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1.
Summary. A variety of N-[(4,6-diaryl-3-pyridinecarbonitrile)-2-yl] amino acid esters 2–4 were synthesized through the reaction of 2-bromo-3-pyridinecarbonitriles 1 with the appropriate -amino acid ester hydrochloride in refluxing dioxane in the presence of triethylamine as dehydrohalogenating agent. Similarly, N-glycylglycine analogues 5 were obtained through the reaction of 1 with the dipeptide ester. On the other hand, attempts were made towards the construction of amino acid derivatives 7 through the reaction of 1 with aqueous solution -amino acids 6 in refluxing pyridine, but were unsuccessful, and instead the unexpected 2-amino-3-pyridinecarbonitriles 8 were isolated. The fluorescence properties of the newly synthesized pyridines 2–5 were evaluated. Some of the prepared compounds show considerable antibacterial activity. 相似文献
2.
Hanson RL Shi Z Brzozowski DB Banerjee A Kissick TP Singh J Pullockaran AJ North JT Fan J Howell J Durand SC Montana MA Kronenthal DR Mueller RH Patel RN 《Bioorganic & medicinal chemistry》2000,8(12):2681-2687
Synthesis of lobucavir prodrug, L-valine, [(1S,2R,3R)-3-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methyl ester monohydrochloride (BMS 233866), requires regioselective coupling of one of the two hydroxyl groups of lobucavir (BMS 180194) with valine. Either hydroxyl group of lobucavir could be selectively aminoacylated with valine by using enzymatic reactions. N-[(Phenylmethoxy)carbonyl]-L-valine, [(1R,2R,4S)-2-(2-amino-6-oxo-1H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methyl ester (3, 82.5% yield), was obtained by selective hydrolysis of N,N′-bis[(phenylmethoxy)carbonyl]bis[L-valine], O,O′-[(1S,2R,3R)-3-(2-amino-6-oxo-1H-purin-9-yl)cyclobuta-1,2-diyl]methyl ester (1) with lipase M, and L-valine, [(1R,2R,4S)-2-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methyl ester monohydrochloride (4, 87% yield) was obtained by hydrolysis of bis[L-valine], O,O′-[(1S,2R,3R)-3-(2-amino-6-oxo-1H-purin-9-yl)cyclobuta-1,2-diyl]methyl ester, dihydrochloride (2), with lipase from Candida cylindracea. The final intermediate for lobucavir prodrug, N-[(phenylmethoxy)carbonyl]-L-valine, [(1S,2R,4R)-3-(2-amino-6-oxo-1H-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methyl ester (5), could be obtained by transesterification of lobucavir using ChiroCLEC™ BL (61% yield), or more selectively by using immobilized lipase from Pseudomonas cepacia (84% yield). 相似文献
3.
Moreno-Díaz H Villalobos-Molina R Ortiz-Andrade R Díaz-Coutiño D Medina-Franco JL Webster SP Binnie M Estrada-Soto S Ibarra-Barajas M León-Rivera I Navarrete-Vázquez G 《Bioorganic & medicinal chemistry letters》2008,18(9):2871-2877
N-(6-Substituted-1,3-benzothiazol-2-yl)benzenesulfonamide derivatives 1–8 were synthesized and evaluated for their in vivo antidiabetic activity in a non-insulin-dependent diabetes mellitus rat model. Several compounds synthesized showed significant lowering of plasma glucose level in this model. As a possible mode of action, the compounds were in vitro evaluated as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. The most active compounds (3 and 4) were docked into the crystal structure of 11β-HSD1. Docking results indicate potential hydrogen bond interactions with catalytic amino acid residues. 相似文献
4.
Zhu S Ruchelman AL Zhou N Liu AA Liu LF LaVoie EJ 《Bioorganic & medicinal chemistry》2005,13(24):6782-6794
The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC50 values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells. 相似文献
5.
Mitsuo Murata Satsuki Miyashita Chihiro Yokoo Musaharu Tamai Kazunori Hanada Katsuo Hatayama Takae Towatari Takeshi Nikawa Nobuhiko Katunuma 《FEBS letters》1991,280(2):307-310
A series of new epoxysuccinyl peptides were designed and synthesized to develop a specific inhibitor of cathepsin B. Of these compounds, N-(L-3-trans-ethoxycarbonyloxirane-2-carbonyl)-L-isoleucyl-L-proline (compound CA-030) and N-(L-3-trans-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline (compound CA-074) were the most potent and specific inhibitors of cathepsin B in vitro. The carboxyl group of proline and the ethyl ester group or n-propylamide group in the oxirane ring were necessary, the ethyl ester group or the n-propylamide group being particularly effective for distinguishing cathepsin B from other cysteine proteinases such as cathepsins L and H, and calpains. 相似文献
6.
A variety of 2-substituted-4,6-diaryl-3-pyridinecarboxamides 5 were synthesized through aromatic nucleophilic substitution reaction of secondary amines with 2-bromo analogues 4. The latter were obtained via bromination of 2-cyano-3,5-diaryl-5-oxo-N-substituted pentamides 3 in glacial acetic acid. Moreover, pentamide derivatives 3 were prepared through base-catalyzed Michael addition of cyanacetanilides 2 with 1,3-diaryl-2-propen-1-ones 1. Otherwise, reaction of 2-bromo-3-pyridinecarboxamides 4 with primary aromatic amines in refluxing pyridine afforded the corresponding 2-(arylamino)-3-pyridinecarboxamides 6 besides the unexpected 2-unsubstituted amino analogues 7. Antitumor properties of the synthesized pyridinecarboxamides utilizing 59 different human tumor cell lines, representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate as well as kidney, were screened. Many of the tested compounds show considerable in vitro antitumor properties especially 5c and 7a, which reveal moderate activities against most of the used human tumor cell lines. It has also been achieved that, all the tested nicotinamide derivatives reveal promising antitumor properties against MDA-MB-231/ATCC (breast cancer). 相似文献
7.
Sanjay Batra Amiya P. Bhaduri Bhawani S. Joshi Raja Roy Ashok K. Khanna Ramesh Chander 《Bioorganic & medicinal chemistry》2001,9(12):3093-3099
A new series of compounds belonging to N,N′- [bis (1-aryl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkanediamines (2–5a–f) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds namely 2c, 2e, 4c, 5b, 5c, 5e and 5f exhibit potent antioxidant activity. These compounds have also been evaluated for hypolipidemic activity. 相似文献
8.
T. A. Gudasheva V. P. Lezina E. P. Kir’yanova O. A. Deeva L. G. Kolik S. B. Seredenin 《Russian Journal of Bioorganic Chemistry》2013,39(3):259-267
The biologically active conformation of N-(6-phenylhexanoyl)glycyl-tryptophan amide (GB-115), a highly active cholecystokinin-4 retro dipeptide analogue with the anxiolytic activity, has been studied using the conformational analysis by 1H NMR spectroscopy in solution and the method of sterically restricted analogues. A study of the relationship between the preferable conformation in solution and the anxiolytic activity in the series of GB-115 derivatives showed that the biologically active conformation of this compound is the β-turn. Based on the data on the nuclear Overhauser effect 1H NMR spectroscopy, this structure was identified as the β-turn of type II. Subsequent synthesis and study of the pharmacological activity of novel sterically restricted analogues of dipeptide GB-115: (2S)-2-{(3R)-3-[(6-phenylhexanoyl)amino]-2-oxopyrrolidine-1-yl}-3-(1H-indole-3-yl)propionic acid ethyl ester, N-(6-phenylhexanoyl)glycyl-N α-methyltryptophan ethyl ester, (2S)-2-[(10,11-dihydro-5H-dibenzo[b, f]azepin-5-ylcarbonyl)amino]-3-(1H-indole-3-yl)propionic acid methyl ester, and (2S)-2-[({3-[(ethoxycarbonyl)amino]-10,11-dihydro-5H-dibenzo[b, f]azepin-5-yl}carbonyl)amino]-3-(1H-indole-3-yl)propionic acid methyl ester confirmed that the β-turn of type II is the active conformation of GB-115. 相似文献
9.
Indolones 4 and 5, and indolyl-aminoacids 6a-e, 7a-e, and 8a and 8b were designed by structural modification of lead compound 3. These compounds were tested on six tumor cell lines to determine the role of the azepinone ring and the N-phenyl substituent in the cytotoxicity of 3. Our results show that 4 and 5 have dramatically reduced cytotoxicity, due to the loss of the azepinone moiety of lead compound 3. In contrast, indolyl-aminoacids 6a, 7a, and 8a (N-(L)-cysteine ethyl ester derivatives) inhibited the proliferation of almost all cancer cell lines tested, even though they lack the azepinone ring. In addition, derivative 6c (N-(D)-alanine methyl ester group) was selectively cytotoxic to HCT-15 cells. Preliminary structure-activity relationship (SAR) studies with these compounds revealed the importance of the ethyl ester moiety on the amino acid moiety. Compounds 6a-e, 7a-e, and 8a and 8b were obtained in good yields by a catalytic Paal-Knorr reaction carried out under microwave irradiation using commercially available chiral amino esters or amino acids and 1,4-dicarbonyl compounds. 相似文献
10.
Jin-Yang Zhang Wen-Jun Xue Min Wang Wen Li Ru Dong Ming-Tao Li Li-Ping Sun 《化学与生物多样性》2021,18(5):e2100095
Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea ( 8b ) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 μM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea ( 8b ) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization. 相似文献
11.
Synthesis of a series of ganglioside GM3 analogs containing a deoxy-N-acetylneuraminic acid residue.
Akira Hasegawa Keisuke Adachi Masahiro Yoshida Makoto Kiso 《Carbohydrate research》1992,230(2):273-288
Ganglioside GM3 analogs containing 4-, 7-, 8-, and 9-deoxy-N-acetylneuraminic acids in the place of N-acetylneuraminic acid (Neu5Ac) have been synthesized. Glycosylation of 2-(trimethylsilyl)ethyl O-(6-O-benzoyl-β-
- galactopyranosyl)-(1 → 4)-2,6-di-O-benzoyl-β-
-glucopyranoside with the methyl 2-thioglycoside derivatives of the respective deoxy-N-acetylneuraminic acids, using dimethyl(methylthio)sulfonium triflate as a promoter, gave the four required 2-(trimethylsilyl)ethyl -sialosyl-(2 → 3b)-β-lactosides. These were converted via O-acetylation, selective removal of the 2-(trimethylsilyl)ethyl group, and subsequent imidate formation, into the corresponding -sialosyl-(2 → 3b)--lactose trichloroacetimidates 15, 17, 19, and 21. Glycosylation of (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol with 15, 17, 19, and 21 in the presence of boron trifluoride etherate afforded the expected β glycosides, which were transformed in good yields, via selective reduction of the azido group, coupling with octadecanoic acid, O-deacylation, and de-esterification, into the target compounds. 相似文献
12.
Vasdev N LaRonde FJ Woodgett JR Garcia A Rubie EA Meyer JH Houle S Wilson AA 《Bioorganic & medicinal chemistry》2008,16(9):5277-5284
Protein kinase A (PKA) is an important signal transduction target for drug development because it influences critical cellular processes implicated in neuropsychiatric illnesses such as major depressive disorder. The goal of the present study was to develop the first imaging agent for measuring the levels of PKA with positron emission tomography (PET). By rational derivatization of 5-isoquinoline sulfonamides, it was found that the introduction of a methyl group to the sulphonamidic nitrogen on the known PKA inhibitors N-(2-aminoethyl)isoquinoline-5-sulfonamide (H-9, 1) and N-(2-(4-bromocinnamylamino)ethyl)isoquinoline-5-sulfonamide (H-89, 2), (yielding N-(2-aminoethyl)-N-methyl-isoquinoline-5-sulfonamide (4) and N-(2-(4-bromocinnamylamino)ethyl)-N-methyl-isoquinoline-5-sulfonamide (5), respectively) does not appreciably reduce in vitro potency toward PKA. We have facilitated the synthesis of 4 by reacting isoquinoline-5-sulfonyl chloride with N-methylethylenediamine (20% yield). Several techniques were used to thoroughly characterize 4 including multi (1H, 13C and 15N) NMR spectroscopy and X-ray crystallography. Compound 4 and 1-(4-bromophenyl)-1-propen-3-yl bromide were reacted to produce 5 in 16% yield. Compound 2 was reacted with [11C]CH3I to prepare N-(2-(4-bromocinnamylamino) ethyl)-N-[11C]methyl-isoquinoline-5-sulfonamide ([11C]5), with a decay-corrected radiochemical yield of 32%, based on [11C]CO2. [11C]5 was produced with >98% radiochemical purity and 1130 mCi/μmol specific activity after 40 min (end of synthesis). Conscious rats were administered [11C] 5 and sacrificed at 5, 15, 30 and 60 min after injection. Radioactivity from all excised brain regions was <0.2%ID/g at all time points. The modest brain penetration of [11C]5 may limit its use for studying PKA in the central nervous system. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2014,24(13):2892-2896
Various substituted 4,6-diarylpyrimidin-2-amine (4), 4,6-diaryl-2-(heteroaryl)pyrimidine (6) and 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone (7) derivatives were synthesized in good yields using simple methodology. The synthesized compounds (4–7) were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Compounds 4a, 6b, 7b, and 7c exhibited significant anti-tubercular activity at MIC values 25, 25, 12.5 and 12.5 μM concentration. In vitro cytotoxicity data using non cancerous hepatic monocytes (THP-1) cells indicated that most active compounds 7b and 7c were safe as their MIC values were much lower than their cytotoxic values. 相似文献
14.
Farhanullah Sil D Tripathi BK Srivastava AK Ram VJ 《Bioorganic & medicinal chemistry letters》2004,14(10):2571-2574
A series of (3-pyridin-2-yl-thiouriedo)alkanoic acid esters (5a-j) have been synthesized by the reaction of pyridin-2-yl-dithiocarbamic acid methyl ester (2) and amino acid esters (4). Most of the synthesized compounds have been evaluated against glucose-6-phosphatase enzyme but only four compounds (5g-j) displayed significant inhibitory activity of the enzyme. 相似文献
15.
Alexander D. Ryabov Gregory M. Kazankov Sergey A. Kurzeev Pavel V. Samuleev Vladimir A. Polyakov 《Inorganica chimica acta》1998,280(1-2):57-61
The ester cleavage of R- and S-isomers N-CBZ-leucine p-nitrophenyl ester intermolecularly catalyzed by R- (a) and S-stereoisomers (b) of the Pd(II) metallacycle [Pd(C6H4C*HMeNMe2)Cl(py)] (3) follows the rate expression kobs = ko + kcat [3], where the rate constants kcat equal 25.8 ± 0.4 and 7.6 ± 0.5 dm3 mol−1 s−1 for the S- and R-ester, respectively, in the case of 3a, but are 5.7 ± 0.6 and 26.7 ± 0.5 dm3 mol−1 s−1 for the S- and R-ester, respectively, in the case of 3b (pH 6.23 and 25°C). Thus, the best catalysis occurs when the asymmetric carbons of the leucine ester and Pd(II) complex are R and S, or S and R configured, respectively. Molecular modeling suggests that the stereoselection results from the spatial interaction between the CH2CHMe2 radical of the ester and the -methyl group of 3. A hydrophobic/stacking contact between the leaving 4-nitrophenolate and the coordinated pyridine also seems to play a role. Less efficient intramolecular enantioselection was observed for the hydrolysis of N-t-BOC-S-metthionine p-nitrophenyl ester with R- and S-enantiomers of [Pd(C6H4C*HMeNMe2)Cl] coordinated to sulfur. 相似文献
16.
Xia J Song J Zhen L Zhang X Lei X Zheng L Wang Q Sun H 《Bioorganic & medicinal chemistry letters》2011,21(13):3894-3897
A series of novel 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3,3-diphenyl butyric acid derivatives were synthesized and evaluated for their antagonistic activity for endothelin-1-induced contraction in rabbit aorta. Within this series of compounds, 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-cyano-3,3-diphenylpropionic acid (4) displays comparable potency with ambrisentan (1), and warrants further investigation. 相似文献
17.
R. M. Kondratenko L. A. Baltina E. V. Vasil'eva Kh. M. Nasyrov R. M. Kireeva N. Zh. Baschenko S. M. Fridman L. A. Baltina Jr. G. A. Tolstikov 《Russian Journal of Bioorganic Chemistry》2004,30(2):148-153
New amino acid derivatives of glycyrrhizic acid and its methyl ester were selectively synthesized using active N-succinimide esters. The compounds with residues of glycine ethyl ester and alanine methyl and butyl esters increased the level of agglutinins and hemolysins in blood serum of mice two- to threefold in comparison with the control upon parenteral administration at a dose of 2 mg/kg for 14 days. 相似文献
18.
Gunnar Kampf Michael Willermann Eva Freisinger Bernhard Lippert 《Inorganica chimica acta》2002,330(1):179-188
A series of diplatinum(III) complexes derived from cis-(NH3)2PtII and the model nucleobase 1-methylcytosine (1-MeC) has been prepared and X-ray structurally characterized, all of which contain two anionic base ligands (1-MeC−) in a head–tail (ht) arrangement: ht-cis-[(ONO2)(NH3)2Pt(1-MeC−-N3,N4)2Pt(NH3)2(ONO2)](NO3)2·HNO3·3H2O (2b), ht-cis-[(NO2) (NH3)2 Pt(1-MeC−-N3,N4)2Pt(NH3)2(OH2)](ClO4)3·3.5H2O (3), ht-cis-[(OH2)(NH3)2Pt(1-MeC−-N3,N4)2Pt(NH3)2(OH2)](ClO4)4·H2O (4b), and ht-cis-[(9-EtGH-N7)(NH3)2Pt(1-MeC−-N3,N4)2Pt (NH3)2(9-EtGH-N7)](NO3)4·9H2O (7b) (9-EtGH=9-ethylguanine). Several other compounds, differing in the nature of the axial ligands, have been isolated and or observed in solution by 1H and 195Pt NMR spectroscopy. The chemistry of these diplatinum(III) compounds is dominated by facile substitution reactions of the axial ligands. Of particular interest in this context is the ready reaction of 2b or 3 with guanine nucleobases. Since similar compounds are not obtained with any of the other common nucleobases, 2b and 3 can be considered guanine-specific chemical probes. 相似文献
19.
Liangyu Zheng Suoqin Zhang Yan Feng Shugui Cao Jisheng Ma Lifang Zhao Gui Gao 《Journal of Molecular Catalysis .B, Enzymatic》2004,31(4-6):117-122
The enzyme (BSL2), a highly active lipase expressed from newly constructed strain of Bacillus subtilis BSL2, is used in the kinetic resolution of N-(2-ethyl-6-methylphenyl)alanine from the corresponding racemic methyl ester. Reaction conditions are optimized to enhance the enantioselectivity. The effects of various racemic alkyl esters, substrate concentration, operating temperature, pH of the aqueous medium and organic solvents on activity and enantioselectivity of BSL2 for kinetic resolution are also studied. A high enantiomeric ratio (E = 60.7) is reached in diisopropyl ether/water (10%, v/v) and the enantioselectivity is about 22-fold higher than that in pure buffered aqueous solution. The results show that the reaction medium greatly influences BSL2 reaction and its enantioselectivity in the hydrolysis of racemic methyl ester. 相似文献
20.
3-Aryl-4-formylsydnone 4'-phenylthiosemicarbazones (3a-d) and 3-aryl-4-formylsydnone thiosemicarbazones (3e-h), which are precursors of 3-aryl-4-heterocyclic sydnones, are prepared by the condensation of 3-aryl-4-formylsydnones (1a-d) with 4'-phenylthiosemicarbazide (2a) and thiosemicarbazide (2b), respectively. The thiosemicarbazones 3 reacted with cyclic reagents such as ethyl chloroacetate (4a), ethyl 2-chloroacetoacetate (4b) and 2-bromoacetophenone (4c) to produce heterocyclic substituted sydnone derivatives 5-7 that possess 4-oxo-thiazolidine and thiazoline groups. The antioxidant activity of synthesized compounds 5a-7h was evaluated. Among these compounds, 4-methyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydro-thiazole-5-carboxylic acid ethyl ester (6e-h) and 4-phenyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydro-thiazoles (7e-h) exhibit the potent DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity, comparable to that of vitamin E. 相似文献