SYNTHESIS AND BIOLOGICAL ACTIVITY OF BRANCHED CHAIN-SUGAR NUCLEOSIDES1

Abstract

2′-Alkyl derivatives of cytidine and thymidine have been synthesized. 2′-Deoxy-6,2′-methanocytidine has also been prepared. Among them, 2′-deoxy-2′-methylidene-cytidine exhibited potent antitumor activities.     

SYNTHESIS AND BIOLOGICAL EVALUATION OF BORONATED NUCLEOSIDES FOR BORON NEUTRON CAPTURE THERAPY (BNCT) OF CANCER

Several N-3 substituted carboranyl Thd analogs were synthesized. These agents as well as some non-boronated nucleosides were evaluated in phosphoryl transfer assays with recombinant human TK1 and TK2. For some carboranyl thymidine analogs, TK1 phosphorylation rates approached 38% that of thymidine. Their in vitro cytotoxicty appeared to correlate with the TK1 levels in the tested cells. In some cases increased uptake in tumor cell nuclei compared with the surrounding cytoplasm was detected in vitro.     

SYNTHESIS OF 3-ALKYL PIPERAZIN-2-ONE NUCLEOSIDES WITH POTENTIAL ANTIRETROVIRAL ACTIVITY

Abstract

Piperazinone nucleosides can be formed by N-glycosylation with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose of either piperazin-2-ones or pyrazin-2-ones followed by reduction of the heterocycle with rhodium on alumina. All the prepared compounds were tested for their activity against the Visna virus, but did not show significant antiviral activity.     

SYNTHESIS AND BIOLOGICAL EVALUATION OF S-GLYCOSYLATED PYRIDINES

ABSTRACT

The formation of thioglycosides 7a-j and 10a-j via the reaction of sodium salts of thiopyridines 3a-e with glycosyl bromides 6a,b has been studied. Comparison with the products obtained from silylated thiopyridines 8a-e and peracetylated sugars 9a,b is made. ¹³C NMR was utilized to elucidate the proposed structures of the products.     

SYNTHESIS AND EVALUATION OF ANTIVIRAL ACTIVITY OF HIGHER HOMOLOGUES OF XYLO-CARBOCYCLIC NUCLEOSIDES

New carbocyclic nucleosides with purine (compounds 3a and 3b), and 8-azapurine (compounds 3c and 3d) as base were prepared and assayed for in vitro activity.     

SYNTHESIS AND NMR-ANALYSIS OF TRICYCLIC NUCLEOSIDES

Two anomeric tricyclic nucleosides have been synthesised from diacetone-D-glucose using oxidation, stereoselective Grignard-addition of a vinyl-group, a stereoselective dihydroxylation followed by a tandem ring closing reaction, and finally a nucleobase coupling. The main β-configured product was examined and its configuration confirmed using NMR-spectroscopy in connection to ab initio calculations. The preferred conformation of this tricyclic nucleoside was described.     

SYNTHESIS AND IN VITRO EVALUATION OF NOVEL ANTI-VARICELLA-ZOSTER VIRUS (VZV) NUCLEOSIDES

A series of alkyl-aryl, -phenoxy, and -thiophenoxy bicyclic furo pyrimidine nucleosides have been successfully synthesised by Pd-coupling of 5-iodo-2′-deoxyuridine (IDU) with terminal alkynes, followed by in situ copper-cyclisation. Synthesised compounds (4a-i) showed an anti-VZV activity at low μM concentration, comparable to that of current treatment acyclovir.     

DESIGN AND SYNTHESIS OF NOVEL FLUOROCYCLOPROPANOID NUCLEOSIDES

Novel fluorocyclopropanoid nucleosides were designed, synthesized and evaluated their antiviral activities against poliovirus, HSV, HIV, and HBV.     

SYNTHESIS AND ANTIVIRAL ACTIVITY OF METHYLENEDIFLUOROCYCLOPROPANE ANALOGUES OF NUCLEOSIDES

Synthesis and antiviral activity of methylenedifluorocyclopropane analogues 8a, 8b and 9a, 9b are described.     

SYNTHESIS AND ANTI-HCMV ACTIVITY OF NOVEL ACYCLIC NUCLEOSIDES

ABSTRACT

A series of novel acyclic nucleosides 10, 11, 21, and 22 were synthesized efficiently starting from D-lactose. The condensation of the mesylate 5 and 16 with an adenine and cytosine base under standard nucleophilic substitution conditions (K₂CO₃, 18-Crown-6, DMF) afforded a series of acyclic novel nucleosides. Compound 21 displayed moderate anti-HCMV activity in the AD-169 cells (EC₅₀=18.5 µg/mL) without exhibiting any cytotoxicity up to 100 µM.     

SYNTHESIS OF SELENIUM-DERIVATIZED NUCLEOSIDES AND OLIGONUCLEOTIDES FOR X-RAY CRYSTALLOGRAPHY

We report here the synthesis of nucleoside and oligonucleotide analogs containing selenium, which serves as an anomalous scattering center to enable MAD phase determination in nucleotide X-ray crystallography. We have developed a phase transfer approach to introduce the selenium functionality in A, C, G, T, and U nucleosides at 5′-positions. In the incorporation of the selenium functionality, the leaving groups (bromide, mesyl, and tosyl) were readily displaced by sodium selenide, sodium diselenide, and sodium methyl selenide with yields higher than 90%. Selenium-derivatized oligonucleotides have been synthesized via phosphoramidite chemistry.     

SYNTHESIS AND ANTIVIRAL ACTIVITY OF NOVEL EXOMETHYLENE CYCLOPROPYL NUCLEOSIDES

Novel cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5, prepared from Feist's acid 1 was condensed with purine derivatives by the S_N2 type reaction. All the synthesized compounds were evaluated for antiviral activity.     

SYNTHESIS AND BIOLOGICAL EVALUATION OF N- AND O-ALKYLATED BICYCLIC FURANOPYRIMIDINES AS NON-NUCLEOSIDIC INHIBITORS OF HUMAN CYTOMEGALOVIRUS

2′,3′-Dideoxy furanopyrimidines were shown to display anti-HCMV activity via a non-nucleoside mechanism. Further studies into highly modified sugar derivatives led to the preparation of N-and O-alkylated C₁₀ furanopyrimidine analogues, and this work is described herein. These compounds were tested against HCMV strains, and the first case of submicromolar activity was observed.     

SYNTHESIS AND BIOLOGICAL EVALUATION OF NAD ANALOGS AS HUMAN PYRIDINE NUCLEOTIDE ADENYLYLTRANSFERASE INHIBITORS

NAD analogs modified at the ribose adenylyl moiety, named N-2′-MeAD and Na-2′-MeAD, were synthesized as ligands of pyridine nucleotide (NMN/NaMN) adenylyltransferase (NMNAT). Both dinucleotides resulted selective inhibitors against human NMNAT-3 isoenzyme.     

抗凝血灭鼠剂大隆和鼠得克的生物学效果评价

大隆(brodifacoum)和鼠得克(difenacoum)是1975-1976年新发展的第二代抗凝血灭鼠剂,化学名称分别为3-(3-(对溴联苯基)-1,2,3,4-四氢化萘基)-4-羟基香豆素和3-(3-联苯基-1,2,3,4-四氢化萘基)-4羟基香豆素。这一类抗凝血灭鼠剂有2个突出的特性:(1)能杀灭抗药性鼠种,指对杀鼠灵(warfarin)产生抗药的鼠种,(2)兼有急性和慢性灭鼠剂的优点,单剂量对多种鼠类都有防制效果。这样不仅可以解决鼠类对杀鼠灵的抗药问题,而且可以节约灭鼠用粮和人力,有可能使抗凝血灭鼠剂推广用于防制野鼠。根据全国除四害规划安排,军事医学科学院微生物流行病研究所于1979年合成了这2种灭鼠剂样品,供全国新药协作组15个单位进行生物学效果评价。本文为部份试验结果。     

NAPHTHYL PHOSPHORAMIDATE DERIVATIVES OF BVdU AS POTENTIAL ANTICANCER AGENTS: DESIGN,SYNTHESIS AND BIOLOGICAL EVALUATION

The phosphoramidate technology we have developed has been recently applied to BVdU, leading to NB1011 (NewBiotics Inc., California), a novel potential anticancer compound recently entered into phase 2 of the clinical trials for colon cancer. We report in this work a new series of derivatives containing naphthol as aryl masking group on the phosphate moiety, which has shown a significant increase in anticancer activity in preliminary biological evaluations.     

取代P物质类似物的合成及生物活性

使用固相法合成含有不同D-型氨基酸取代的八个P物质类似物。纯化采用凝胶过滤,硅胶柱层或反相高效液相色谱。化合物的SP样作用及拮抗SP样作用在离体豚鼠迴肠纵行肌上进行了试验。所有化合物都显示了不同程度的拮抗作用。其中化合物A-58[D-Arg~1,D-Phe~5,D-Trp~(7,9),Leu~(11)]SP拮抗活性最高。它拮抗SP样作用的剂量比率(EC_(50)之比)在10~(-6)M时为24,在3×10~(-6)M时为52.2。     

SYNTHESIS AND STRUCTURAL STUDY OF PYRIMIDYL CARBOCYCLIC ANALOGUES OF NUCLEOSIDES BASED ON CYCLOPENTENE RINGS

A series of 1,2-disubstituted carbonucleoside analogues of pyrimidine and 5-halopyrimidines with the unsaturated carbocycle cyclopentene was synthesized. AIM theory was applied to analyse the conformational and electronic effects of 5-halogenation.     

CONVENIENT SYNTHESIS OF FLUORINATED NUCLEOSIDES WITH PERFLUOROALKANESULFONYL FLUORIDES

ABSTRACT

Perfluoroalkanesulfonyl fluorides are effective dehydroxy-fluorination agents for the hydroxyl group at the sugar moiety of nucleoside derivatives and give the corresponding fluorinated nucleosides in good yield with an inversion of configuration in a single step.