The synthesis of di- and oligo-nucleotides containing a phosphorodithioate internucleotide linkage with one of the sulfur atoms in a 5'-bridging position.

A new type of internucleotide phosphorodithioate linkage is described, wherein one of the sulfur atoms occupies a 5'-bridging position. Representative dinucleotides possessing such a bond were synthesized by S-alkylation of nucleoside-3'-O-phosphorodithioates with 5'-halogeno-5'-deoxy-nucleosides. A fully protected dithymidylate containing internucleotide 5'-S-phosphorodithioate linkage was converted into a 3'-O-phosphoramidite derivative and employed for introduction of a modified dinucleotide into a predetermined position of the oligonucleotide sequence. The 5'-S-phosphorodithioate linkage in dinucleotide analogues was found to be resistant toward nucleolytic degradation with snake venom PDE and nuclease P1. However, P-stereoselective degradation was observed for diastereomers of 5'-S-phosphorodithioate dithymidine analogs under treatment with calf spleen PDE. The new 5'-S-phosphorodithioate linkage was readily degraded by iodine solutions in the presence of water. It was also found that oligothymidylates containing a single 5'-S-phosphorodithioate linkage form much weaker duplexes with their complementary sequences.

[1]  D. Burgess,et al.  DNA-based therapeutics and DNA delivery systems: A comprehensive review , 2005, The AAPS Journal.

[2]  Lisa Jarvis,et al.  BACK IN THE GAME , 2006 .

[3]  H. Sigel,et al.  Acid-base properties of the nucleic-acid model 2'-deoxyguanylyl(5'-->3')-2'-deoxy-5'-guanylate, d(pGpG)3-, and of related guanine derivatives. , 2006, Organic & biomolecular chemistry.

[4]  Gerhardt Attard,et al.  Making sense of antisense. , 2005, European journal of cancer.

[5]  R. Fong,et al.  Nucleotide analogues to investigate RNA structure and function. , 2005, Current opinion in chemical biology.

[6]  Hongbin Yan,et al.  Further studies with adenosine 5'-dithiophosphoromorpholidate. a convenient preparation of nucleoside phosphorodithioates by a 'triester' approach , 2004 .

[7]  S. Martin,et al.  Design, synthesis, and evaluation of water-soluble phospholipid analogues as inhibitors of phospholipase C from Bacillus cereus. , 2003, The Journal of organic chemistry.

[8]  M. Caruthers,et al.  Solid-phase synthesis and biochemical studies of O-boranophosphopeptides and O-dithiophosphopeptides. , 2002, Journal of the American Chemical Society.

[9]  M. Wenska,et al.  A new method for the synthesis of nucleoside 2′,3′-O,O-cyclic phosphorodithioates via aryl cyclic phosphites as intermediates , 2001 .

[10]  J. Micklefield,et al.  Backbone modification of nucleic acids: synthesis, structure and therapeutic applications. , 2001, Current medicinal chemistry.

[11]  D. L. Cole,et al.  Highly efficient solid phase synthesis of oligonucleotide analogs containing phosphorodithioate linkages. , 2000, Nucleic acids research.

[12]  S. Agrawal,et al.  Importance of nucleotide sequence and chemical modifications of antisense oligonucleotides. , 1999, Biochimica et biophysica acta.

[13]  D. Gorenstein,et al.  Aptamers containing thymidine 3'-O-phosphorodithioates: synthesis and binding to nuclear factor-kappaB. , 1999, Bioorganic & medicinal chemistry letters.

[14]  M. Caruthers,et al.  Synthesis of phosphorodithioate DNA by the H-phosphonothioate method , 1999 .

[15]  J. Piccirilli,et al.  A new metal ion interaction in the Tetrahymena ribozyme reaction revealed by double sulfur substitution , 1999, Nature Structural Biology.

[16]  D. Shugar,et al.  Nucleoside H-Phosphonates. 18. Synthesis of Unprotected Nucleoside 5‘-H-Phosphonates and Nucleoside 5‘-H-Phosphonothioates and Their Conversion into the 5‘-Phosphorothioate and 5‘-Phosphorodithioate Monoesters , 1998 .

[17]  M. Michalska,et al.  Highly efficient synthesis of phosphorodithioates derived from 3′-thiothymidine by anhydro-ring opening of 2,3′-anhydro-5′-O-tritylthymidine with O,O-disubstituted phosphorodithioic acids , 1998 .

[18]  I. Tworowska,et al.  New efficient synthesis of phosphonofluorodithioates ROP(S)(S–)F and their structural analogues , 1998 .

[19]  F. Eckstein,et al.  Modified oligonucleotides: synthesis and strategy for users. , 1998, Annual review of biochemistry.

[20]  E. Kool,et al.  A Novel 5'-Iodonucleoside Allows Efficient Nonenzymatic Ligation of Single-stranded and Duplex DNAs. , 1997, Tetrahedron letters.

[21]  W. Stec,et al.  Efficient One-Pot Synthesis of 2'-Deoxyribonucleoside 3'-O- and 5'-O-Phosphorodithioates. , 1997, The Journal of organic chemistry.

[22]  J. Kehler,et al.  Solution Phase Synthesis of Dithymidine Phosphorodithioate Using New S-Protecting Groups in Combination with a Chemoselective Coupling Reagent (PyNOP) , 1997 .

[23]  M. Caruthers,et al.  5‘-Dithiophosphoryl Deoxyoligonucleotides: Synthesis and Biological Studies1 , 1996 .

[24]  K. Eckart,et al.  Synthesis and Properties of Diuridine Phosphate Analogues Containing Thio and Amino Modifications. , 1996, The Journal of organic chemistry.

[25]  Martin Bollmark,et al.  A facile access to nucleoside phosphorofluoridate, nucleoside phosphorofluoridothioate, and nucleoside phosphorofluoridodithioate monoesters , 1996 .

[26]  M. Caruthers,et al.  Biochemical and physicochemical properties of phosphorodithioate DNA. , 1996, Biochemistry.

[27]  M. Caruthers,et al.  Synthesis of Phosphorodithioate DNA via Sulfur-Linked, Base-Labile Protecting Groups(1). , 1996, The Journal of organic chemistry.

[28]  W. Stec,et al.  Dinucleoside (5′ → 3′)-O,S-Phosphorodithioates - New Class of Dinucleotide Analogues , 1996 .

[29]  N. Usman,et al.  Synthesis and biological activities of a phosphorodithioate analog of 2',5'-oligoadenylate. , 1995, Nucleic acids research.

[30]  W. Stec,et al.  Synthesis of Oligo(Deoxyribonucleoside Phosphorodithioate)s by the Dithiaphospholane Approach , 1995 .

[31]  M. Caruthers,et al.  2'-Deoxynucleoside Dithiophosphates: Synthesis and Biological Studies1 , 1995 .

[32]  J. Balzarini,et al.  The synthesis of nucleoside 5'-O-(1,1-dithiotriphosphates). , 1994, Journal of medicinal chemistry.

[33]  J. Kehler,et al.  Preparation of oligodeoxyribonucleoside phosphoro-dithioates by a triester method , 1994 .

[34]  R. Varma.  Synthesis of Oligonucleotide Analogues with Modified Backbones , 1994 .

[35]  M. Caruthers,et al.  Phosphorodithioate DNA as a potential therapeutic drug. , 1993, Science.

[36]  S. Martin,et al.  A general and efficient route to phosphorodithioate analogs of naturally occurring lipids , 1993 .

[37]  W. Stec,et al.  Stereoselective interaction with chiral phosphorothioates at the central DNA kink of the EcoRI endonuclease-GAATTC complex. , 1992, The Journal of biological chemistry.

[38]  W. Stec,et al.  The synthesis of di- and oligo(deoxyribonucleoside phosphorodithioates) by dithiaphospholane method , 1992 .

[39]  O. Dahl.  Preparation of Nucleoside Phosphorothioates, Phosphorodithioates and Related Compounds , 1991 .

[40]  O. Dahl,et al.  Solid phase synthesis of oligodeoxyribonucleoside phosphorodithioates from thiophosphoramidites. , 1991, Nucleic acids research.

[41]  M. Caruthers,et al.  Synthesis of deoxydinucleoside phosphorodithioates , 1991 .

[42]  Fritz Eckstein,et al.  Synthesis of nucleoside 5'-O-(1,3-dithiotriphosphates) and 5'-O-(1,1-dithiotriphosphates) , 1991 .

[43]  R. Cosstick,et al.  Synthesis and properties of dithymidine phosphate analogues containing 3'-thiothymidine. , 1990, Nucleic acids research.

[44]  J. H. Boom,et al.  A Convenient Approach Towards the Conversion of H-Phosphonate and H-Phosphonothioate Diesters into Phosphoro(di)thioate Derivatives , 1990 .

[45]  J. Nielsen,et al.  Deoxynucleoside phosphorodithioates. Preparation by a triester method , 1990 .

[46]  E. Ohtsuka,et al.  Synthesis and characterization of a substrate for T4 endonuclease V containing a phosphorodithioate linkage at the thymine dimer site. , 1990, Nucleic acids research.

[47]  O. Dahl,et al.  Deoxyribonucleoside Phosphorodithioates. Preparation of Dinucleoside Phosphorodithioates from Nucleoside Thiophosphoramidites. , 1990 .

[48]  R. Zain,et al.  Nucleoside H-phosphonates. X: Studies on nucleoside hydrogenphosphonothioate diester synthesis , 1989 .

[49]  G. Nagendrappa,et al.  A facile route to bicyclo[3.3.0]octanes through clean transannular cyclisation of 1-trimethylsilylcyclooctene under friedel-crafts condition , 1989 .

[50]  C. Reese,et al.  Nucleoside phosphonodithioates as intermediates in the preparation of dinucleoside phosphorodithioates and phosphorothioates , 1989 .

[51]  M. Caruthers,et al.  Oxidative and nonoxidative formation of internucleotide linkages , 1989 .

[52]  F. Eckstein,et al.  Inhibition of deoxyribonucleases by phosphorothioate groups in oligodeoxyribonucleotides. , 1988, Nucleic acids research.

[53]  M. Caruthers,et al.  Synthesis of dinucleoside phosphorodithioates via thioamidites , 1988 .

[54]  M. Caruthers,et al.  Synthesis and characterization of dinucleoside phosphorodithioates , 1988 .

[55]  D. Gorenstein,et al.  Preparation of a deoxynucleoside thiophosphoramidite intermediate in the synthesis of nucleoside phosphorodithioates , 1988 .

[56]  F. Eckstein,et al.  Stereochemistry of internucleotide bond formation by polynucleotide phosphorylase from Micrococcus luteus. , 1979, Biochemistry.

[57]  J. G. Moffatt,et al.  Halo sugar nucleosides. 3. Reactions for the chlorination and bromination of nucleoside hydroxyl groups. , 1972, The Journal of organic chemistry.

[58]  J. G. Moffatt,et al.  Halo sugar nucleosides. I. Iodination of the primary hydroxyl groups of nucleosides with methyltriphenoxyphosphonium iodide. , 1970, The Journal of organic chemistry.

[59]  A. Cook.  Nucleoside S-alkyl phosphorothioates. IV. Synthesis of nucleoside phosphorothioate monoesters , 1970 .

[60]  R. Pearson,et al.  Application of the Principle of Hard and Soft Acids and Bases to Organic Chemistry , 1967 .

[61]  J. Cassaday,et al.  The Reaction of O,O-Dialkyl Thiophosphoric Acid Salts with Some α-Haloacyl Derivatives , 1951 .