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1.
Mulakayala N Kandagatla B Ismail Rapolu RK Rao P Mulakayala C Kumar CS Iqbal J Oruganti S 《Bioorganic & medicinal chemistry letters》2012,22(15):5063-5066
A convenient and practical methodology for the synthesis of 2-aryl quinazolin-4(3H)-ones by the condensation of o-aminobenzamides with aromatic aldehydes under mild conditions using catalytic InCl(3) with good yields and high selectivities. This method has been extended for the synthesis of 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones which have potential applications in medicinal chemistry. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules. 相似文献
2.
Hollick JJ Golding BT Hardcastle IR Martin N Richardson C Rigoreau LJ Smith GC Griffin RJ 《Bioorganic & medicinal chemistry letters》2003,13(18):3083-3086
6-aryl-2-morpholin-4-yl-4H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones were synthesised and evaluated as potential inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). Several compounds in each series exhibited superior activity to the chromenone LY294002, and were of comparable potency to the benzochromenone NU7026 (IC(50)=0.23 microM). Importantly, members of both structural classes were found to be selective inhibitors of DNA-PK over related phosphatidylinositol 3-kinase-related kinase (PIKK) family members. A multiple-parallel synthesis approach, employing Suzuki cross-coupling methodology, was utilised to prepare libraries of thiopyran-4-ones with a range of aromatic groups at the 3'- and 4'-positions on the thiopyran-4-one 6-aryl ring. Screening of the libraries resulted in the identification of 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones bearing naphthyl or benzo[b]thienyl substituents at the 4'-position, as potent DNA-PK inhibitors with IC(50) values in the 0.2-0.4 microM range. 相似文献
3.
Synthesis of 5-chloroformycin A, 5-chloro-2''-deoxyformycin A and certain related 5,7-disubstituted 3-beta-D-ribofuranosylpyrazolo[4,3-d] pyrimidines from formycin A.
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K G Upadhya Y S Sanghvi R K Robins G R Revankar B G Ugarkar 《Nucleic acids research》1986,14(4):1747-1764
A facile synthesis of 7-amino-5-chloro-3-beta-D-ribofuranosylpyrazolo [4,3-d]pyrimidine (5-chloroformycin A, 6), 7-amino-5-chloro-3-(2-deoxy-beta-D-erythro-pentofuranosyl) pyrazolo [4,3-d]-pyrimidine (5-chloro-2'-deoxyformycin A, 13) and certain related 5,7-disubstituted pyrazolo[4,3-d]pyrimidine ribonucleosides is described starting with formycin A. Thiation of tri-O-acetyloxoformycin B (4b) with phosphorus pentasulfide, followed 3-beta-D-ribofuranosyl-7-thioxopyrazolo[4,3-d] pyrimidin-5(1H,4H,6H)-one (3b) in excellent yield. Chlorination of 4b with either phosphorus oxychloride or phenyl phosphonicdichloride furnished the key intermediate 5,7-dichloro-3-(2,3, 5-tri-O-acetyl-beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine (5a), which on deacetylation afforded 5,7-dichloro-3-beta-D-ribofuranosylpyrazolo [4,3-d]pyrimidine (5b). Ammonolysis of 5a with liquid ammonia gave 6, whereas with MeOH/NH3, a mixture of 6 and 7-methoxy-5-chloro-3-beta-D-ribofuranosylpyrazolo[4,3-d]pyrimidine (7) was obtained. Reaction of 6 with lithium azide and subsequent hydrogenation afforded 5-aminoformycin A (10). Treatment of 5a with thiourea gave 5-chloro-3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl) pyrazolo[4,3-d]pyrimidine-7(1H,6H)-thione (8a), which on further reaction with sodium hydrosulfide furnished 3-beta-D-ribofuranosylpyrazolo [4,3-d]pyrimidine-5,7(1H,4H,6H)-dithione (11). The four-step deoxygenation procedure using phenoxythiocarbonylation of the 2'-hydroxy group of the 3', 5'-protected 6 gave 5-chloro-2'-deoxyformycin A (13). 相似文献
4.
《Bioorganic & medicinal chemistry》2016,24(19):4576-4586
A series of novel 2,5,7-tricarbo-substituted indoles were prepared via sequential Sonogashira and Suzuki–Miyaura cross-coupling of 2-amino-5-bromo-3-iodoacetophenone with terminal acetylenes and aryl/styrylboronic acids followed by palladium chloride-mediated heteroannulation of the incipient 5-aryl/styryl-substituted 2-amino-3-(arylalkynyl)acetophenones. These polycarbo-substituted indole derivatives were evaluated for potential in vitro antiproliferative activity against the human breast adenocarcinoma (MCF-7) and human cervical cancer (HeLa) cell lines. Compounds 6f, 6i, 6k, 6m and 6n were found to exhibit significant cytotoxicity and selectivity against the HeLa cells. Compounds 6i and 6m were chosen as representative examples to evaluate their pro-apoptotic efficacy against the HeLa cell line. The compounds induced apoptosis through cell membrane alteration and DNA fragmentation caspase-dependent pathways. 相似文献
5.
Emmanuel Deau Yvonnick Loidreau Pascal Marchand Marie-Renée Nourrisson Nadège Loaëc Laurent Meijer Vincent Levacher Thierry Besson 《Bioorganic & medicinal chemistry letters》2013,23(24):6784-6788
The efficient synthesis of 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49 nM and proved to be specific to CLK1 among the panel of tested kinases. 相似文献
6.
Xiaoyuan Li Ellyn Shocron Aimin Song Neela Patel Connie L. Sun 《Bioorganic & medicinal chemistry letters》2009,19(10):2860-2864
A new series of compounds, 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones, have been designed and identified as potent and selective inhibitors of Hsp90. These compounds demonstrated nanomolar potency toward both Hsp90-regulated Her2 degradation and the growth of a panel of human tumor cell lines in cell-based assays. High selectivity of these compounds toward Hsp90 was evident given that they did not inhibit a panel of 34 kinases at 10 μM. The structure–activity relationship (SAR) of this series is reported here. 相似文献
7.
E M Logvinenko G M Shavlovski? N Iu Kontorovskaia 《Ukrainski? biokhimicheski? zhurnal》1987,59(1):80-82
2,4-dihydroxy-5-amino-6-ribitylaminopyrimidine and 2,4-dihydroxy-5-amino-6-ribitylaminopyrimidine-5'-phosphate are studied for their effect on the activity of 6,7-dimethyl-8-ribityllumazine synthase of Pichia guilliermondii yeasts. It is shown that when nonphosphorylated form of pyrimidine and ribose-5-phosphate (donor C-4--a fragment) is used as a substrate, the specific activity of 6,7-dimethyl-8-ribityllumazine synthase is high and Be2+ and F- ions, inhibitors of alkaline phosphatases, do not inhibit it. The value of Km for this pyrimidine is 1.1 X 10(-5) M. Phosphorylated pyrimidine being used as a substrate in the presence of Be2+ and F-, the reaction practically does not proceed. Therefore, only 2,4-dihydroxy-5-amino-6-ribitylaminopyrimidine is a pyrimidine substrate of 6,7-dimethyl-8-ribityllumazine synthase of yeast. 相似文献
8.
Chohan ZH Scozzafava A Supuran CT 《Journal of enzyme inhibition and medicinal chemistry》2003,18(3):259-263
Reaction of 2-acetamidobenzaldehyde with 2-amino-, 2-amino-4-methyl-, 2-amino-4-methoxy-, 2-amino-4-chloro-, 2-amino-6-nitro- and 2-amino-6-methylsufonylbenzothiazole afforded a series of Schiff bases. These compounds have been used for complexation reactions to obtain Zn(II) chelates having the same metal ion but different anions of the type [Zn(L)2]Xn [L = Schiff base derivative, X = SO4, NO3, C2O4 and CH3CO2 and n = 1 or 2] These complexes (Table I) have been characterized by physical, spectral, and analytical data. The Schiff bases act tridentately and their metal complexes were proposed to possess an octahedral geometry. To evaluate the antibacterial role of the anion, these compounds have been screened for antibacterial properties against pathogenic strains such as Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. 相似文献
9.
Kumar D Tomar RS Deolia SK Srivastava R Mitra M Tyagi S 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2008,869(1-2):45-53
The degradation of epirubicin hydrochloride aqueous formulation has been investigated during stability study. Some unknown degradation impurities were detected and out of these, three were characterized. These degradation impurities were isolated, enriched and were subjected to mass and NMR spectral studies. Based on the spectral data these were characterized as epirubicin dimer (impurity-1), 4-(4-amino-5-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-naphthacene-2-carboxylic acid hydroxymethyl ester (impurity-3) and 4-(4-amino-5-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-naphthacene-2-carboxylic acid (impurity-4). Structure elucidations of these degradation impurities are discussed in detail. Out of these degradation impurities, epirubicin dimer (impurity-1) has been previously identified while the other two impurity-3 and impurity-4 were previously unreported. 相似文献
10.
E G Sander J H Priest J E Scheffler 《Biochemical and biophysical research communications》1979,89(4):1341-1346
At room temperature, hydroxylamine dehalogenates 5-Br-and 5-I-uracil. 5-Cl-uracil reacts to a much less extent. Reaction with 5-F-uracil yields the 6-hydroxyamino-adduct as a product. Kinetics monitored spectrally indicate that dehalogenation involves the formation of a 5-halo-6-hydroxyamino-5, 6-dihydrouracil intermediate which then slowly dehalogenates. 5-Bromo-6-methoxy-5,6-dihydrothymine, a model for the above intermediate, also dehalogenates yielding thymine as a product.Hydroxylamine (NH2OH), a mutagenic agent (1,2) reacts with pyrimidine rings promoting such reactions as the formation of 5,6-dihydro-N4-hydroxy-6-hydroxyaminocytosine from cytosine (3,4) and both urea and isoxazoles from uracil derivatives (2,5,6). It is believed to be unreactive toward 5-substituted uracil derivatives (2,5,6) but has been reported to cause the dehalogenation of 5-bromouracil derivatives yielding Br? and uracil as products (2,7,8). The object of this report is to demonstrate the generality of NH2OH addition to the 5-halouracils with the subsequent dehalogenation of both 5-Br-and 5-I-uracil; reactions which appear to proceed via pathways similar to bisulfite buffer mediated halouracil dehalogenation (9–13). A preliminary report of this work has appeared (14). 相似文献
11.
Guo X Li Y Tao L Wang Q Wang S Hu W Pan Z Yang Q Cui Y Ge Z Dong L Yu X An H Song C Chang J 《Bioorganic & medicinal chemistry letters》2011,21(22):6770-6772
Three novel 4-subsituted-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine analogues were designed, synthesized, and tested for their anti-HIV-1 activity. Initial biological studies indicated that among these pyrrolo[2,3-d]pyrimidine ribonucleoside analogues, 4-amino-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 10 exhibited the most potent anti-HIV-1 activity (EC(50)=0.5±0.3 μM), while 4-hydroxy-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d] pyrimidine 9 and 4-amino-5-fluoro-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d] pyrimidine 11 showed moderate activity (EC(50)=13±8 and 5.4±0.3 μM, respectively). The cytotoxicity of these compounds has also been assessed. No significant cytotoxicities were found for any of these compounds with concentrations up to 25 μM. 相似文献
12.
We describe an efficient total synthesis of triciribine, a tricyclic nucleoside with antineoplastic and antiviral properties, starting from 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine. 相似文献
13.
Manuel Nogueras Luisa Quijano Miguel Melgarejo Adolfo Sqnchez 《Nucleosides, nucleotides & nucleic acids》2013,32(3):301-312
Abstract Reaction between 1, 6-dihydro-4-β-D(2, 3, 4, 6-tetra-O-acetyl) glucopyranosylamino-l-methyl-2-methoxy-6-oxo pyrimidine and chloracetyl chloride yields the corresponding 5-α-chloracetyl derivative and 2,6-di oxo-4-β -D (2,3,4,6-tetra-0-acetyl) glucopyranosylamino-l-methyl-1,2,3,6 tetrahdro pyrimidine. The first compund has been cyclized to the corresponding 7-β-D-glucopyranosyl-pyrrolo 2, 3-d pyrimidine and the second one to 3-βD-glucopyranosyl-vic-triazolo 4,5-d pyrimidine. 相似文献
14.
Kern JC Terefenko EA Fensome A Unwallla R Wrobel J Zhu Y Cohen J Winneker R Zhang Z Zhang P 《Bioorganic & medicinal chemistry letters》2007,17(1):189-192
We previously disclosed that 6-aryl benzoxazin-2-ones were PR modulators. In a continuation of this work we examined the SAR of new 6-arylamino benzoxazinones and found the targets 1-25, with an extra amino linker between the pendent 6-aryl groups and benzoxazinone or benzoxazine-2-thione core, were PR antagonists. A series of compounds with substituents at the 1- and 4-positions as well as different 6-aryl groups were prepared and tested in the T47D cell alkaline phosphatase assay. Interestingly, the SAR unveiled from the 6-arylamino benzoxazinones was quite different from those of their parent compounds. For example, in contrast to the 6-aryl benzoxazinones, methyl substitution at the 1-position significantly increased the potency of 6-arylamino benzoxazinones. Several 6-arylamino benzoxazinones (e.g., 12, IC(50)=5.0 nM) had low nanomolar in vitro potency as PR antagonists in the T47D cell alkaline phosphatase assay. 相似文献
15.
Horchler CL McCauley JP Hall JE Snyder DH Craig Moore W Hudzik TJ Chapdelaine MJ 《Bioorganic & medicinal chemistry》2007,15(2):939-950
Multiparallel amenable syntheses of 6-methoxy-8-amino-4-oxo-1,4-dihydroquinoline-2-carboxylic acid-(4-morpholin-4-yl-phenyl)amides (I) and 4-amino-6-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)amides (II) which facilitate late-stage diversification at the 8-position of (I) and at the 4- and 8-positions of (II) are described. The resulting novel series were determined to contain potent 5HT(1B) antagonists. Preliminary SAR data are presented. 相似文献
16.
The synthesis of a series of novel 2-aryl substituted 4H-3,1-benzoxazin-4-ones and their evaluation as specific inhibitors of the Tissue Factor (TF)/Factor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory activities (IC50 values) in the range 0.17 to > 40 microM on the activation of Factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F, Cl and NO2 in the 2-aryl substituent. Different substitutions both electron-attracting and donating groups were allowed in the 5, 6, 7 and 8 positions. Several of the compounds showed a selectivity ratio towards FX and thrombin of > 50, thus being the first small molecules described as potential drugs for oral antithrombotic treatment without side effects such as bleeding which is observed especially with thrombin inhibitors. The best substituent pattern being the 2-aryl group substituted with: 2-F; 2,6-F2; or 2-FX; 6-Cl; together with electronegative substitution in the 5, 6, 7, or 8 positions. 2-Heteroaryl substituents like thienyl and furanyl were of low activity while some 2-(2-chloro-3-pyridyl) derivatives had inhibitory activity < 10 microM and a good selectivity. 相似文献
17.
Kumar R 《Journal of enzyme inhibition and medicinal chemistry》2003,18(3):273-278
The 5-halo-6-methoxy-5,6-dihydro derivatives of 5-[1-methoxy-2-halo(or 2,2-dihalo)ethyl]-2'-deoxyuridines (3-12) were synthesized and investigated as potential anti-herpes agents. These 5,6-dihydro derivatives were designed to act as potential prodrugs to 5-[1-methoxy-2-halo(or 2,2-dihalo)ethyl]-2'-deoxyuridines (2a-e), with enhanced metabolic stability, and ready conversion to the parent molecules. These 5,6-disubstituted-5,6-dihydro analogs are stable to E. coli thymidine phosphorylase, and undergo regeneration of the 5,6-olefinic bond to provide parent moieties (2a-e), upon incubation with glutathione at 37 degrees C. The compounds (3-12) themselves were found to be non-inhibitory against herpes simplex virus type-1 (HSV-1), likely due in part to their inability to undergo conversion to parent compounds in cell culture medium. 相似文献
18.
The synthesis of a series of 2-aryl substituted hetero annulated 1,3-oxazin-4-ones and their evaluation as specific inhibitors of the tissue factor (TF)/factor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory activities (IC50 values) in the range 0.64 to >40 μM on the activation of factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F and NO2 in the 2-aryl substituent. Some of the compounds showed a selectivity ratio towards FX and thrombin of >50, thus being similar in specificity to 2-aryl substituted 4H-3,1-benzoxazin-4-ones described as potential drugs for oral antithrombotic treatment without side effects, such as bleeding, which is observed especially with thrombin inhibitors. 相似文献
19.
Birch HL Buckley GM Davies N Dyke HJ Frost EJ Gilbert PJ Hannah DR Haughan AF Madigan MJ Morgan T Pitt WR Ratcliffe AJ Ray NC Richard MD Sharpe A Taylor AJ Whitworth JM Williams SC 《Bioorganic & medicinal chemistry letters》2005,15(23):5335-5339
The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II). 相似文献
20.
Some 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a-f and 5a-d) have been synthesized by cyclisation of 4-amino-5-[1-(6-methoxy-2-naphthyl)ethyl]-3-mercapto-(4H)-1,2,4-triazole (3) with various substituted aromatic acids and aryl/alkyl isothiocyanates, through a single step reaction. The target compounds were pharmacologically evaluated for their anti-inflammatory and analgesic potentials by known experimental models. Several of these showed significant activity. Very low ulcerogenic index was observed for potent compounds. 相似文献