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AssigneeHK Pharmaceuticals, Inc.
InventorsHUBERT KOSTER, ECKART LEIKAUF
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In general, the invention features the use of novel protection schemes and solid phase synthesis reactions to generate molecules of core structure M, which have a plurality of functionalities, each of which can be individually protected or functionalized. In a preferred process, M is a multifunctional low molecular weight compound, such as a saccharide, aminosugar, deoxysugar, nucleoside, nucleotide, coenzyme, amino acid, lipid, steroid, vitamin, hormone, alkaloid, or small molecule drug. In a particularly preferred process, M is an oligomeric compound (e.g. a polysaccharide, polynucleotide, peptide or protein).
A process for generating a combinatorial set of molecules of core structure M, comprising the steps of:
A process for generating a combinatorial set of oligomers, comprising the steps of:
A composition comprising an oligonucleotide, which is further comprised of monomers of the general formula 49a:
A combinatorial set of compounds with core structure M and having a plurality of reactive moieties, containing blocking groups, wherein at least three groups are independently removable under different conditions, thereby allowing selective derivatization after deblocking and wherein one flinctional group is utilized for immobilization.
Dependencies are inferred from the claim text.
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Heterocyclic radicals containing only nitrogen atoms as ring hetero atom: pyrimidine radicals
Nanotechnology for materials or surface science
Heterocyclic radicals containing only nitrogen atoms as ring hetero atom: purine radicals
Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate
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Traditionally, drug development has not been based on genetic information. More rational approaches are currently possible, however, based on accumulated knowledge regarding the molecular mechanisms of infectious particles (viruses, bacteria, yeast, fungi and protozoa) and the target sites for antibiotics on the molecular level. Two new approaches which have promise for a more rational drug design are combinatorial chemistry (Gordon, E. M., et. al., J. Med. Chem., 1994, 37, 1385-1401; Alper, J., Science, 1994, 264, 1399-1401) and antisense (Cohen, J. S., et al., Scientific American international edition, December 1994, pages 50-55).
In combinatorial chemistry, a large number of all variants of a specific family of compounds is synthesized and investigated for specific affinity to targeted modules i.e. receptor binding sites. The antisense approach utilizes suitably modified oligonucleotide sequences, which are designed to bind to essential regions for gene expression or virus or cellular replication resulting in complete suppression of the encoded functions.
H-phosphonate or phosphoamidite chemistries employing solid phase methods in automated DNA synthesizers are most efficient for the synthesis of oligonucleotides. The phosphoamidite method using β-cyanoethyl phosphoamidites as reactive nucleotide building blocks is the most prevalent synthesis method due to the quantitative condensation yields despite an oxidation step in every cycle (Sinha, N. D. et. al., Tetrahedron Lett., 1983, 24, 5843-46; Sinha, N. D. et. al., Nucleic Acids Res., 1984, 12, 4539-57; Froehler, B. C. et. al., Nucleic Acids Res., 1984, 14, 5399-5407; Froehler, B. C. and Matteuci, M. D., Tetrahedron Lett., 1986, 27, 469-72; Garegg, P. J. et. al., Tetrahedron Lett., 1986, 27, 4051-54; Sonveaux, E., Bioorg. Chem., 1986, 14, 274-325; Uhlmann, E. and Peyman, A., Chem. Rev., 1990, 90, 543-84).
The above and further features and advantages of the instant invention will become clearer from the following Detailed Description and Claims.
FIG. 1 is an HPLC chromatograrn of a mixture of the oligodeoxynucleotide d(TAGCT) obtained by 5′-3′ and 3′-5′ directed syntheses.
FIG. 2 is an HPLC chromatogram of a mixture of the oligodeoxynudeotide d(TTTT) obtained by 5′-3′ and 3′-5′ directed syntheses.
As used herein, the following terms and phrases shall have the following meanings:
“monomer”, or “building block” shall refer to a molecule with core structure M and plural reactive moieties that can be selctively protected or functionalized.
“oligomer”, “oligomeric compound” or “polymer” refers to more than one covalently linked monomer or building block.