Synthesis of Cytidylyl(3′→5′)cytidylyl(3′→5′)-(2′)3′-O-[Lα-alanyl]adenosine

Abstract

A new synthesis of protected C-C-A-[L^α-Ala] 14 is reported using a new set of complementary groups such as 2-phenylsulfonylethoxycarbonyl (PSEC) for the protection of exocyclic amino functions, o-chlorophenyl (o-CIPh) for the internucleotide phosphotriester, 3-methoxy-1,5-dicarbomethoxypentan-3-yl (MDMP) and the 4-monomethoxytrityl (MMTr) for the protection of the ã-amino fuction of the amino acid. 14 could be deprotected in two steps by treatments with 1,1,3,3-tetramethylguanidinium oximate under a dry condition and then by neat trifluoroacetic acid. Treatment with neat trifluoroacetic acid produced a stable salt: [C-C-A-Ala-N^ãH₃+ CF₃CO₂-] and did not promote any internucleotide phosphate migration or degradation of the oligomeric molecule. This salt was considerably more stable than C-C-A-Ala conjugate with a free ã-amino group, and, therefore, it could be easily purified on a silica gel column and was isolated in 82 % yield. This strategy should be useful for the synthesis of longer oligonucleotide-aminoacyl conjugate.     

Synthesis of 5′-Substituted Analogues of Carbocyclic 3-Deazaadenosine as Potential Antivirals

Abstract

Various 5′-substituted analogues of carbocyclic 3-deazaadenosine (la), a potent antiviral agent, have been prepared and tested against nine viruses.     

Synthesis of Amide-Linked [(3′)CH2CO-NH(5′)] Nucleoside Analogues of Small Oligonucleotides

Abstract

We report syntheses of new amide-linked (di-penta)nucleoside analogues of antisense oligonucleotide components. Solution-phase coupling of 3′-(carboxymethyl)-3′-deoxy- and 5′-amino-5′-deoxynucleoside derivatives provides amide dimers. Activated [3′-(carboxymethyl)-3′-deoxy] units with a 5′-azido-5′-deoxy function provide “masked” 5′-amino-5′-deoxy residues for chain extension, and a 5′-O-DMT-protected unit provides the 5′-terminus for attachment to a phosphodiester linkage.     

Synthesis of P-Thioadenylyl (2′-5′) Adenosine and P-Thioadenylyl (2′-5′)-P-Thioadenylyl-(2′-5′)-Adenosine

Abstract

Dimer and trimer adenylates with 2′-5′ phosphorothioate linkages were synthesized via the phosphoramidite method using p-nitrophenyl-ethyl group for phosphate protection and followed by sulfur oxidation. The various diastereoisomers were separated and characterized.     

Synthesis and Properties of Oligoribonucleotide Analogues Having Amide (3″-CH2-CO-NH-5′) Internucleoside Linkages

Abstract

Amide linked ribonucleoside dimer 5 was prepared and converted into selectively protected H-phosphonate building block 9. Oligoribonucleotide duplexes having amide linkages at selected sites were synthesized and their stability was studied by UV melting experiments.     

Synthesis of 5, 6-Dichloro-Benzimidazole-(2′, 5′)-Nucleotide Trimer

Abstract

The chemical synthesis of the trimeric 5, 6-dichloro-1-β-D-ribofuranosylbenzimidazole-(2′, 5′)-diphosphate using the phosphotriester approach is described.     

Synthesis of 1′,2′-Seco-nucleoside Analogues of AZT

Abstract

1′,2′-Seco-AZT (3) and its 3′R,4′S diastereomer (19) were prepared and evaluated as antiviral agents. The chiral, acyclic side chains of these thymine acyclonuleosides were derived from D-isoascorbic acid. The two AZT analogues, 3 and 19, were screened against HIV, other RNA viruses, and two DNA viruses and they were found to be inactive.     

Synthesis of O-β-D-Ribofuranosyl-(1″-2′)-adenosine-5″-O-phosphate

Abstract

The first synthesis of O-β-D-ribofuranosyl-(1″-2′)-adenosine-5″-O-phosphate starting from protected 2′-O-β-D-ribofuranosyladenosine has been performed.     

Two-dimensional 1H NMR study of two cyclobutane type photodimers of thymidylyl-(3′→5′)-thymidine

2D NMR spectroscopy and J coupling constant analysis are applied to resolve the structure of two photoproducts of thymidylyl-(35)-thymidine. These products are cyclobutane type thymine dimers possessing the cis-syn (the predominant one) and trans-syn geometry. The cis-syn is formed in an ANTI-ANTI conformation about the N-glycosyl linkages and resembles the normal base-stacked configuration. The glycosidic conformation in solution of the 5 terminal fragment differs from the crystal in which the less common SYN conformation is observed. In this isomer only the sugar pucker of the 3 terminal fragment is changed substantially with respect to the dinucleotide. The trans-syn isomer is formed in a SYN-ANTI glycosidic conformation. In this isomer the sugar puckers of both deoxyribose rings are affected and a preference for a pure 2-endo conformation is observed.Abbreviations dTpdT 2-deoxythymidylyl-(35)-2-deoxythymidine - dTp[]dT cyclobutane type photodimers of dTpdT - dTp- and dTp[]- their 5' terminal fragments (fragment A) - -pdT and-[]pdT their 3 terminal fragments (fragment B) - RP-HPLC reversed-phase high-performance liquid chromatography - COSY two-dimensional correlated spectroscopy - 2D NOE two-dimensional nuclear Overhauser spectroscopy     

Synthesis of Deoxyribonucleotidyl (3′-5′) Arabinonucleosides

Abstract

Two different synthetic routes using phosphotriester methodology have been utilized to prepare deoxyribonucleotidyl (3′–5′) arabinonucleosides containing 9-β-D-arabinofuranosyladenine (ara-A, vidarabine) and 1-β-D-arabinofuranosylcytosine (ara-C, cytarabine) at the 3′-terminus in amounts and purity (greater than 95%) suitable for NMR analysis.     

Synthesis of (2′,5′)-Oligoadenylate Antisense Chimeras Targeting Steroid 5α-Reductase

Abstract

2–5A antisense chimeras have been synthesized which target human steroid 5α-reductase mRNA. To enhance the stability of the chimera towards degradative enzymes the terminal phosphodiester bond was isomerized from 3′,5′ to 3′,3′ and the 5′-phosphate group was thiolated.     

Studies on the Chemical Synthesis of Potential Antimetabolites. 31.1 A Novel Synthesis of 1-Deazaadenosine and Its Conversion to 5′-Deoxy-5′-Isobutylthio-1-Deazaadenosine (1-Deaza-Siba) and S-(1-Deazaadenosyl)-Homocysteine (1-DEAZA-SAH)

Abstract

A novel route for the preparation of 7-amino-3-(β-D-ribofuranosyl)-3H-imidazo [4,5-b] pyridine (1-deazaadenosine) has been developed. Synthesis of 5′-deoxy-5′-isobutylthio-1-deazaadenosine (1-deazaSIBA) and S-(1-deazaadenosyl)-homocysteine (1-deazaSAH) is also described.     

Chemical Synthesis of Cap Analogues: P1,P2-Dinucleoside-5′-diphosphates

Abstract

A procedure was developed for the chemical synthesis of P¹,P²-dinucleoside-5′-diphosphates (N₁(5′)pp(5′)N₂) on a nanomolar scale Reaction conditions for activating purine-5′-monophosphates (pA, pG, and pm⁷G) by 1,1′-carbonyldiimidazole were studied and optimized in respect to solvents and amount of activating reagent used. Various dinucleoside-5′-diphosphates were synthesized in 62-98% yield by incubating activated and non-activated purine-5′-monophosphates. Two unexpected by-products were formed by competition reactions: the imidazolidate of the non-activated nucleotide and the corresponding symmetrically substituted dinucleoside-5′-diphosphate. A mechanism is proposed to explain the observed side reactions.     

Synthesis of Isoxazolidino Analogues of 2′,3′-Dideoxynucleosides

Abstract

The complete set of the 4′-aza analogues of 2′,3′-dideoxynucleosides was synthesized by cycloaddition of N-tetrahydropiranyl or N-trityl methylene nitrones on suitably protected vinyl nucleobases. The convertible nucleoside approach was used in the preparation of cytosine and 5-methyl cytosine analogues.     

pppA_(2′)p_(5′)A_(2′)p_(5′)A 对甲胎蛋白抑制巨噬细胞功能的对抗作用

干扰素是一类由干扰素诱生剂诱导生物机体有关细胞产生的糖蛋白,具有广泛的生物学活性,能抗病毒、抗癌肿、及免疫调节等功能。pppA_(2′)p_(5′)A_(2′)p_(5′)A(简称2′-5′P_3A_3)是由干扰素作用于细胞以后诱导产生的一种寡聚腺苷酸,它能表现干扰素的许多生物学功     

Thermodynamic and NMR Study of Proton Complex Formation of 2′-Deoxyadenylyl-(3′→5′)-2′-Deoxyadenosine in Aqueous Solution

Abstract

A thermodynamic and proton NMR study has been carried out in order to characterize the behaviour of 2′-deoxyadenylyl-(3′→5′)-2′-deoxyadenosine towards the protonation. Conformational changes occurring following two protonation steps are discussed.     

2′-5′寡聚腺苷酸衍生物的研究——Ⅱ.pppA~(2′)p~(5′)A~(2′)p~(5′)A~(3′)p~(5′)Cp的合成及生物活性的观察

本文研究了以T_4RNA连接酶为工具,合成pppA2p~(5′)A~(2′)p~(5′)A~(3′)p~(5′)Cp(2′-5′P_3A_3-Cp)的条件,建立了分离产物的方法,连接得率可达83.1%,获得了紫外水平的量。初步研究了它的一些性质。2′-5′P_3A_3-Cp的分子结构与2′-5′P_3A_3不同,但在体外它也能抑制蛋白质的生物合成,有抗病毒等生物作用,它激活巨噬细胞的能力比2′-5′P_3A_3强。说明将pCp加到2′-5′P_3A_3的3′末端对其生物活性并无大的影响。     

Synthesis of Analogues of 3′-Deoxypsicothymidine

Abstract

Preparation of 3′-deoxypsicothymidines bearing a tether group at O1′ is described. Selective protection of the primary hydroxy functions of the starting nucleoside is briefly discussed.     

Synthesis of β-H-Phosphono-α-phosphonomethyl Analogues of Nucleoside 5"-Diphosphates

Novel -H-phosphono--phosphonomethyl analogues of nucleoside 5"-diphosphates were synthesized by phosphonylation of 5"-O-phosphonomethylthymidine and 9-[2-phosphonomethyloxy)ethyl]adenine with sodium pyrophoshite. The structures of the resulting individual compounds were confirmed by NMR and UV spectroscopy.     

Synthesis of 5-Substituted 2′-Deoxyuridine-5′- Phosphonate Analogues and Evaluation of their Antiviral Activity

A small series of 5-(hetero)aryl-modified nucleoside phosphonates was synthesized via an 8-step procedure including a Wittig reaction and Suzuki–Miyaura coupling. An unanticipated anomerization during phosphonate deprotection allowed us to isolate both anomers of the 5-substituted 2′-deoxy-uridine phosphonates and assess their antiviral activity against a broad panel of viruses.