An Efficient Alternative Route To 3,6-Disubstituted-Furo[2,3-d]Pyrimidin-2-One Analogues

Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2 Robins, M. J. and Barr, P. J. 1983. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides. J. Org. Chem, 48: 1854–1862. [CSA][CROSSREF][Crossref], [Web of Science ®] , [Google Scholar], 3 De Clercq, E., Descamps, J., Balzarini, J., Giziewicz, J., Barr, P. J. and Robins, M. J. 1983. Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem, 26: 661–666. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2 Robins, M. J. and Barr, P. J. 1983. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides. J. Org. Chem, 48: 1854–1862. [CSA][CROSSREF][Crossref], [Web of Science ®] , [Google Scholar], 3 De Clercq, E., Descamps, J., Balzarini, J., Giziewicz, J., Barr, P. J. and Robins, M. J. 1983. Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem, 26: 661–666. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrimidin-2-one analogues.     

USE OF THE SODIUM SALT GLYCOSYLATION HETBOD IN NUCLEOSIDE SYNTHESIS

Abstract

A general and stereospecific method has been developed for the direct preparation of βD-ribofuranosyl, βD-arabinofuranosyl and 2-deoxy-βD-erythro-pentofuranosyl derivatives of a number of nitrogen heterocycles. The azoles thus far employed include appropriately substituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, indole, imidazo[4,5-c]pyridine, pyrrolo[2,3-d]pyrimidine, pyrro10[3,2-c]pyridine, pyrrolo[4,2-c]pyrimidine, purine, pyrazolo[3,4-b]pyridine and pyrazolo-[3,4-d]pyrimidine. This simple high-yield methodology provided a facile route to the large-scale preparation of biologically significant nucleo-sides, such as 2′-deoxyribavirin, 2-chloro-2′-deoxyadenosine, tuber-cidin, Z'-deoxytubercidin, =sangivarnycin, 2′-deoxytoyocamycin, cade-guomycin, 2′-deoxycadeguomycin, G-cadeguomycin, kanagawamicin, 2′-deoxy-3-deazaguanosine, sG, brunfelsarnidine ribonucleoside and 2′-deoxyribofuranosyl derivative of the antibiotic SF-2140. This procedure appears to be considerably superior to the previously reported glycosylation methods.     

Synthesis of Brunfelsamidine Ribonucleoside and Certain Related Compounds by the Stereospecific Sodium Salt Glycosylation Procedure

Abstract

A synthesis of 2,4-dideazaribavirin ( 2 ), brunfelsamidine ribonucleoside ( 8c ) and certain related derivatives are described for the first time using the stereospecific sodium salt glycosylation procedure. Glycosylation of the sodium salt of pyrrole-3-carbonitrile ( 4 ) with 1-chloro-2, 3-O-t-isopropylidene-5-O-t-butyldimethylsilyl-α-D-ribofuranose ( 5 ) gave exclusively the corresponding blocked nucleoside ( 6 ) with β-anomeric configuration, which on deprotection provided 1-β-D-ribofuranosylpyrrole-3-carbonitrile ( 7 ). Functional group tranformation of 7 gave 2 , 8c and related 3-substituted pyrrole ribonucleosides. These compounds are devoid of any significant antiviral/antitumor activity invitro.     

Purine Nucleoside 3′,5′-Cyclic Monophosphates as Hormonal Modulators of Cellular Proliferation,Metastases and Lymphocyte Response

Abstract

A review of the potential role of cAMP and cGMP as hormonal regulators of tumor cell proliferation, metastases and lymphocyte activation reveals that several synthetic purine nucleoside 3′,5′-cyclic monophosphates are more potent and more selective in modulating certain specific responses than the parent natural cyclic nucleotides. cAMP derivatives have been prepared which will temporarily restore transformed cells to the normal phenotype. cAMP analogs may well be found which will selectively inhibit tumor metastases. Certain cGMP analogs could selectively stimulate the lymphocyte response toward the destruction of tumor cells. The synthesis of new cyclic nucleotides should provide unique nontoxic agents that could combat neoplasia on a hormonal basis.     

A New Synthesis of 7-Methyl-8-Oxoguanosine

Abstract

A new, facile synthesis of 7-methyl-8-oxoguanosine is reported. 2-Chloro-7-methylpurine-6, 8-dione (5) was silylated with hexamethyldi-silazane and the silylated intermediate, 6, glycosylated with 1-0-acetyl-2, 3, 5-tri-0-benzoyl-D-ribofuranose to yield 2-chloro-7-methyl-9-(2′, 3′,-5′-tri-0-benzoyl-β-D-ribofuranosyl) purin-6, 8-dione (8). Deprotection of 8 with sodium hydroxide in aqueous methanol gave 2-chloro-7-methyl-9-(β-D-ribofuranosyl) purine-6,8-dione (9), which was aminated with liquid ammonia or methanolic ammonia to yield 7-methyl-8-oxoguanosine (3).     

Ribonucleotide Reductase Targets for Chemotherapy; Mechanistic Aspects and Biologically Active Agents

Abstract

Ribonucleotide reductases are essential for the de novo biosynthesis of the 2′-deoxynucleotide components of DNA. These enzymes have complex cofactors and execute novel chemistry involving C2′ via radical abstraction of H3′. Mechanistic aspects of these transformations and selected nucleotide analogues that cause mechanism-based inactivation of ribonucleotide reductases are discussed.     

Hepatitis C Transmission and Treatment in Contact Networks of People Who Inject Drugs

Hepatitis C virus (HCV) chronically infects over 180 million people worldwide, with over 350,000 estimated deaths attributed yearly to HCV-related liver diseases. It disproportionally affects people who inject drugs (PWID). Currently there is no preventative vaccine and interventions feature long treatment durations with severe side-effects. Upcoming treatments will improve this situation, making possible large-scale treatment interventions. How these strategies should target HCV-infected PWID remains an important unanswered question. Previous models of HCV have lacked empirically grounded contact models of PWID. Here we report results on HCV transmission and treatment using simulated contact networks generated from an empirically grounded network model using recently developed statistical approaches in social network analysis. Our HCV transmission model is a detailed, stochastic, individual-based model including spontaneously clearing nodes. On transmission we investigate the role of number of contacts and injecting frequency on time to primary infection and the role of spontaneously clearing nodes on incidence rates. On treatment we investigate the effect of nine network-based treatment strategies on chronic prevalence and incidence rates of primary infection and re-infection. Both numbers of contacts and injecting frequency play key roles in reducing time to primary infection. The change from “less-” to “more-frequent” injector is roughly similar to having one additional network contact. Nodes that spontaneously clear their HCV infection have a local effect on infection risk and the total number of such nodes (but not their locations) has a network wide effect on the incidence of both primary and re-infection with HCV. Re-infection plays a large role in the effectiveness of treatment interventions. Strategies that choose PWID and treat all their contacts (analogous to ring vaccination) are most effective in reducing the incidence rates of re-infection and combined infection. A strategy targeting infected PWID with the most contacts (analogous to targeted vaccination) is the least effective.     

Dynamic Chromatin Remodeling Mediated by Polycomb Proteins Orchestrates Pancreatic Differentiation of Human Embryonic Stem Cells

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Highlights? Pancreatic lineage progression is governed by PcG-dependent chromatin remodeling ? A temporal chromatin signature predicts regulators of pancreatic development ? Endocrine cells differentiated from hESCs in vivo are similar to native human islets ? In vitro-produced malfunctioning endocrine cells exhibit aberrant chromatin structure