Synthesis of biologically active compounds in cells

Details Synthesis of biologically active compounds in cells Synthesis of biologically active compounds in cells

2001-10-03

2004-12-14

Riley, Jezia (Department: 1637)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S001000, C435S006120, C435S007100, C435S007200, C530S300000, C530S350000, C536S023100

Reexamination Certificate

active

06831071

ABSTRACT:

OTHER REFERENCES
Walder, J. a., et al., (1979), Complementary carrier peptide synthesis: General strategy and implications for prebiotic origin of peptide synthesis. Proc.Natl.Acad.Sci USA, vol. 76, pp. 51-55.
Ebata K., et al. (1995), Nucleic acids hyridization accompanied with excimer formation from two pyrene-labeled probes.
Photochemistry and Photobiology, vol. 62(5), pp. 836-839.
Nielsen P. E., (1995), DNA analogues with non phosphodiester backbones. Annu.Rev.Biophys. Biomol.Struct. vol.24, pp. 167-83.
Tam J. P., et al., (1995), Peptide synthesis using unprotected peptides through orthogonal coupling methods.
Proc.Natl.Acad.Sci. USA, vol.92, pp.12485-12489.
Uhlmann G. A. et al., (1990) Antisense Oligonucleotides: A New Therapeutic principle, Chemical Rev., vol. 90, pp.543-584.
Moser H. E. and Dervan P. B., (1987), Sequence-specific cleavage of double helical DNA by triple helix formation. Science, vol. 238, pp.645-650.
Tulchinsky E. et al., (1992) “Transcriptional analsis of the mts 1 gene with the specific reference to 5′ flanking sequences. Proc.Natl.Acad.Sci USA, vol. 89, pp. 9146-9150.
BACKGROUND ART
The use of oligo(ribo)nucleotides and their analogues as anticancer and antiviruses theraupetic agents was first proposed several years ago. (Uhlmann, 1990) The great number of different modifications of the oligonucleotides and the methods of their use have since been developed.
Two basic interactions between oligonucleotides and nucleic acids are known (Moser and Dervan, 1987)
1. Watson-Crick base pairing (Duplex structure)
2. Hoogsten base pairing (Triplex structure)
Oligonucleotides can form duplex and/or triplex structures with DNA or RNA of cells and so regulate transcription or translation of genes.
It has been proposed that different substances which can cleave target nucleic acids or inhibit important cellular enzymes could be coupled to oligomers. The use of such conjugates as therapeutic agents has been described.(U.S. Pat. Nos., 5,177,198; 5,652,350).
Other methods are based on the coupling of different biologically active substances, such as toxins, to monoclonal antibodies which can then recognise receptors or other structures of cancer cells, or cells infected with viruses. Monoclonal antibodies can then specifically recognise cancer cells and in this way transport toxins to these cells. But these methods are inefficient due to the high level of nonspecific interactions between antibodies and other cells, which leads to delivary of the toxins or other biologically active compounds to the wrong cells.
In 1979 I. M. Klotz and co-authors proposed a method for complementary carrier peptide synthesis based on a template-directlyed scheme (J. A. Walder et al. 1979) The method proposed the synthesis of peptides on a solid support using unprotected amino acids, and the subsequent hybridization of oligonucleotides on the template. This method was established only for synthesis of peptides in vitro using solid supports of a different origin, and involved many synthesis steps to obtain peptides of the determined structure.
M. Masuko and co-authors proposed another method for in vitro detection of specific nucleic acids by excimer formation from two pyrene-labeled probes (Ebata, K. et al. 1995).
My invention allows the synthesis of different BACs of determined structure directly in living organisms only in cells which have specific RNA or DNA sequences. In this way, BACs will be delivered only to those cells where specific nucleic acids are produced.
DISCLOSURE OF INVENTION
Definitions
“Nulceomonomer”
The term “nucleomonomer” means a “Base” chemically bound to “S” moieties. Nucleomonomers can include nucleotides and nucleosides such as thymine, cytosine, adenine, guanine, diaminopurine, xanthine, hypoxanthine, inosine and uracil. Nucleomonomers can bind each other to form oligomers which can be specifically hybridised to nucleic acids in a sequence and direction specific manner.
The “S” moieties used herein include D-ribose and 2′-deoxy-D-ribose. Sugar moieties can be modified so that hydroxyl groups are replaced with a heteroatom, aliphatic group, halogen, ethers, amines, mercapto, thioethers and other groups. The pentose moiety can be replaced by a cyclopentane ring, a hexose, a 6-member morpholino ring; it can be aminoacids analogues coupled to base, bicyclic riboacetal analogues, morpholino carbamates, alkanes, ethers, amines, amides, thioethers, formacetals, ketones, carbamates, ureas, hydroxylamines, sulfamates, sulfamides, sulfones, glycinyl amides other analogues which can replace sugar moieties. Oligomers obtained from the mononucleomers can form stabile duplex and triplex structures with nucleic acids. (Nielsen P. E. 1995, U.S. Pat. No. 5,594,121).
“Base”
“Base” (designated as “Ba”) includes natural and modified. purines and pyrimidines such as thymine, cytosine, adenine, guanine, diaminopurine, xanthine, hypoxanthine, inosine, uracil, 2-aminopyridine, 4,4-ethanocytosine, 5-methylcytosine, 5-methyluracil, 2-aminopyridine and 8-oxo-N(6)-methyladenine and their analogues. These may include, but are not limited to adding substituents such as —OH, —SH, —SCH(3), —OCH(3), —F, —Cl, —Br, —NH(2), alkyl, groups and others. Also, heterocycles such as triazines are included.
“Nucleotide”
Nucleotide as used herein means a base chemically bound to a sugar or sugar analogues having a phosphate group or phosphate analog.
“Oligomer”
Oligomer means that at least two “nucleomonomers” (defined above) are chemically bound to each other. Oligomers can be oligodeoxyribonucleotides consisting of from 2 to 200 nucleotides, oligoribonucleotides consisting of from 2 to 200 nucleotides, or mixtures of oligodeoxyribonucleotides and oligoribonucleotides. The nucleomonomers can bind each other through phosphodiester groups, phosphorothioate, phosphorodithioate, alkylphosphonate, boranophosphates, acetals, phosphoroamidate, bicyclic riboacetal analogues morpholino carbamates, alkanes, ethers, amines, amides, thioethers, formacetals, ketones, carbamates, ureas, hydroxylamines, sulfamates, sulfamides, sulfones, glycinyl amides and other analogues which can replace phosphodiester moiety. Oligomers are composed of mononucleomers or nucleotides. Oligomers can form stable duplex structures via Watson-Crick base pairing with specific sequences of DNA, RNA, mRNA, rRNA and tRNA in vivo in the cells of living organisms or they can form stable triplex structures with double stranded DNA or dsRNA in vivo in the cells of living organisms.
“Alkyl”
“Alkyl” as used herein is a straight or branched saturated group having from 1 to 10 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
“Alkenyl”
“Alkenyl” as used herein is a straight- or branched-chain olefinically-unsaturated group having from two to 25 carbon atoms. The groups contain from one to three double bounds. Examples include vinyl (—CHdbdCH(2), 1-propenyl (—CHdbdCH—CH(3)), 2-methyl-1-propenyl (—CHdbdC(CH(3))—CH(3)) and the like
“Alkynyl”
“Alkynyl” as used herein is a straight or branched acetynically-unsaturated groups having from two to 25 carbon atoms. The groups contain from one to three triple bounds. Examples include 1-alkynyl groups include ethynyl (—CtbdCH), 1-propynyl (—CtbdC—CH(3)), 1-butynyl (—CtbdC—CH(2 —CH(3)), 3-methyl-butynyl (—CtbdC—CH(CH(3)) —CH(3)), 3,3-dimethyl-butynyl (—CtbdC—C(CH(3))(3)), 1-pentynyl (—CtbdC—CH(2, —CH(2 —CH(3)) and 1,3-pentadiynyl (—CtbdC—CtbdC—CH(3)) and the like.
“Aryl”
“Aryl” as used herein includes aromatic groups having from 4 to 10 carbon atoms. Examples include phenyl, naphtyl and like this.
“Heteroalkyl”
“Heteroalkyl” as used herein is an alkyl group in which 1 to 8 carbon atoms are replaced with N (nitrogen), S (sulfur) or O (oxygen) atoms. At any carbon atom there can be one to three substituents. The substituents are selected from: —OH, —SH, —SCH
3
, —OCH
3
, halogen, —NH
2
, —NO
2
, —S(O)—, —S(O)(O)—, —O—S(O)(O)—O—, —O—P(O)(O)—O—, —NHR. Here R is alkyl, alkenyl, aryl, heteroaryl, alkynyl, heterocyclic, carbocyclic and l

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