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1.
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
2.
《Bioorganic & medicinal chemistry》2016,24(21):5197-5205
A series of arylidene N-alkoxydiketopiperazines was designed and stereoselectively synthesized via oxime-ether formation and intramolecular acylation. Possible cyclization and acid-catalyzed rearrangement-fragmentation mechanisms were discussed. The crystal structure of the novel diketopiperazine further confirmed the rearrangement mechanism. Most compounds exhibited antitumor activity. Several compounds were more potent against caspase-3. Specifically, compounds 6e, 6g, and 6f inhibited caspase-3 at IC50 values lying within the low micromolar range and demonstrated good selectivity. The binding modes of alkoxydiketopiperazines in the active center of caspase-3 were also discussed based on the molecular docking results. 相似文献
3.
Thed mutagenic activities of 11 N-methyl-N′-alkyl-N-nitrosoureas were tested on Samonellatyphimurium TA1535 and compared with chemical properties (alkylating activity and decompostion rate). In their relative mutagenicities the N-nitrosoureas that had a cyclic N′-alkyl group showed far more mutagenic activity than those having a chain N′-alkyl group. M(1-A)NU and M(2-A)NU, which had the most bulky N′-alkyl group in this series, exhibited lethal effects at high concentrations. The mutagenicity showed a small positive correlation with decomposition rates but not with alkylating activities on 4-(p-nitrobenzyl_prridine. The highest mutagenicity in this series was observed in N-methyl-N′-cyclobutyl-N-nitrosourea.These results suggest that, in this series of N-methyl-M′-alkyl-N-nitrosoureas, structural differences in the N′-alkyl groups had great significance in mutagenicity. 相似文献
4.
6-O-[2-(N,N-Dichlorocarbamoyl)ethyl]-1,2:3,4-di- O-isopropylidene-α-d-galactopyranose, a highly reactive pseudo-halogen, was conveniently prepared in 97% yield by addition of sodium hypochlorite to an aqueous acidic (pH <2) solution of 6-O-(2-carbamoylethyl)-1,2:3,4-di-O-isopropylidene-α-d-galactopyranose. Mild, reductive dechlorination or alkaline hydrolysis readily converted the nonpolar N,N-di-chloroamide sugar derivative into the corresponding water-soluble N-monochloroamide form. Hofmann rearrangement of the N-chloroamide group provides a synthetic route to novel binary sugar-derivatives having carbamoyl, ureylene, and allophanoyl linkages. Structural proof for the pseudo-halogens and their Hofmann-rearrangement products was obtained from i.r., 1H-n.m.r., mass-spectral, and chemical data. 相似文献
5.
《Inorganica chimica acta》1986,115(2):141-146
A series of new aromatic N-oxide ligands have been prepared by converting the 2-amino group of 2-aminopyridine N-oxide, 2-aminopicoline N-oxides and 2-amino-4,6-lutidine N-oxide into a urethane. Two series of copper(II) complexes have been prepared and characterized by their infrared, electronic and ESR spectra along with other physicochemical methods. One series has the stoichiometry [Cu(UOH)4](ClO4)2 and involves monodentate coordination via the N-oxide oxygen and the other series is prepared from copper(II) acetate and has the stoichiometry [Cu(UO)2]. In this latter series coordination occurs via the N-oxide oxygen and the deprotonated amino function. 相似文献
6.
Amitabh Jha Chandrani Mukherjee Ashok K. Prasad Virinder S. Parmar Manjula Vadaparti Umashankar Das Erik De Clercq Jan Balzarini James P. Stables Anuraag Shrivastav Rajendra K. Sharma Jonathan R. Dimmock 《Bioorganic & medicinal chemistry letters》2010,20(5):1510-1515
Several series of compounds containing the 1,4-dioxo-2-butenyl moiety have been prepared as candidate cytotoxins, including the methyl N-arylmaleamates, methyl N-arylfumaramates, and N-arylmaleimides. In addition, the N-arylisomaleimides were synthesized which are the structural isomers of N-arylmaleimides. These compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells. Methyl N-arylfumaramates showed the highest cytotoxic potencies and, in particular, methyl N-(3,4-dichlorophenyl)fumaramate is six times more potent than melphalan towards L1210 cells and is equipotent with this drug in the Molt 4/C8 assay. Electrophilicity of compounds under investigation was demonstrated by carrying out thiolation using model benzyl mercaptan on representative compounds. Methyl N-(3,4-dichlorophenyl)fumaramate and methyl N-(4-chlorophenyl)maleamate inhibited human N-myristoyltransferase, a possible molecular target, in high micromolar range. QSAR and molecular modeling revealed some correlations between different structural features of a number of the molecules and cytotoxic potencies. Methyl N-arylfumaramates were well tolerated in mice in comparison to the analogs in other series of compounds tested. The data obtained in this investigation affords guidelines for preparing new series of molecules with greater potencies. 相似文献
7.
Karla-Sue C. Marriott Andrew Z. Morrison Misty Moore Olarongbe Olubajo Leonard E. Stewart 《Bioorganic & medicinal chemistry》2012,20(23):6856-6861
Novel benzofuran-2-carboxamide ligands, which are selective for sigma receptors, have been synthesized via a microwave-assisted Perkin rearrangement reaction and a modified Finkelstein halogen-exchange used to facilitate N-alkylation. The ligands synthesized are the 3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides (KSCM-1, KSCM-5 and KSCM-11). The benzofuran-2-carboxamide structure was N-arylated and N-alkylated to include both N-phenyl and N-(3-(piperidin-1-yl)propyl substituents, respectively. These new carboxamides exhibit high affinity at the sigma-1 receptor with Ki values ranging from 7.8 to 34 nM. Ligand KSCM-1 with two methoxy substituents at C-5 and C-6 of the benzofuran ring, and Ki = 27.5 nM at sigma-1 was found to be more selective for sigma-1 over sigma-2. 相似文献
8.
Francavilla C Turtle ED Kim B O'Mahony DJ Shiau TP Low E Alvarez NJ Celeri CE D'Lima L Friedman LC Ruado FS Xu P Zuck ME Anderson MB Najafi RR Jain RK 《Bioorganic & medicinal chemistry letters》2011,21(10):3029-3033
Antimicrobial compounds with broad-spectrum activity and minimal potential for antibiotic resistance are urgently needed. Toward this end, we prepared and investigated a novel series of N-chloroheterocycles. Of the compounds examined, the N-chloroamine series were found superior over N-chloroamide series in regards to exhibiting high antimicrobial activity, low cytotoxicity, and long-term aqueous stability. 相似文献
9.
A series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The influence of each substituent on the affinity and selectivity for D1 and D2 dopaminergic receptors was studied. Moreover, N-alkyl salts of these tetrahydroisoquinolines were used as starting material to synthesize a series of new 1-aryl-7,8-dihydroxy 3-tetrahydrobenzazepines derivatives with electron-withdrawing substituents at C-2 position by the diastereoselective Stevens rearrangement. The structure-activity relationship of these compounds was explored to evaluate the effect of the functional group at C-2 in benzazepines and the modification in the aryl group at the isoquinoline C-1 position towards the affinity and selectivity for the mentioned receptors. The 1-aryl-6,7-dihydroxy tetrahydroisoquinoline 4c shows significant affinity towards D2 receptor, with Ki value of 31 nM. This significant affinity can be attributed to the presence of a thiomethyl group, and it is the most active 1-aryl-6,7-dihydroxy tetrahydroisoquinoline derivative reported to date. 相似文献
10.
Ruth Y. Schmitz Folke Skoog Adam Vincze Graham C. Walker Leslie H. Kirkegaard Nelson J. Leonard 《Phytochemistry》1975,14(7):1479-1484
The cytokinin activities of adenosine 3′,5′-monophosphate, N6,O2″-dibutyryladenosine 3′,5−'monophosphate, 8-bromoadenosine 3′,5′-monophosphate, N6-(Δ2-isopentenyl)adenosine 3′,5′-monophosphate, and N6-benzyladenosine 3′,5′-monophosphate were determined in the tobacco bioassay and compared with the activities of the corresponding non-cyclic nucleotides, nucleosides and bases of the N6-isopentenyl-substituted, N6-benzyl-substituted, 8-bromo-substituted, and unsubstituted adenine series. In each of these series the cytokinin activities in decreasing order were: bases ⪢ nucleosides ⪖ nucleotides > cyclic nucleotides. All members of the N6-isopentenyl- substituted and N6-benzyl-substituted series were highly active cytokinins, reaching maximum activity at concentrations of 1 μM or less, whereas, as expected, all members of the unmodified adenine series were inactive in the tested concentration ranges of up to 180 and 200 μM for adenosine and adenine, and 40 μM for the adenine nucleotides. Members of the 8-bromo-substituted adenine series were much weaker cytokinins than the N6-substituted adenine derivatives but showed activity in the same sequence starting at a concentration of about 5 μM. Thus, in the cases of 8-bromoadenosine 3′,5′-monophosphate and N6,O2′-dibutyryl-adenosine 3′,5′-monophosphate, both of which have been reported to promote cell division and growth of plant tissues, the cytokinin activity is related to the 8-bromo substituent and to the N6-butyryl substituent, respectively, rather than to the 3′,5′-cyclic monophosphate moiety. 相似文献
11.
The reaction of sodium D-glucuronate with a synthetic peptide, AcTyrLysGlyNH2 acetate, under physiological conditions, gave as major product the sodium salt of AcTyr-N-(D-arabino-5-carboxy-2,3,4,5-tetrahydroxy-1-pentenyl)-N-(D-arabino- 5-carboxy-3,4,5-trihydroxy-2-oxopentylidene)LysGlyNH2 (2). The structure was elucidated on the basis of p.m.r., 13C-n.m.r., i.r., and u.v. spectra, and pH titration. Compound 2 is the product of oxidation of the sodium salt of AcTyr-N,N-bis(D- arabino-5-carboxy-2,3,4,5-tetrahydroxy-1-pentenyl)LysGlyNH2, the bis-enol form of the di-D-fructuronic acid peptide obtained through the Amadori rearrangement. A new type of condensation that gives a product having a conjugated enol-keto-immonium group might take place when D-glucuronic acid reacts with peptides or proteins containing a lysine residue. 相似文献
12.
Anahid Omran Shakiba Eslamimehr A. Michael Crider William L. Neumann 《Bioorganic & medicinal chemistry letters》2018,28(10):1897-1902
A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3-hydroxyphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary binding pocket for enhancing affinity and selectivity for the D3 receptor. The N-alkyl analogues constitute a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary binding pocket of the D3 receptor. Enantiomeric 3-(3-hydroxyphenyl)pyrrolidine analogues were also prepared in order to test the chirality preference of the orthosteric binding site for this scaffold. Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of the homologous series. 相似文献
13.
A series of water-soluble polymers containing side chains derived from N-acryloyl-β-alanine, N-ethylacrylamide and N-[3-(N′,N′,N′-trimethylammonio)propyl] acylamide chloride has been prepared and characterized. A related series of insoluble gels was also prepared. Protein may be attached to these materials by means of amide bond formation between carboxyl groups on the polymers and amino groups of the protein; the preparation and characterization of conjugates formed with α-chymotrypsin are described. Polymers bearing negatively or positively charged side chains are attached to this enzyme at only a single amino acid and the integrity of the active site is largely preserved in these systems. The corresponding gels are not able to bind as much enzyme as are the soluble polymers and bound enzyme is less active in these cases. 相似文献
14.
Wei Feng Mavurapu Satyanarayana Yuan-Chin Tsai Angela A. Liu Leroy F. Liu Edmond J. LaVoie 《Bioorganic & medicinal chemistry》2009,17(7):2877-2885
2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine and a few of its 12-substituted analogs are active as TOP1-targeting agents. Studies were performed to further evaluate the potential of this series of non-camptothecin TOP1-targeting agents. The influence of a hydroxymethyl, formyl, N,N-dimethylaminomethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl), and 4-(N,N-dimethylamino)butyl substituent at the 12-position on TOP1-targeting activity and tumor cell growth was evaluated. In addition, the relative pharmacologic activities of the 12-carboxamide analog, as well as its N-methyl and N,N-dimethyl derivatives were assessed. 相似文献
15.
Specificity and stereospecificity of α-chymotrypsin 总被引:2,自引:2,他引:0
1. The optically pure p-nitrophenyl esters of the d and l enantiomers of N-acetyl-tryptophan, N-acetylphenylalanine and N-acetyl-leucine, and the p-nitrophenyl ester of N-acetylglycine, have been prepared. 2. These materials are all substrates of α-chymotrypsin, and the rates of deacylation of the corresponding acyl-α-chymotrypsins have been determined. 3. As the size of the amino acid side chain increases, the l series deacylate progressively faster than the N-acetylglycyl-enzyme, and the d series progressively more slowly. 4. The results are interpreted in terms of a three-locus model of the enzyme's active site, which accounts for the interrelationship between substrate specificity and stereospecificity observed. 5. The concepts of negative specificity and of specificity saturation are introduced. 相似文献
16.
The Notch (N) locus of Drosophila hydei and a series of its alleles and phenotypes are described. Some models are discussed to explain the opposite effects of some alleles on the structure of the wing, the neomorphic action of NAx over typical N alleles and the interaction with the mutation Costal-nick (Cnk). 相似文献
17.
We studied a collection of 746 chromosome rearrangements all induced by the activity of members of the P family of transposable elements in Drosophila melanogaster. The chromosomes ranged from simple inversions to complex rearrangements. The distribution of complex rearrangement classes was of the kind expected if each rearrangement came about from a single multibreak event followed by random rejoining of chromosome segments, as opposed to a series of two-break events. Most breakpoints occurred at or very near (within a few hundred nucleotide pairs) the sites of preexisting P elements, but these elements were often lost during the rearrangement event. There were also a few cases of apparent gain of P elements. In cases in which both breakpoints of an inversion retained P elements, that inversion was capable of reverting at high frequencies to the original sequence or something close to it. This reversion occurred with sufficient precision to restore the function of a gene, held-up-b, which had been mutated by the breakpoint. However, some of the reversions had acquired irregularities at the former breakpoints that were detectable either by standard cytology or by molecular methods. The revertants themselves retained the ability to undergo further rearrangements depending on the presence of P elements. We interpret these results to rule out the simplest hypotheses of rearrangement formation that involve cointegrate structures or homologous recombination. The data provide a general picture of the rearrangement process and its possible relationship to transposition. 相似文献
18.
《Mutation Research/Genetic Toxicology》1981,88(1):81-88
2-Naphthohydroxamic acid, 4-N-butoxyphenylacetohydroxamic acid, and their O-sulfonate, O-formate, O-acetate, and O-propionate derivatives were studied for cytotoxicity and sister chromatid exchange (SCE) induction in Chinese hamster ovary (CHO) cells. 2-Naphthylisocyanate, 2-aminonaphthalene (2 Lossen rearrangement products of the O-sulfonate derivative of 2-naphthohydroxamic acid), and N-methyl-2-naphthohydroxamic acid were also studied. All of these chemicals were cytotoxic and significantly increased SCE frequency, although there was a lack of correlation between these 2 effects. 2-Naphthylisocyanate and 2-aminonaphthalene were not as cytotoxic nor as active in inducing SCEs as the O-sulfonate ester of 2-naphthohydroxamic acid suggesting that the cytotoxicity and SCE induction of the latter are not due to its decomposition products. 相似文献
19.
A series of N-nicotinyl- and N-isonicotinyl-N′-(substituted) ureas were synthesized by a condensation of the appropriate amide with various alkyl or aryl isocyanates, and examined as potential antimetabolites of nicotinamide. No significant microbial toxicity was observed; however, several derivatives in the nicotinyl series proved to be toxic to fish, especially N-nicotinyl-N′-hexylurea which possessed a TL50 of 27 μg/ml. The toxicity was reversed by supplements of nicotinamide but not tryptophan, and may be due to the formation of an inactive NAD complex through the mediation of NADase. Evidence for this possibility is presented by the formation in vitro of an N-nicotinyl[7-14C]N′-ethylurea-NAD analog which was characterized through spectral, chemical, and chromatographic studies. 相似文献
20.
《Bioorganic & medicinal chemistry》2020,28(15):115578
Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HT1AR, 5-HT2AR, 5-HT6R and 5-HT7AR. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10 N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HT7AR and also had moderate 5-HT7AR affinity. Compounds from the C10 N-monosubstituted series generally lacked affinity for 5-HT2AR and 5-HT6R and showed strong affinity for 5-HT1A or 5-HT7AR. Compounds in this series that contained an N6-methyl group were up to 27-fold selective for 5-HT7AR over 5-HT1AR, whereas compounds with an N6-propyl substituent showed a reversal in this selectivity. The C10 benzofused aminothiazole analogues showed a similar binding profile as the C10 N-monosubstituted series i.e. strong affinity for 5-HT1AR or 5-HT7AR, with selectivity between the two receptors being similarly influenced by N6-methyl or N6-propyl substituents. Compounds 29 and 34a exhibit high 5-HT7AR affinity, excellent selectivity versus dopamine receptors and function as antagonists in 5-HT7AR cAMP-based assays. Compounds 29 and 34a have been identified as new lead molecules for further tool and pharmaceutical optimization. 相似文献