques facilitate the construction of oligopeptide libraries.
Simon, et al. (
Proc, Natl. Acad. Sci. USA,
1992, 89, 9367-9371) disclose oligopeptide analogs in which amino acid side chain groups are attached not to conventional peptide backbone carbons but to peptide backbone nitrogens. Such analogs are termed peptoids. Simon also discloses the construction of peptoid libraries as a modular approach to drug discovery. Simon's oligopeptoids are shown by calculation to have greater conformational freedom as compared to conventional oligopeptides. Accordingly, oligopeptoids are thought to have greater potential as pharmaceutically useful binding ligands as compared to conventional oligopeptides having close sequence homology to such oligopeptoids.
Von Roedern et al. disclose a carbohydrate amino acid (
Angew. Chem, Int. Ed. Engl.
1994, 31, 687-689). Although von Roedern discloses that carbohydrate amino acids may be coupled to peptides, he does not disclose that they may also be polymerized so as to form oligosaccharides.
SUMMARY
A first aspect of the invention involves the molecular design and chemical synthesis of a class of carbohydrates designated as carbopeptoids (CPD's). Glycopeptoids are preferred carbopeptoids. Carbopeptoids and glycopeptoids are oligosaccharides which employ peptide-like amide bonds for linking the various carbohydrate subunits within an oligomer assembly. Amide bond formation may be achieved by employing oligopeptide synthesis technology and instrumentation. The method allows for the design and synthesis of specific compounds for biological and pharmacological investigations. The method also allows for the generation of libraries of compounds for biological and pharmacological screening. Conventional screening techniques employed with respect to peptide and peptoid libraries (Simon et al., supra) may also be employed with respect to carbopeptoid libraries. The design takes advantage of the multifunctionality of carbohydrate subunits to maximize the binding properties of the molecules. The ease and high efficiency by which the peptide-like linkages can be constructed make the synthesis of these molecules a practical proposition. Furthermore, non-carbohydrate units may be inserted into the sequence making this approach even more flexible and versatile for the generation of new libraries of organic compounds.
More particularly, the invention is directed to a oligomeric carbopeptoid or glycopeptoid compound having carbohydrate amino acid subunits (CA's) or glycoside amino acid subunits (GA's) coupled to one another via an amide linkage. The amide linkage may be represented by the formula CA
1
—(CO—NH)—CA
2
. The amide linkage (CO—NH) includes a carbonyl carbon and an amido nitrogen. A first carbohydrate amino acid subunit CA
1
or glycoside amino acid subunit GA
1
has an anomeric carbon bonded to the carbonyl carbon of the amide linkage. The anomeric carbon of the first carbohydrate amino acid subunit CA
1
forms a C-glycosidic bond with the carbonyl carbon of the amide linkage and maintains the carbohydrate in a closed ring configuration. A second carbohydrate amino acid subunit CA
2
has a non-anomeric carbon bonded to the amido nitrogen of the amide linkage. The second carbohydrate amino acid subunit CA
2
, like the first amino acid subunit CA
1
, may include an anomeric carbon bonded to the carbonyl carbon of a second amide linkage linking the second carbohydrate amino acid subunit CA
2
to a third carbohydrate amino acid subunit CA
3
, etc. In this instance, the anomeric carbon of the second carbohydrate amino acid subunit CA
2
forms a C-glycosidic bond with the carbonyl carbon of the amide linkage and maintains the carbohydrate in a closed ring configuration. On the other hand, if the second carbohydrate amino acid subunit CA
2
is a terminal subunit, then its anomeric carbon may form a hemiacetal, a hemiketal, or a glycoside.
The invention is also directed to a process for synthesizing the above oligomeric carbopeptoid or glycopeptoid compound. The synthetic process involves the coupling of two or more carbohydrate amino acid subunits (CA's) or glycoside amino acid subunits (GA's) to one another by means of amide linkages.
The invention is also directed to libraries of oligomeric carbopeptoid or glycopeptoid compounds. Such libraries are employable for drug screening. Each oligomeric carbopeptoid or glydopeptoid compound includes at least two carbohydrate amino acid subunits (CA's) or glycoside amino acid subunits (GA's) coupled to one another via an amide linkage as indicated above. The invention is also directed to an improved process for synthesizing the above library of ol
Lee Howard C.
Lewis Donald G.
The Scripps Research Institute
LandOfFree
Carbopeptoids and carbonucleotoids does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Carbopeptoids and carbonucleotoids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Carbopeptoids and carbonucleotoids will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2436712