Manganese Tetraphenylporphyrins Catalyzed Selective Oxidation of Purine Derivatives

Abstract

The oxidation of purine derivatives using porphyrins as catalysts and dimethyldioxirane (DMDO) as oxygen atom donor is reported. The regioselectivity of the oxidation was found to be dependent on the presence of a free OH moiety on the N(9)-side chain of the substrate and on the structure of the catalyst.     

Introduction of Fluorine Into the C8 Position of Purine Nucleosides

Abstract

We have synthesized 2-amino-6,8-difluoro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (3) from 2-amino-6,8-dichloro-9-(2,3,5-tri-O-acetyl-ß-D-ribofuranosyl)purine (1) in a two-step procedure. The reaction of 3 with anhydrous ammonia in dry 1,2-dimethoxyethane gave 2,8-diamino-6-fluoro-9-(2,3,5-tri-O-acetyl-ß-D-ribofuranosyl)purine (4) in 64.1% yield. Compound 4 was deaminated with t-butylnitrite in tetrahydrofuran to give 2-amino-6-fluoro-9-(2,3,5-tri-O-acetyl-ß-D-ribofuranosyl)purine (6). The ¹H, ¹⁹F, and ¹³C NMR spectral data were determined and evaluated for each of the compounds.     

Synthetic Approaches to Rare 2-Substituted Purine Nucleosides

Abstract

The syntheses of several novel functional1zed 2-subst1tuted purine nucleosides are described. Key reactions In these transformations Include photolnduced reductive dehalogenatlon, radical deamlnatlon-halogenatlon, and functional1zed carbon-carbon bond formation Involving palladium catalysis. An Interesting ring opening reaction of 2-iodopur1ne nucleoside to an Imidazole derivative under S_RN conditions is mentioned. High-f1eld ¹³C NMR data suggest that the 2-subst1tuted purine nucleosides prefer the anti conformation 1n solution. Biological evaluation of these compounds is currently being carried out.     

Synthesis of Some 2-Alkylated-5-Aminoimidazoles Related to Intermediates in Purine Nucleotide de novo and Thiamine Biosynthesis

Abstract

Routes to 2-alkylated-5-aminoimidazole nucleosides have been investigated in which the 2-substituent has up to 3 carbon atoms and capable of being interconverted into suitable oxy and 0x0 alkyl derivatives for use in enzyme inhibition and biochemical incorporation studies involving both purine nucleotide de novo and thiamine biosynthesis.     

Oligonucleotides With Purine Nitrogen-7 as Glycosylation Site

Abstract

The synthesis of phosphoramidites (2 and 3) derived from hypoxanthine and isoguanine N⁷-2¹-deoxyribonucleosides is described. Solid-phase synthesis furnishes oligonucleotides containing N⁷-glycosylated purines. New base pairs between purine N⁷- and N9-nucleosides are proposed.     

Transglycosylation Reactions of Purine Nucleosides. A Review

Abstract

Mechanism, regio- and stereoselectivity, reversibility as well as some practical applications of transglycosylation reactions in the chemistry of purine nucleosides are reviewed. There are two main reaction pathways of glycosylation and transglycosylation in the purine series; i) the better known and generally accepted 3→9 sequence of adenine and its derivatives ii) the equally conceivable 7?9 mechanism for guanine and other 6-oxopurines, which is hereby supported by the author's study.

     

Carboxyamidation of Purine Nucleosides: New Secondary 8-Carboxamidopurine Nucleosides

Abstract

Palladium catalyzed carboxyamidation at the 8-position of 8-bromoadenosine and 8-bromoguanosine nucleosides is a versatile reaction, which allows primary, secondary, heterocyclic, aromatic mine and amino acids to be incorporated into purine nucleosides.     

Nucleoside Analogues of Purine with a 1,2-Disubstituted Cyclopentene Ring

Abstract

One, two-disubstituted carbonucleoside analogues of purine with unsaturated carbocyclic were synthesized by construction of the heterocyclic base about the primary amino group of the amino alcohol 4 intermediate, which was also synthesized in good yield starting from cyclopentadiene.     

8-Substituted Purine Ribosides: Synthesis and Biological Activity

Abstract

The syntheses of a series of 8-substituted purine ribofuranosides are described. Reductive deaminalion of 8-bromoadenosine triacetate (1) provides the key intermediate (2) for subsequent displacement reactions. Four compounds show significant activity in two cell culture Screens.     

Novel Acyclic Analogues of Purine Nucleosides: 2,3-Dihydroxy-1-Methoxypropyl and 3-Hydroxy-1-Methoxypropyl Derivatives

Abstract

Novel purine nucleoside analogues in which the N-9 ribosyl moiety is replaced by a 2,3-dihydroxy-1-methoxypropyl or 3-hydroxy-1-methoxypropyl substituent and their N-7 substituted isomers have been synthesized and tested for antiviral activity.     

Anti-Inflammatory Activity of Purine Nucleoside Analogs

Abstract

It is well known that adenosine plays an important role in inflammatory processes. A collection of adenosine analogs modified in the base and/or sugar functional moiety have been synthesized and submitted for biological testing. Each purine nucleoside analog was tested for inhibition of endothelial cell activation by various inflammatory stimuli. A number of analogs exhibited potent anti-inflammatory activity. Animal studies have been carried out on AMG002370 which was found to potently inhibit adjuvant induced arthritis in the Lewis rat.     

Inhibition of Purine Nucleoside Phosphorylase by Phosphonoalkylpurines 1

Abstract

Optimum inhibition of human erythrocyte purine nucleoside phosphorylase by 9-(phosphonoalkyl)hypoxanthines required an alkyl chain of five carbons or longer. Appropriate modifications of either the base or phosphonate side chain resulted in increased inhibitory activity.     

Identification of Purine Binding Sites on Torpedo Acetylcholine Receptor

Abstract

Electrophysiological studies from this and other laboratories have suggested a direct action of ATP on nicotinic acetylcholine receptors (nAChR). To determine the site of binding of this purine derivative, we have covalently modified the nAChR from Torpedo marmorata electrocytes employing 2-[³H]-8-azido-ATP as a photoactivable affinity label. Covalently attached radioactivity was predominantly found in the β-polypeptide of the receptor. Based on the results of protection studies with several nAChR ligands whose target sites at the receptor are known, we conclude that the purine site(s) differ from those of acetylcholine and of physostigmine, galanthamine and related ligands, and those of local anesthetics.     

Crystal Structure of Calf Spleen Purine Nucleoside Phosphorylase in a Complex with Multisubstrate Analogue Inhibitor with 2,6-Diaminopurine Aglycone

Abstract

The crystal structure at 2.05 Å resolution of calf spleen PNP complexed with stoichiometric concentration of acyclic nucleoside phosphonate inhibitor, 2,6-diamino-(S)-9-[2-(phosphonomethoxy)propyl]purine, in a new space group P2₁2₁2₁ which contains two full trimers in the asymmetric crystal unit is described.     

Interactions of Calf Spleen Purine Nucleoside Phosphorylase with Antiviral Acyclic Nucleoside Phosphonate Inhibitors: Kinetics and Emission Studies

Abstract

Association between calf spleen purine nucleoside phosphorylase and a series of phosphonylalkoxyalkyl derivatives of purine bases was studied by inhibition kinetics and fluorimetric titrations. Dissociation constants, determined by fluorimetric titration in phosphate-free conditions, were lower than inhibition constants in 1 mM phosphate, and inhibition was still weaker in 50 mM phosphate, in accord with the postulated bisubstrate analogue character of this class of inhibitors.     

A First Microwave-Assisted Synthesis of a New Class of Purine and Guanine Thioglycoside Analogs

A first microwave-assisted synthesis of a new class of novel purine thioglycoside analogs from readily available starting materials has been described. The key step of this protocol is the formation of sodium pyrazolo[1,5-a]pyrimidine-7-thiolate and 7-mercaptopyrazolo[1,5-a]pyrimidine derivatives via condensation of 5-amino-1H-pyrazoles with sodium 2,2-dicyanoethene-1,1-bis(thiolate) salts or 2-(dimercaptomethylene)malononitrile, respectively, under microwave irradiation, followed by coupling with halo sugars to give the corresponding purine thioglycoside analogs. The obtained purines and purines thioglycosides derivatives were evaluated in vitro against lung (A549), colon (HCT116), liver (HEPG2), and prostate (PC3) cancer cell lines. Some of these compounds (5b, 5d, 5f, and 9a–d) exhibited little potency toward the four cell lines. On the other hand, compound 5a elicited higher cytotoxicity on both prostate (PC3) and colon (HCT116), respectively, while it was found moderate on lung (A549), and inactive on liver (HEPG2). Moreover, compound 5c was found moderate with LC₅₀ values 52.0–88.9 μM for almost all the cell lines.     

Substrate/Inhibitor Properties of Tumour Purine Nucleoside Phosphorylase

Abstract

Substrate/inhibitor properties of purine nucleoside phosphorylase (PNP), isolated from human lung and kidney tumour tissues, have been characterised and compared with those of the enzyme from the corresponding normal organs.     

Purine Salvage in Two Halophilic Archaea: Characterization of Salvage Pathways and Isolation of Mutants Resistant to Purine Analogs

In exponentially growing cultures of the extreme halophile Halobacterium halobium and the moderate halophile Haloferax volcanii, growth characteristics including intracellular protein levels, RNA content, and nucleotide pool sizes were analyzed. This is the first report on pool sizes of nucleoside triphosphates, NAD, and PRPP (5-phosphoribosyl-α-1-pyrophosphate) in archaea. The presence of a number of salvage and interconversion enzymes was determined by enzymatic assays. The levels varied significantly between the two organisms. The most significant difference was the absence of GMP reductase activity in H. halobium. The metabolism of exogenous purines was investigated in growing cultures. Both purine bases and nucleosides were readily taken up and were incorporated into nucleic acids. Growth of both organisms was affected by a number of inhibitors of nucleotide synthesis. H. volcanii was more sensitive than H. halobium, and purine base analogs were more toxic than nucleoside analogs. Growth of H. volcanii was inhibited by trimethoprim and sulfathiazole, while these compounds had no effect on the growth of H. halobium. Spontaneous mutants resistant to purine analogs were isolated. The most frequent cause of resistance was a defect in purine phosphoribosyltransferase activity coupled with reduced purine uptake. A single phosphoribosyltransferase seemed to convert guanine as well as hypoxanthine to nucleoside monophosphates, and another phosphoribosyltransferase had specificity towards adenine. The differences in the metabolism of purine bases and nucleosides and the sensitivity to purine analogs between the two halobacteria were reflected in differences in purine enzyme levels. Based on our results, we conclude that purine salvage and interconversion pathways differ just as much between the two archaeal species as among archaea, bacteria, and eukarya.     

木荷属和柃木属植物的嘌呤代谢及嘌呤碱合成研究

以［8-¹⁴C］标记的腺嘌呤和黄嘌呤为底物,对两种可以合成少量咖啡碱和茶叶碱的木荷属和柃木属植物（Schima mertensiana,Eurya japonica）叶片的嘌呤代谢进行了检测研究。发现木荷属和柃木属植物中嘌呤代谢相似,¹⁴C标记的腺嘌呤可以整合到嘌呤核苷酸、RNA、酰脲（包括尿囊素和尿囊酸）、二氧化碳中。经过24 h培养,在叶片吸收的放射能中,仅有6%～7%用于甲基黄嘌呤类化合物的合成（3-甲基黄嘌呤、7-甲基黄嘌呤核苷、7-甲基黄嘌呤、茶叶碱）。和其他植物一样,绝大多数¹⁴C标记的黄嘌呤整合到嘌呤的分解代谢物中（二氧化碳和酰脲）,少量的放射能分布在3-甲基黄嘌呤及茶叶碱中。根据结果可以推断木荷属和柃木属植物具有N-甲基转移酶活性,可以用来合成咖啡碱和茶叶碱,相对于茶树而言,活性不高。综上,本文对木荷属和柃木属植物的嘌呤代谢以及嘌呤碱合成进行了研究。     

Purine Functionalized Congeners as Molecular Probes for Adenosine Receptors

Abstract

The effects of distal structural changes on biological activity may be studied, using a “functionalized congener” strategy, in which suitably placed chemically reactive chains lead to biologically active conjugates. Probes for photoaffinity labeling, chemical affinity labeling, spectroscopic characterization and affinity chromatography of adenosine receptors have been derived from purine amine congeners (XAC, ADAC for At-receptors and APEC for Ap-receptors). Also, drug conjugates, including prodrugs and lipids, have been designed as potential Pharmacological agents.