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The 35S-labeled, dinucleoside phosphorothioate 1, an orally available agent against hepatitis B virus, was prepared in eight steps with high specific activity and radiochemical purity. Radiolabeled 3H-benzodithiole-3-one-1,1-dioxide was synthesized in four steps from 35S8 and was used as the sulfurizing reagent. Copyright © 2012 John Wiley & Sons, Ltd.

Open-chain bis-Reissert compounds 1 were converted to the corresponding bis-oxazolium intermediates via acid-catalyzed intramolecular cyclization. These oxazolium compounds exist in a variety of tautomeric structures in which the meso-ionic form can be intercepted by reaction with dipolarophiles in a 1,3-dipolar-cycloaddition reaction to produce a variety of highly functionalized bis-pyrrole esters 2. In turn, the bis-pyrrole esters could be converted to the corresponding bis-pyrrole tetrols 3 in high yields. J. Heterocyclic Chem., 2011.

The acyloxyalkyl derivatives of a model anti-HBV dinucleotide were synthesized and evaluated as orally bioavailable prodrugs. Our studies have led to the identification of the first orally bioavailable dinucleotide prodrugs for further therapeutic development against the hepatitis B virus (HBV).

Several pronucleotide analogs of the model anti-HBV dinucleotide 3 ′ - dA - U 2 ′ OMe have been synthesized and evaluated for stability, bioreversibility and cytotoxicity. These studies have helped identify potential candidates for further evaluation.

Rapid and efficient functionalization of solid-support by microwave-assisted procedures has been achieved. The functionalized solid-support can be readily loaded with nucleosides for use in oligonucleotide synthesis. This method can also be extended to rapid functionalization of other solid matrices for application in microarrays and combinatorial chemistry.

The preparation of a controlled-pore-glass (CPG) support carrying a novel linker is described. This support was compatible with the established phosphoramidite method of solid-phase oligonucleotide synthesis. The use of this linker for the synthesis of a library of 3′-thiophosphorylated dinucleotides is described.

The nucleoside bicylic oxazaphospholidine derived from L-, or D-prolinol is a novel synthon with potential for solid-phase stereoselective synthesis of oligonucleoside phosphorothioates.

The use of NH3 gas under pressure offers an efficient alternative to hot aqueous ammonium hydroxide for the deprotection, and cleavage steps during the large-scale synthesis of oligonucleotides, and their analogs prepared using N-pent-4-enoyl (PNT) nucleoside phosphoramidites and H-phosphonates.

Rapid synthesis of phosphoric diester and phosphorothioate oligonucleotides in 1 micromol to 1 millimol scale has been achieved using PNT nucleoside phosphoramidites. Furthermore, facile synthesis of mixed backbone oligonucleotides (MBOs) as antisense agents can be carried out using PNT nucleoside phosphoramidites in conjunction with PNT nucleoside H -phosphonates and PNT nucleoside phosphonamidites. The versatility of the PNT group is further demonstrated by its use in the preparation of bioreversible oligonucleotide conjugates.

Oligonucleotide analogs which are site-specifically derivatized with O-acyloxyaryl groups were prepared using phosphoramidite chemistry. Upon their incubation with pig liver esterase (PLE) or chymortrypsin, the analogs were shown to revert to the parent compound.

The synthesis of mixed-backbone-oligonucleotides (MBOs) (15 to 25-mers) which contain phosphoric diester (PO) or phosphorothioate (PS) backbones along with segments of internucleotidic O-methylphosphate (POOMe) or O-methylphosphorothioate (PSOMe) linkages have been accomplished using N-pent-4-enoyl (PNT) nucleoside phosphoramidite synthons. The Tms of the MBOs reveal that they form stable duplexes with complementary DNA and RNA. The MBOs also showed increased resistance to degradation by nucleases. Consequently, the MBOs with methylphosphotriester segments represent a novel class of antisense oligonucleotides with potential for therapeutic and diagnostic applications.

Improved design, synthesis, and evaluation of an oligonucleotide prodrug is described.

As part of a therapeutic strategy involving multiple targeting, we have synthesized oligonucleotides which are linked via 3′-3′ phosphoric diester linkages. These 3′-3′ analogs showed increased resistance against nuclease-mediated degradation compared to the 5′-3′-linked oligonucleotides.

Dowex® resin (H+ form) is a convenient reagent for detritylation of 5′-O-DMT-oligonucleotides. With Dowex, detritylation is rapid and quantitative compared to that with acetic acid. As the liberated dimethoxytrityl species remain bonded to the resin, further processing of oligonucleotides is simplified.

Synthesis of iodoalkylacylates 3a-f and use of 3 c in the preparation of an oligonucleoside phosphorothiate prodrug analog 5 is described.

Tritium was incorporated into oligonucleotides at a predetermined site in high specific activity through a combination of redox chemistry on solid support.

The stereoselective synthesis of the nucleoside phosphoramidite 6 by reaction of the chiral oxazaphospholidine 4 with 5′-DMT-T is reported. The novel phosphoramidite synthon, 6 , is stereoselectively converted to 8 by oxidative sulfurization with 1 . The oxazaphospholidines, 6 and 8 , are a new class of potential nucleoside synthons for the synthesis of oligonucleotides.

In model studies toward development of prodrugs of oligonucleoside phosphorothioates, R p and S p , S -alkyl phosphorothiolates 3a-d were prepared by chemoselective S-alkylation of R p acid S p dinucleoside phosphorothioate 2 with iodoalkyl acylates 9a-d. When incubated with human serum or porcine liver esterase (PLE), stereospecific conversion of 3a-d to R p and S p 2 was observed. Stereodifferentiation was also noted in the hydrolysis- S p faster than R p 3a-c, with serum, and R p faster than S p 3a-c, with PLE. In the case of hindered analogs 3c, desulfurized product 4 was also formed along with 2. Mechanisms to account for this product profile obtained during the hydrolysis are proposed. Similarly, bioreversion of acyloxyalkyl oligonucleoside phosphorothioates 15, 16, and 17 to 18, 19, and 20, respectively, was demonstrated by 31 P NMR and PAGE.

The synthesis of [ 35 S]3H-1,2-benzodithiole-3-one-1,1-dioxide ( 1 ) and its use in the preparation of site-specifically 35 S-labeled oligonucleotides is illustrated.

The use of diethoxy N, N-diisopropyl phosphoramidite (DDP) as a capping reagent for the synthesis of oligonucleotides, in conjunction with phosphoramidite chemistry, results in overall improvement in quality and yield.

In model studies towards prodrugs of oligonucleoside phosphorothiolates eg., 1, the dinucleoside S-alkyl phosphorothiolates 3a-c were prepared by chemoselective alkylation of d[TpsT] with the iodoalkyl acylates 8a-c. Upon incubation with serum or porcine liver esterase, stereospecific conversion of Rp and Sp 3c to 2 was observed along with the desulfurized product 4.

Open-chain bis-Reissert compounds (I) are converted in a one-pot reaction to the corresponding bis-pyrrole esters (III).

With the emergence of high throughput screening of bioactive molecules, there is constant need for the development of new strategies for diversity-oriented synthesis. We describe here a novel one-pot multicomponent reaction for the synthesis of uracil derivatives using easily available starting materials. This new synthetic strategy provides easy access to diverse uracil derivatives in moderate to good yields.

Several polysulfides were tested as potential sulfur-transfer reagents during the automated synthesis of oligodeoxyribonucleoside phosphorothioates via the «deoxyribonucleoside phosphoramidite» approach. The thiosulfonate 3H-1,2-benzodithiol-3-one 1,1-dioxide (12) was particularly efficient as a sulfurizing reagent

Combinatorial chemistry is playing an increasingly prominent role in the process of drug discovery. A nucleic acid-based (NAB TM ) scaffold can be engineered to create functional group and topological diversity in a library. Described herein is the parallel solid-phase synthesis of combinatorial libraries of nucleoside phosphoramidates, and the first evaluation of antiviral activity against hepatitis B virus (HBV).

The present invention provides for compositions and methods to generate a library of small molecules that mimic the repertoire of interactions that exist amongst nucleic acids, and proteins, as well as, that which exist between proteins and nucleic acids. The designed library of nucleoside analogs are for use as competitive and non-competitive viral replication inhibitors or serve as pro-drugs of inhibitors in anti-viral drug discovery. A facile parallel solution-phase chemistry has been developed to carry out the combinatorial synthesis of nucleoside analogs as a source of pharmacore-based chemical diversity.

Solution-phase parallel synthesis of nucleotide library 1 consisting of 150 members is reported.

Oligonucleotides carrying a variety of chemical modifications including conjugates are finding increasing applications in therapeutics, diagnostics, functional genomics, proteomics, and as research tools in chemical and molecular biology. The successful synthesis of oligonucleotides primarily depends on the use of appropriately protected nucleoside building blocks including the exocyclic amino groups of the nucleobases, the hydroxyl groups at the 2′-, 3′-, and 5′-positions of the sugar moieties, and the internucleotide phospho-linkage. This unit is a thoroughly revised update of the previously published version and describes the recent development of various protecting groups that facilitate reliable oligonucleotide synthesis. In addition, various protecting groups for the imide/lactam function of thymine/uracil and guanine, respectively, are described to prevent irreversible nucleobase modifications that may occur in the presence of reagents used in oligonucleotide synthesis. © 2017 by John Wiley & Sons, Inc. Keywords: carbamates; cyanoethylation; depurination; nucleobases; N-acylation; photolytic cleavage; silyl protection

The use of 2′-OMe-ribonucleoside bicyclic oxazaphospholidines derived from (R)- or (S)-2-pyrrolidinemethanol has enabled the stereoselective synthesis of (Rp)-, and (Sp)-2′-O-methyloligoribonucleoside phosphorothioates. Interestingly, higher stereoselectivity (96–98%) was observed in the synthesis of (Sp)-2′-O-methyl-oligoribonucleoside phosphorothioates compared to that in the case of (Sp)-oligodeoxyribonucleoside phosphorothioates (90%).

Conjugates of oligodeoxyribonucleotide phosphorothioate (ODN-PS) with folic acid, retinoic acid, arachidonic acid, and methoxypoly(ethylene glycol)propionic acid have been synthesized. The procedure involved the initial solid-phase preparation of 5'-amino-functionalized ODN-PS using N-pent-4-enoyl-derived (PNT) nucleoside phosphoramidites followed by conjugation of the oligonucleotide either to the ligand acids, using 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide as a coupling reagent, or to their corresponding succinimidyl derivatives. Subsequent exposure of the support to aqueous ammonium hydroxide (28%, 2 h, 55 degrees C) resulted in the release of the fully deprotected ODN conjugates, which were purified by reversed-phase HPLC or by preparative polyacrylamide gel electrophoresis. The identity of the oligonucleotide conjugates was confirmed by MALDI-TOF mass spectral analysis.

We have designed and synthesized hybrid oligonucleotides 2–5 , as analogues of oligodeoxynucleoside phosphorothioates, in an effort to have agents with improved ‘antisense activity’ with reduced phosphorothioate content. The hybrid oligonucleotides contain segments of 2′- O -methyl ribonucleoside phosphoric diesters and oligodeoxynucleoside phosphorothioates. Thus, compared with the ‘all’ phosphorothioate analogues 1 and 6 , the analogues 2–5 showed significantly reduced effect on complement activation. In addition, thermal denaturation studies with complementary RNA revealed that the analogues 2–5 had higher T m compared with that with oligodeoxynucleoside phosphorothioates. Additionally, the RNA component of the oligo/RNA duplex is efficiently cleaved by RNase H, the site of endonucleolytic cleavage being dictated by the length of the oligodeoxynucleoside phosphorothioate segment.

N -pent-4-enoyl nucleoside H -phosphonates are versatile building blocks for the synthesis of oligonucleotide phosphoramidates.

N-pent-4-enoyl nucleoside H-phosphonates are versatile building blocks for the synthesis of support-bound and free oligonucleotide analogs.

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Bis(trimethylsilyl) acylphosphonates via their silver salts couple with iodoalkyl esters to provide an efficient synthesis of the corresponding acyloxyalkyl esters as potential prodrugs of the antiviral agent, trisodium phosphonoformate. These compounds were tested as inhibitors of HIV-1 in chronically infected H9 cells.

A partir de propanal, d'ethylenediamine, de KCN et de chlorure de benzoyle, via le N,N'-dibenzoyl ethylenediimino-2,2' bis-butyronitrile, synthese du diperchlorate de diamino-5,5' diethyl-4,4' diphenyl-2,2' ethylene-3,3' bis-oxazolium; reactions de ce compose avec l'acrylate de methyle ou le butynedioate de dimethyle: obtention respectivement de phenyl-5 propionyl-2 pyrrolecarboxylate-3 de methyle et de diethyl-2,2' diphenyl-5,5' ethylene-1,1' bis-pyrroledicarboxylate-3,4 de tetramethyle