Synthesis of novel pyrimidine nucleoside analogues (original) (raw)
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Synthesis and Biological Activity of Reversed Pyrimidine Nucleosides
Croatica Chemica Acta, 2015
An efficient approach to reversed nucleosides which enables their synthesis in gram quantities is described. N-1′-Pyrimidine reversed nucleosides were prepared by treating of the sodium salt of pyrimidine bases with protected 5-tosyl ribose. Additionally, N-1′,N-3′-disubstituted reversed nucleosides were isolated in the condensation reactions with the 5-halogen pyrimidines. Using the Sonogashira coupling of 5′-iodouracil reversed nucleoside with ethynyltrimethyl silane gave 5′-ethynyl derivative which was further transformed into 5′-acetyl reversed nucleoside. Biological activity of deprotected reversed nucleosides was validated on the panel of six human carcinoma cell lines (HeLa, MIAPaCa2, Hep2, NCI-H358, CaCo-2, and HT-29). 5′-Iodouracil derivative displayed moderate growth inhibition activity against human colon carcinoma (CaCo-2) cells.
Synthesis, structure, and biological evaluation of C-2 sulfonamido pyrimidine nucleosides
Tetrahedron, 2003
The C-2 sulfonamido pyrimidine nucleosides were prepared by opening the 2,2′- or 2,3′-bond in anhydronucleosides under nucleophilic attack of sulfonamide anions. Reaction of the sodium salt of p-toluenesulfonamide or 2-(aminosulfonyl)-N,N-dimethylnicotinamide with 2,2′-anhydro-1-(β-d-arabinofuranosyl)cytosine gave the C-2 sulfonamido derivatives in excellent yields. Ring opening of the less reactive 2,2′-anhydrouridine and 2,3′-anhydrothymidine could be accomplished with DBU/CH3CN activation of p-toluenesulfonamide, giving moderate yields for C-2 sulfonamido derivatives. The action of acetic acid or ZnBr2/CH2Cl2 on 5-methyl-N2-tosyl-1-(2-deoxy-5-O-trityl-β-d-threo-pentofuranosyl)isocytosine led to the cleavage of both the protection group and the nucleoside bond, yielding 5-methyl-N2-tosylisocytosine as the major product. Structures of the prepared C-2 sulfonamido nucleosides were confirmed by the 1D and 2D NMR experiments, and X-ray structural analysis of 4-imino-N2-tosylamino-1-(β-d-arabinofuranosyl)pyrimidine. Both methods confirmed β-configuration and anti-conformation of the 2-sulfonamido nucleosides. The investigated compounds displayed moderate inhibition of tumor cell growth in vitro, as determined by the MTT assay using six different human tumor cell lines.Graphic
Archiv der Pharmazie, 2001
The syntheses, antiviral activities, and partition coefficients (P) of 3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-coupled nucleosides are described. These novel compounds were designed in an effort to enhance the lipophilicity, and thereby the delivery to the CNS, without compromising the anti-HSV-1 activity of the parental nucleosides. We have previously reported the synthesis of 3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl) analogs of 5-iodo-(5), 5-vinyl-(6), and (E)-5-(2-iodovinyl)-2′-deoxyuridines (7). We now report the synthesis of 5-iodo-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-5′-O-acetyl-2′-deoxyuridine (15) and 3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (17). Quarternization of the 3′-O-(3-pyridylcarbonyl) compounds (10,12) using iodomethane afforded the corresponding 1-methyl pyridinium salts (13,14) which were reduced with sodium dithionite to yield the corresponding 3′-O-1-methyl-1,4-dihydropyridyl-3-carbonyl compounds (15,16). The deprotection of 3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-5′-O-t-butyldimethylsilyl-2′-deoxyuridine (16) with Bu4N + Fafforded 3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (17). Compounds 5-7 and 15 were evaluated for their antiviral activity in vitro against HSV-1, HSV-2, HCMV, and VZV, and were found to retain anti-HSV-1, HSV-2 and VZV activity as compared to their parental nucleosides (1-3). In addition, the cellular toxicity of 3′-O-(1methyl-1,4-dihydropyridyl-3-carbonyl)-coupled compounds (5-7 and 15) was found to be lower than the parent nucleosides. The lipophilicity of compounds (5-7,15,17) are enhanced substantially, compared to the parent nucleosides, as indicated by an increase in corresponding P values (1-octanol-water) upon replacement of the C-3′ hydroxyl by 1-methyl-1,4-dihydropyridyl-3-carbonyl moiety.
Synthesis and biological evaluation of certain C-4 substituted pyrazolo[3,4-b]pyridine nucleosides
Journal of Medicinal Chemistry, 1989
The key intermediate 9-(2,3,5,-tri-O-acetyl-beta-D-arabinofuranosyl)purine-6-carbonitrile (7) was synthesized in four steps from 9-beta-D-arabinofuranosylpurine-6-thione (3) via 6-(methylsulfonyl)-9-(2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)purine (6). Reaction of compound 7 with methanolic ammonia provided the rearranged compound 4-amino-8-(beta-D-arabinofuranosylamino)pyrimido[5,4-d]pyrimidine (8). Treatment of 7 with ammonium hydroxide and hydrogen peroxide provided 9-beta-D-arabinofuranosylpurine-6-carboxamide (9). Compound 7 was also treated with sodium hydrosulfide to yield 9-beta-D-arabinofuranosylpurine-6-thiocarboxamide (10). Similarly, 9-(2-deoxy-3,5-di-O-acetyl-beta-D-erythro-pentofuranosyl)purine 6-carbonitrile (17) was prepared from 6-chloro-9-(2-deoxy-beta-D-erythro-pentofluranosyl)purine (11) via 9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine-6-thione. Compound 17 was converted into 4-amino-8-[(2-deoxy-beta-D-erythro-pentofuranosyl)amino]pyrimido[5,4-d]pyrimidi ne (18) and 9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine-6-carboxamide (20), respectively. Compound 2 showed immunosuppressive activity and also inhibited the growth of L-1210 leukemia in mice. Arabinonucleoside analogues 8-10 were inactive when tested against RNA and DNA viruses in cell culture.
Pharmacia, 2021
Nucleoside derivatives are important therapeutic drugs and are the focal point in the ongoing search for novel, more potent drug targets. In this study, a new series of pyrimidine nucleoside i.e., uridine (1) derivatives were synthesized via direct method and evaluated for their antimicrobial potential activity. The title compound uridine (1) was treated with triphenylmethyl chloride in pyridine to give the 5´-O-(triphenylmethyl)uridine derivative (2), which was subsequently derivatized to create a series of 2´,3´-di-O-acyl analogs containing a wide variety of functionalities in a single molecular framework. In vitro antimicrobial functionality tests were determined against both human and plant pathogens by disc diffusion and food poisoned techniques. The chemical structures of the synthesized compounds were confirmed on the basis of their spectral, analytical, physicochemical data. The antimicrobial results indicated that the synthesized derivatives exhibited moderate to good antib...
Some New Pyrido[2,3-d]pyridimines and their Nucleoside of Biological Importance
E-Journal of Chemistry, 2010
Chalcones (I) reacted with malanonitrile and ammonium acetate yielded 2-amino-3-cyano-4,6-disubstituted pyridines (II) in excellent yield. 4-Amino-5,7-disubstituted pyrido [2,3-d]pyrimidine-2(1H)-thiones (III), 4-amino-5,7-disubstituted pyrido[2,3-d]pyrimidines (IV) and 4-imino-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-2(1H)-ones (V) have been synthesized by the condensation of compound (II) with thiourea, formamide and arylisocynate respectively. The ribofuranosidesviz. 4-amino-5,7-disubstituted-1- [2',3',5'-tri-o-benzoyl-β,D-ribofuranosyl]pyrido[2,3-d]pyrimidine-2-(1H)-thiones (VI) and 4-imino-3,5,7- trisubstituted-1- [2',3',5'-tri-o-benzoyl-β,D-ribofuranosyl] pyrido [2,3-d] pyrimidine-2(1H)-one (VII) were synthesized by converting compounds III and V to trimethylsilyl derivative in situ by reacting them with hexamethyldisilazane to give corresponding ribofuranosides withβ-D-ribofuranose-1-acetate-2,3,5-tribenzoate. Compounds III-V and their ribofuranosid...
Collection of Czechoslovak Chemical Communications, 2006
A series of 4′-C-(hydroxymethyl) analogs of pyrimidine and purine nucleosides have been prepared utilizing standard methodologies, and the α and β anomers were separated. These analogs are part of our continuing efforts to identify new anticancer drugs as well as to explore the substrate specificities of these analogs with the initial activating enzymes in the metabolic pathway leading to nucleoside triphosphates. Although not cytotoxic to CCRF-CEM cells (an acute lymphoblastic leukemia of T-cell origin), many of these compounds were utilized as substrates for the various human nucleoside kinases, including deoxycytidine kinase, thymidine kinase 1, and thymidine kinase 2. Because the 4′-C-(hydroxymethyl) analog of arabinofuranosyl cytosine was identified as a good substrate with deoxycytidine kinase, its metabolism in CEM cells was evaluated. These results indicated that nucleosides with this modification could be activated in human cells without cytotoxicity, which suggested that they should be examined for antiviral activity.