Catalysts for the self-polymerization of adenosine cyclic 2′,3′-phosphate

Summary When adenosine cyclic 2,3-phosphate is evaporated from solution in the presence of simple catalysts such as aliphatic diamines at alkaline pH, and maintained in a dry state at moderate temperatures (25-85°C), self-polymerization to give oligonucleotides of chainlength up to at least 6 is observed. The products contain an excess of [35]-linkages over [25]-linkages. The effects of different catalysts and reaction conditions on the efficiency of the reaction are described. The prebiological relevance of these reactions is discussed.     

New Approach to the Synthesis of 2′,3′-dideoxyadenosine and 2′,3′-Dideoxyinosine

Abstract

A new approach to the synthesis of 2′,3′-dideoxyadenosine and 2′,3′-dideoxyinosine based on deoxygenation of 2′,3′-di-O-mesylnucleosides was developed.     

Stannylation Approach to the Synthesis of 2′- and 3′-Substituted Analogues of 2′,3′-Didehydro-2′,3′-dideoxynucleosides

Abstract

Three methods are described for the introduction of a tributylstannyl group to the sp²-carbon of 2′,3′-didehydro-2′,3′-dideoxy nucleosides (d44Ns). The resulting stannylated products serve as versatile intermediates for the synthesis of d4Ns having various types of carbon-substituent.     

Diastereoselective Synthesis of 2′,3′-Dideoxy- β-C- Glucopyranosides as Intermediates for the Synthesis of 2′,3′-Dideoxy-β-D-Glucopyranosyl-C-Nucleosides

An extension of the Vorbrüggen method of nucleotide synthesis for the synthesis of C-glucopyranosides, as intermediates for C-nucleosides, is described. It could be shown that the diastereoselectivity of the reaction can be tuned by a simple change of protecting groups.     

Synthesis of 2′,3′-Didehydro-2′,3′-Dideoxy-3′-C-Methyl Substituted Nucleosides

Abstract

1-(2,3-Dideoxy-3-C-hydroxmethyl-β-D-threo-pentofuranosyl) -,1- (2,3-didehydro-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl) -and 1-(3-C-azidomethyl-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl)uracil, thymine and cytosine were synthesized and evaluated for anti-HIV activity. The synthetic strategy was based on an allylic alcohol transposition of the corresponding 3′-C-methylene-nucleoside analogues.     

The Use of Acetyl Bromide for the Multigram Synthesis of the Anti-HIV Agent 2′,3′-Didehydro-2′,3′-Dideoxycytidine (d4C)

Abstract

Treatment of uridine (1) with acetyl bromide produced bromoacetate 2 which was reduced with Zn/Cu to give the 2′,3′-unsaturated uridine (d4U; 3). Conversion of the uracil moiety of 3 to thioamide 7 with Lawesson's reagent, followed by amination and deprotection with methanolic ammonia, afforded d4C (9). This multigram scale process for the synthesis of d4C proceeded in 20% yield from uridine.     

Evidence for the presence of 3′, 5′-cyclic AMP in plant tissues

3′, 5′-cyclic AMP has been highly purified by chromatography from sterile higher plant tissues and assayed by bioluminescence as well as by activation of protein kinase. Both methods give comparable results: the amount of cyclic AMP was found to vary between 30 and 200 pmoles per mg of protein nitrogen.     

Phosphonates Derivatives of 2′,3′-Dideoxy-2′,3′-didehydro-pentopyranosyl Nucleosides

Abstract

Adenine and thymine derivatives of 2′,3′-dideoxy-2′,3′-didehydropento-pyranosyl nucleosides carrying a phosphonomethyl moiety at their 4′-O-position and in a cis relationship with the heterocyclic base have been synthesized.     

Synthesis of 6,1′,6′-tri-O-(mesitylenesulfonyl)sucrose,further examination of “tri-O-tosylsucrose”, and the chemistry of 3,6:1′,4′:3′,6′-trianhydrosucrose

Selective trimolar mesitylenesulfonylation of sucrose resulted in the formation of a highly crystalline trimesitylenesulfonate (1), which was isolated in greater than 50% yield without recourse to chromatography. As anticipated, the sulfonyl groups in 1 were located at the primary positions, as treatment with alkali afforded 3,6:1′,4′:3′,6′-trianhydrosucrose (4) in high yield. Fractionation of “tri-O-tosylsucrose” by high-pressure liquid chromatography effected separation of the minor isomer from the known, preponderant 6,1′,6′-isomer 3. ¹³C-N.m.r. spectroscopy indicated that the minor isomer was 2,6,6′-tri-O-p-tolylsulfonylsucrose (2). The trianhydride 4 was found to be dimorphous and was further characterized as the diacetate (5), the dibenzoate (6), the di-p-toluenesulfonate (7), and the dimethyl ether (8). Considerable differences in the reactivities toward acylation and etherification of the two axial hydroxyl groups in 4 permitted the preparation, in good yields, of the 4-acetate (9) and the 4-methyl ether (12). Several derivatives of methyl 3,6-anhydro-α-d-glucopyranoside (13) were prepared for comparison with corresponding derivatives of 4, and the hydroxyl groups in 13 also showed differences in reactivities analogous with those of 4.     

Structure of 2′,3′-0-Isopropylidene-6-cyanouridine

Abstract

The crystal and molecular structure of the title compound has been determined by the X-ray diffraction method. Crystals belong to the orthorhombic space group P2₁2₁2₁ and the cell dimensions are a=7.832(1), b=20.466(2) and c=9.159(1) Å. The structure was solved by direct methods and refined by the full matrix least-squares method to R=0.070. The conformation about the glycosidic bond is syn probably because of the steric hindrance between the sugar moiety and the cyano group at the C(6) position of the base. The sugar puckering is C(4′)-exo, and the orientation of C(5′)-0(5′) bond is gauche-trans.     

2,3-Dideoxy-3-Phthalimidopentoses in the Synthesis of 3′-Amino-2′,3′-Dideoxynucleosides

Abstract

3′-Amino-3′deoxythymidine is a very effective drug in vivo against L 1210 leukemia. It mives 1441 increase in lifespan with very little drug-induced toricitylil. Therefore, it was attractive to synthesize a large series of cuialogues, but unfortunately, such compounds are only achievable through a 1inear synthesis via the corresponding nucleoside which typically is transformed into the 3′-azido derivative and finally reduced.     

Evidence for the Stereoelectronic Control of the Acid Hydrolysis of Adenosine Cyclic 3′,5′-Phosphoramidate Diastereoisomers

Abstract

The substitution by a methyl group of the axial 5′hydrogen atom of adenosine cyclic 3′,5′-phosphoramidate diastereoisomers significantly increases the P-N bond breaking for the R^?p diastereoisomer, but does not change that for the S^?p diastereoisomer as anticipated on the basis of ground state stereoelectronic effects.     

The synthesis of 4′,6′-diacetamido-4′,6′-dideoxycellobiose hexa-acetate from lactose

Reaction of methyl 4′,6′-di-O-mesyl-β-lactoside pentabenzoate (8), synthesised via the 4′,6′-O-benzylidene derivative (6), with sodium azide in hexamethylphosphoric triamide gave three products. In addition to the required 4′,6′-diazidocellobioside (9), an elimination product, methyl 4-O-(6-azido-2,3-di-O-benzoyl-4,6-dideoxy-α-L-threo-hex-4-enopyranosyl)-2,3,6-tri-O-benzoyl-β-D-glucopyranoside (12), and an unexpected product of interglycosidic cleavage, methyl 2,3,6-tri-O-benzoyl-β-D-glucopyranoside (13), were formed. The origin of the latter product is discussed. The diazide 9 was converted into 4′,6′-diacetamido-4′,6′-dideoxycellobiose hexa-acetate (16) by sequential debenzoylation, catalytic reduction, acetylation, and acetolysis.     

In vivo binding of 2,3,6,2′,3′,6′-hexachlorobiphenyl and 2,4,5,2′,4′,5′-hexachlorobiphenyl to mouse liver macromolecules

The role of metabolic activation in the binding of polychlorinated biphenyls (PCBs) to cellular macromolecules was investigated in vivo by comparing the relative binding of 2,4,5,2′,4′,5′-[U-¹⁴C]hexachlorobiphenyl (2,4,5), a slowly metabolized PCB, with that of 2,3,6,2′,3′,6′-[U-¹⁴C]hexachlorobiphenyl (2,3,6), a rapidly metabolized PCB, and the appropriate controls. Each hexachlorobiphenyl was administered to mice, orally for 5 days (7.28 mg/kg/day). Following the dosing schedule, animals were killed at 1, 5 and 8 days. The concentration of each PCB was determined in liver, muscle and kidney and in purified macromolecules isolated from those tissues. The concentration of 2,4,5 was consistently higher than the concentration of 2,3,6 in all tissues studied. However, the amount of 2,3,6 bound to the purified macromolecules was consistently at least one order of magnitude greater than that of 2,4,5. The greatest binding was observed in RNA followed by protein and DNA, respectively. The purity of the macromolecules and the presence of PCB-derived radioactivity at the monomer level were confirmed. This is the first report of ¹⁴C-labeled PCB being bound to purified RNA, DNA, and proteins isolated from the tissues of animals treated in vivo. The binding is thought to be covalent and to be the result of metabolic activation.     

Synthesis of 2′,3′-Dideoxyribavirin

Abstract

A synthesis of 1-(2,3-dideoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′,3′-dideoxyribavirin, ddR) is described. Glycosylation of the sodium salt of 1,2,4-triazole-3-carbonitrile (5) with 1-chloro-2-deoxy-3,5-di-0-p-toluoyl-α-D-erythro-pentofuranose (1) gave exclusively the corresponding N-1 glycosyl derivative with β-anomeric configuration (6), which on ammonolysis provided a convenient synthesis of 2′-deoxyribavirin (7). Similar glycosylation of the sodium salt of methyl 1,2,4-triazole-3-carboxylate (2) with 1 gave a mixture of corresponding N-1 and N-2 glycosyl derivatives (3) and (4), respectively. Ammonolysis of 3 furnished yet another route to 7. A four-step deoxygenation procedure using imidazolylthiocarbonylation of the 3′-hydroxy group of 5′-0-toluoyl derivative (9a) gave ddR (11). The structure of 11 was proven by single crystal X-ray studies. In a preliminary in vitro study ddR was found to be inactive against HIV retrovirus.     

Geometry of the dry-state oligomerization of 2′,3′-cyclic phosphates

Summary Evaporation of a solution of thymidine plus either theexo or theendo diastereomer of uridine cyclic 2,3-O, O-phosphorothioate (U > p(S) in 1,2-diaminoethane hydrochloride buffer gave the 2,5 and 3,5 isomers of (P-thio) uridylylthymidine (Up(S)dT) in a ratio of 1:2 with a combined yield of about 20%. These isomers were re-converted to U > p(S) and dT by a reaction that is known to proceed by an in-line mechanism. Both the 2,5 and 3,5 isomers gave as product the same diastereomer of U > p(S) that had been used originally in their formation. These dry-state prebiotic reactions (Verlander, Lohrmann, and Orgel 1973) are thus shown to be stereospecific, and both the 2,5 and 3,5 internucleotide bonds are formed by an in-line mechanism.Abbreviations DAE 1,2-diaminoethane - HPLC high pressure liquid chromatography - RNase bovine pancreatic ribonuclease A, EC 3.1.4.22 - TEAB triethylammonium bicarbonate - tris tris(hydroxymethyl)aminomethane - UMP(S) uridine monophosphorothioate - U > p uridine cyclic 2,3-phosphate - U > p(S) uridine cyclic 2,3-O, O-phosphorothioate - Up(S)dT (P-thio)uridylylthymidine - U2p(R_p-S)5dT (P-thio)uridylylthymidine with theR configuration at phosphorous, and a 2,5 internucleotide linkage     

Synthesis of Novel L-Series 2′, 3′-Dideoxy-3′-Hydroxy-Methyl-Nucleosides and a Convenient Method for the Separation of Nucleosede Anomers

Abstract

Photoinduced addition of methanol to 5(R)-(tert-butyldimethylsilyloxymethyl)-2(5H)-furan-2-one (derived from L-gulono-1, 4-lactone) provided the photoadduct 5(R)-(tert-butyldimethylsiloxymethyl)-4(S)-hydroxymethyl-tetrahydrofuran-2-one, which was converted into two L-series-2′, 3′-dideoxy-3′-hydroxymethyl-nucleosides. In addition, we describe a new method for the chromatographic separation of cytidine anomers using a N-2-(4-nitrophenyl)ethyl carbamate derivative.