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1.
James R. Piper Balakrishnan Ramamurthy Cheryl A. Johnson Joseph A. Maddry Glenys M. Otter Francis M. Sirotnak 《Journal of heterocyclic chemistry》1995,32(4):1205-1212
5-Propyl-5-deaza and 5-butyl-5-deaza analogues of classical antifolates were synthesized by extensions of a previously reported general route which proceeds through 2,4-diamino-5-alkylpyrido[2,3-d]pyrimidine-6-carbonitrile intermediates followed by reductive condensation with diethyl N-4-(aminobenzoyl)-L-glutarnate to give diethyl esters of 5-alkyl-5-deazaaminopterin types. N10-Methyl derivatives, i.e., derivatives of 5-alkyl-5-deazamethotrexate, were also prepared by reductive methylation of the N10-H compounds. 5-Ethyl-5-deazamethotrexate was prepared using an alternative route through 6-(bromomethyl)-2,4-diamino-5-ethylpyrido[2,3-d]pyrimidine. These antifolates were evaluated for inhibition of dihydrofolate reductase (DHFR) from L1210 cells, their effect on L1210 and S180 tumor cell growth in culture, and carrier-mediated transport through L1210 cell membranes. Inhibitory effect on DHFR was lowered relative to methotrexate in 5-propyl-5-deazaaminopterin and 5-propyl-5-deazamethotrexate by 2- to 3-fold (Ki = 9.3 and 11.7 pM, respectively, vs. 4.3 pM for methotrexate) and by 17- to 18-fold in 5-butyl-5-deaza-aminopterin and 5-butyl-5-deazamethotrexate (Ki = 74 and 78 pM, respectively). Molecular modeling using graphics derived from human DHFR show the propyl and butyl compounds interacting with the enzyme in conformations that account for these slight decreases in binding. 相似文献
2.
The phosphonic acids 3 and 4 were prepared to compare their inhibitory activity on Vibrio cholerae sialidase with the one of the corresponding N-acetyl-2-deoxyneuraminic acids 5 and 6 . Thus, hydrogenation and benzylation of methyl N-acetyl-2,3-didehydro-2-deoxyneuraminate (1MeNeu2en5Ac; 7) gave a mixture of the fully O-benzylated benzyl and methyl esters 9 and 10 , the partially O-benzylated benzyl and methyl esters 11 and 12 , and the fully O-and N-benzylated benzyl and methyl esters 13 and 14 (Scheme 1). Transesterification of 9 to 10 and hydrolysis of 10 gave the acid 15 . Oxidative decarboxylation of 15 with Pb(OAc)4 gave a 1:9 mixture of the α-and β-D-glycero-D-galacto-acetates 16 and 17 . Phosphonoylation of 17 with P(OMe)3 and Me3SiOTf gave a 1.3:1 mixture of the phosphonates 18 and 19 , which were deprotected to give the (4-acetamido-2,4-dideoxy-D-glycero-α-and β-D-galacto-octopyranosyl)phosphonic acids 3 and 4 , respectively. The acid 6 was obtained by epimerization of the tert-butyl ester 23 with lithium N-cyclohexylisoproylamide and deprotection. The phosphonic acids 3 (Ki 5.5 10-5 M) and 4 (Ki 2.3.10?4 M ) are stronger inhibitors of Vibrio cholerae sialidase than the anomeric N-acetyl-2-deoxyneuraminic acids 5 (Ki 2.3 10?3 M ) and 6 . Both 3 and 4 inhibit the Vibrio cholerae sialidase, while only the carboxylic acid 5 , possessing an equatorial COOH group is an inhibitor. 相似文献
3.
Aurore Gandubert Konstantin A. Brylev Thi Thuong Nguyen Nikolai G. Naumov Noboru Kitamura Yann Molard Régis Gautier Stéphane Cordier 《无机化学与普通化学杂志》2013,639(10):1756-1762
The reaction of K4[Re6Sei8(OH)a6] · 8H2O with NaN3 in water results in the formation of [Re6Sei8(N3)a]4– units that crystallize with K+ and H2O to form K4[Re6Sei8(N3)a6] · 4H2O [P21/c (N°14), a = 9.0595(3) Å, b = 13.2457(4) Å, c = 13.2040(5) Å, β = 94.472(1)°]. In the solid state, the unit is characterized by N3 linear groups forming bond angles of roughly 120° with the Re6 cluster. The positions of the νas and νsy bands as well as N–N–N deformation modes of the N3 groups are discussed. Luminescence properties of the [Re6Sei8(N3)a]4– unit were measured in the solid state and in an acetonitrile solution. The redox potential of the [Re6Sei8(N3)a]4–/[Re6Sei8(N3)a]3– system was measured in acetonitrile. Experimental results were analyzed in the light of density functional theory calculations. 相似文献
4.
Synthesis and biological activities of tetrahydroquinazoline analogs of aminopterin and methotrexate
Aleem Gangjee Nurulain Zaveri Sherry F. Queener Roy L. Kisliuk 《Journal of heterocyclic chemistry》1995,32(1):243-247
(6R,6S)-5,8-Dideaza-5,6,7,8-tetrahydroaminopterin ( 1 ) and (6R,6S)-5,8-dideaza-5,6,7,8-tetrahydromethotrexate ( 2 ) were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Cyclohexanone-4-carboxaldehyde dimethyl acetal, a key intermediate [10] was synthesized from cyclohexane-1,4-dione monoethylene ketal, which was converted via a Wittig reaction to its exocyclic 4-methylene derivative which in turn, was converted to the 4-aldehyde via a hydroboration-oxidation sequence. Selective protection of the 4-aldehyde as the dimethylacetal and cyclization with dicyandiamide afforded the 6-dimethylacetal of 2,4-diamino-5,6,7,8-tetrahydroquinazoline. Protection of the 2,4-diamino moieties and selective deprotection of the 6-aldehyde followed by reductive amination with p-aminobenzoyl-L-glutamate afforded 2,4-bisacetamido-5,8-dideaza-5,6,7,8-tetrahydroaminopterin ( 11 ). Deprotection of 11 afforded 1 . Compound 2 was obtained from 11 via N10-methylation and deprotection. The N10-methyl analogue 2 was 2–10 fold more potent than 1 as an inhibitor of various DHFRs. In the in vitro preclinical screening program of the National Cancer Institute, compound 2 inhibited the growth of eighteen of the twenty nine tumor cell lines in culture at a GI50 > 1.0 × 10?8 M. 相似文献
5.
Andre Rosowsky Henry Bader Joel E. Wright Richard G. Moran 《Journal of heterocyclic chemistry》1994,31(5):1241-1250
1-[4-(tert-Butyloxycarbonyl)phenyl]-3-pyrrolidinone and 1-[3-(tert-butyloxycarbonyl)phenyl]-4-piperidinone were condensed with ethyl cyanoacetate or malononitrile to form ylidene derivatives, which were then subjected sequentially to (i) catalytic or chemical reduction, (ii) condensation with guanidine, and (iii) gentle tri-fluoroacetic acid treatment to obtain 3-(2,4-diamino-6(5H)-oxopyrimidin-5-yl)-1-(4-carboxyphenyl)pyrrolidine ( 27 ), 4-(2,4-diamino-6(5H)-oxopyrimidin-5-yl)-1-(carboxyphenyl)piperidine ( 35 ), and 3-(2,4,6-triaminopyrimidin-5-yl)-1-(carboxyphenyl)pyrrolidine ( 40 ). Condensation of 27, 35 , and 40 with diethyl or di-tert-butyl L-glutamate followed by removal of the ester groups yielded N-[4-[3-(2,4-diamino-6(5H)-oxopyrimidin-5-yl)pyr-rolidino]benzoyl]-L-glutamic acid ( 13 ), N-[4-[4-(2,4-diamino-6-(5H)-oxopyrimidin-5-yl)piperidino]benzoyl]-L-glutamic acid ( 14 ), and N-[4-[3-(2,4,6-triaminopyrimidin-5-yl)pyrrolidino]benzoyl]-L-glutamic acid ( 15 ). Compounds 13 and 14 may be viewed as 5-deaza-7-desmethylene analogues of 5,10-methylene-5,6,7,8-tetrahydrofolic and 5,10-ethylene-5,6,7,8-tetrahydrofolic acid, respectively. Compounds 13 and 15 were good substrates for mouse liver folylpolyglutamate synthetase, with Km values of 20 and 18 μM and a relative first-order rate constant Vmax/Km of 2.2 (aminopterin = 1.0). In contrast, 14 was a very poor substrate, with a Km of 490 μM and a relative Vmax/Km of 0.052. As expected from its structure, 15 was a dihydrofolate reductase inhibitor. However its potency was unexceptional (IC50 = 1.2 μM). Compounds 13 and 14 were inactive at concentrations of up to 100 μM, and likewise showed no activity against thymidylate synthase or glycinamide ribotide formyltransferase, two other key enzymes of folate-mediated one-carbon metabolism. Compound 15 was moderately active as an inhibitor of the growth of cultured tumor cells (SCC25 human squamous cell carcinoma), with an IC50 of 0.37 μM (72 hour exposure). By comparison the IC50 of aminopterin was 0.0069 μM. Thus, even though 15 is a good folylpolyglutamate synthetase substrate, the deep-seated skeletal changes embodied in this structure are unfavorable for DHFR binding and may also be unfavorable for transport into cells. 相似文献
6.
Chester M. Himel Richard T. Mayer Larry L. Cook 《Journal of polymer science. Part A, Polymer chemistry》1970,8(8):2219-2230
Fluorescent probes which are active-site-directed, reversible, competitive inhibitors of serum cholinesterase (ChE) enzymes have been designed and synthesized. Reversible inhibitors of enzyme active sites have a unique importance when they act as fluorescent probes, allowing fluorescence spectroscopic detection of conformation changes and activesite dynamics. 5-Dimethylamino-naphthalene-1-sulfonamido-N,N-dimethyl-n-propyl-amine and its aliphatic quaternary derivative are fluorescent probes for serum cholinesterase. The quaternary probe forms complexes with acetylcholinesterase (AChE). The dissociation constants Kd for the two probes with serum ChE are 6.0 × 10?7 and 6.5 × 10?7M. The inhibition constants Ki are 3.1 × 10?6 and 6.3 × 10?6M from the slopes of Lineweaver-Burk plots. The Michelis constant Km for the enzyme was 8.8 × 10?4M. 相似文献
7.
Hyungphil Chun Ivan Bernal 《Acta Crystallographica. Section C, Structural Chemistry》2001,57(1):33-35
The reaction of Co(acac)3 with N-(2-aminoethyl)-1,3-propanediamine in the presence of NaNO2 results in the preparation of an unexpected dinitrocobalt(III) compound, (11-amino-4-methyl-5,8-diazaundeca-2,4-dien-2-olato-κ4N5,8,11,O)-dinitrocobalt(III), [Co(C10H20N3O)(NO2)2], containing the tetradentate anion of 11-amino-4-methyl-5,8-diazaundeca-2,4-dien-2-ol. Two isomers of the compound were obtained by recrystallization of the crude product. In one isomer, the two trans nitro groups are staggered, and in the other they are eclipsed. 相似文献
8.
Aleem Gangjee Anil Vasudevant Roy L. Kisliuk 《Journal of heterocyclic chemistry》1997,34(6):1669-1676
Classical inhibitors of thymidylate synthase such as Nl0-propargyl-5,8-dideazafolic acid (1), N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid (ZD1694, 2) and N-[2-amino-4-oxo-3,4-dihydro(pyrrolo[2,3-d]pyrintidin-5-yl)ethylbenzoyl]-L-glutamic acid (LY231514, 3) while potent, suffer from a number of potential disadvantages, such as impaired uptake due to an alteration of the active transport system required for their cellular uptake, as well as formation of long acting, non-effluxing polyglutamates via the action of folylpolyglutamate synthetase, which are responsible for toxicity. To overcome some of the disadvantages of classical inhibitors, there has been considerable interest in the synthesis and evaluation of nonclassical thymidylate synthase inhibitors, which could enter cells via passive diffusion. In an attempt to elucidate the role of saturation of the B-ring of non-classical, quinazoline antifolate inhibitors of thymidylate synthase, analogues 7-17 were designed. Analogues 13-17 which contain a methyl group at the 7-position, were synthesized in an attempt to align the methyl group in an orientation which allows interaction with tryptophan-80 in the active site of thymidylate synthase. The synthesis of these analogues was achieved via the reaction of guanidine with the appropriately substituted cyclohexanone-ketoester. These ketoesters were in turn synthesized via a Michael addition of the appropriate thiophenol with 2-carbethoxycyclohexen-1-one or 5-methyl-2-carbethoxycyclo-hexen-1-one to afford a mixture of diastereomers. The most inhibitory compound was the 3,4-dichloro, 7-methyl derivative 17 which inhibited the Escherichia coli and Pneumocystis carinii thymidylate syntheses 50% at 5 × 105 M. Our results confirm the importance of the 7-CH3 group and electron withdrawing groups on the aromatic side chain for thymidylate synthase inhibition. 相似文献
9.
A series of 7‐fluorinated 7‐deazapurine 2′‐deoxyribonucleosides related to 2′‐deoxyadenosine, 2′‐deoxyxanthosine, and 2′‐deoxyisoguanosine as well as intermediates 4b – 7b, 8, 9b, 10b , and 17b were synthesized. The 7‐fluoro substituent was introduced in 2,6‐dichloro‐7‐deaza‐9H‐purine ( 11a ) with Selectfluor (Scheme 1). Apart from 2,6‐dichloro‐7‐fluoro‐7‐deaza‐9H‐purine ( 11b ), the 7‐chloro compound 11c was formed as by‐product. The mixture 11b / 11c was used for the glycosylation reaction; the separation of the 7‐fluoro from the 7‐chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N‐halogenosuccinimides ( 11a → 11c – 11e ). Nucleobase‐anion glycosylation afforded the nucleoside intermediates 13a – 13e (Scheme 2). The 7‐fluoro‐ and the 7‐chloro‐7‐deaza‐2′‐deoxyxanthosines, 5b and 5c , respectively, were obtained from the corresponding MeO compounds 17b and 17c , or 18 (Scheme 6). The 2′‐deoxyisoguanosine derivative 4b was prepared from 2‐chloro‐7‐fluoro‐7‐deaza‐2′‐deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pKa values of the halogenated nucleosides were determined (Table 3). 13C‐NMR Chemical‐shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7‐halogen substituents (Fig. 3). In aqueous solution, 7‐halogenated 2′‐deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1). 相似文献
10.
C. E. Nordman 《Journal of Chemical Sciences》1983,92(4-5):329-334
The problem of reliably detecting a known set ofn vectors of weight wi embedded in a heavily overlapped Patterson function Pi is investigated by a Monte-Carlo simulation based on searches of computer-generated random number sequences. Several formulations
of the criterion of fit were compared. All were found to improve when the criterion was based on a subset of m “worst fitting”
vectors as judged by a low value of (Pi/wi). The best criteria were Σ
i = 1
m
(wiPi)/Σ
i =1
m
w
i
2
, withm ≈ (0.4−0.5)n, Σ
i=
1/m
wi, withm ≈ 0.3n, and Σ
i=1
m
(wiPi) withm ≈ 0.7n. In each case the detectability of the embedded vectors wi increases with increasing Σ(w) in relation to Σ(N), the standard deviation of the overlaid noise. A related simulation of a Patterson search for non-crystallographic symmetry
shows that for a given size of the non-crystallographically symmetric region, the detectability increases with the order (2-fold,
6-fold, 12-fold) of the symmetry. 相似文献
11.
Musa Özil Fatih İslamoğlu Emre Menteşe Bahittin Kahveci 《Helvetica chimica acta》2010,93(10):1967-1974
The novel 4‐amino‐ or 4‐aryl‐substituted 2,4‐dihydro‐5‐[(4‐trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones 3a – 3g were synthesized by reaction of N‐(ethoxycarbonyl)‐4‐(trifluoromethyl)benzenehydrazonic acid ethyl ester ( 2 ) and primary amines or hydrazine by microwave irradiation. Compounds 3a – 3g were potentiometrically titrated with tetrabutylammonium hydroxide (Bu4NOH) in four nonaqueous solvents, i.e., iPrOH, tBuOH, MeCN, and N,N‐dimethylformamide (DMF). Also half‐neutralization potential values and the corresponding pKa values were determined in all cases. 相似文献
12.
Alexander A. Titov Rosa Purgatorio Arina Y. Obydennik Anna V. Listratova Tatiana N. Borisova Modesto de Candia Marco Catto Cosimo D. Altomare Alexey V. Varlamov Leonid G. Voskressensky 《Molecules (Basel, Switzerland)》2022,27(19)
Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6–C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R3 = CH2OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (Ki = 4.9 μM), equipotent with the corresponding 6-phenyl derivative 3n (R3 = Ph, Ki = 4.5 μM), but 90-fold more water-soluble. 相似文献
13.
T. Daniel Thangadurai Suhee Jeong Sunghak Yun Sangsu Kim Changdae Kim Yong-Ill Lee 《Microchemical Journal》2010,95(2):235-239
The known compounds N-(2,4-dinitrophenyl)-4,4′-bipyridinium (2,4-DNPhQ+), N-phenyl-4,4′-bipyridinium (PhQ+) and N-(4-acetylphenyl)-4,4′-bipyridinium (4-AcPhQ+) have been used to prepare a series of ruthenium complexes of the type [RuCl(CO)(PPh3)2(L)] (where, L = 2,4-DNPhQ+ or PhQ+ or 4-AcPhQ+). The latter complexes reacted with sulphur derivative to give [RuCl(CO)(PPh3)2(L)(L′)] (where, L′ = thio-9-xanthone). These new ruthenium complexes display intense, visible metal-to-ligand charge-transfer (MLCT) absorptions, due to dπ(Ru) → π*(pyridinium) excitations. The MLCT energy decreases as the acceptor strength increases in the order PhQ+ < 4-AcPhQ+ < 2,4-DNPhQ+. The new ruthenium complexes have been characterized by using standard analytical and spectroscopic techniques. Fluorescence and antibacterial activity of the ligands and appropriate complexes has also been carried out. 相似文献
14.
Trieu-Tien Thai Bruno Therrien Georg Süss-Fink 《Journal of organometallic chemistry》2009,694(25):3973-3981
Two families of arene ruthenium oxinato complexes of the types [(η6-arene)Ru(η2-N,O-L)Cl] and [(η6-arene)Ru(η2-N,O-L)(OH2)]+ have been synthesized from the dinuclear precursors [(η6-arene)RuCl2]2 (arene = para-cymeme or hexamethylbenzene) and the corresponding oxine LH (LH = 8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline, 5,7-dichloro-8-hydroxyquinoline, 5-nitro-8-hydroxyquinoline, 5,7-dimethyl-8-hydroxyquinoline, 5,7-dichloro-2-methyl-8-hydroxyquinoline). The molecular structures of the neutral chloro complexes [(η6-C6Me6)Ru(η2-N,O-L)Cl] (LH = 8-hydroxyquinoline, 5,7-dichloro-2-methyl-8-hydroxyquinoline) and [(η6-MeC6H4Pri)Ru(η2-N,O-L)Cl] (LH = 5,7-dichloro-2-methyl-8-hydroxyquinoline) as well as those of the cationic aqua derivatives [(η6-MeC6H4Pri)Ru(η2-N,O-L)(OH2)]+ (LH = 8-hydroxyquinoline, 5,7-dimethyl-8-hydroxyquinoline), isolated as the tetrafluoroborate salts, show in all cases a piano-stool arrangement with the arene ligand, the chelating oxinato ligand and the chloro or the aqua ligand surrounding the ruthenium center in a pseudo-tetrahedral fashion. The analogous reaction of [(η6-MeC6H4Pri)RuCl2]2 with other N,O-chelating ligands such as 2-pyridinemethanol or tetrahydrofurfurylamine did not give the expected analogs but resulted in the formation of the complexes [(η6-MeC6H4Pri)Ru(η2-NC5H4CH2OH)Cl]+ and [(η6-MeC6H4Pri)Ru(η1-NHCH2C4H3O)Cl2]. The neutral and cationic complexes of the types [(η6-arene)Ru(η2-N,O-L)Cl] and [(η6-arene)Ru(η2-N,O-L)(OH2)]+ have been found to catalyze the hydrogenation of carbon dioxide to give formate in alkaline aqueous solution with catalytic turnovers up to 400. 相似文献
15.
Waldemar Gottardi 《Monatshefte für Chemie / Chemical Monthly》1982,113(3):313-322
The equilibrium concentrations of all reaction products emerging from the hydrolysis ofN-bromo compounds in the presence of bromide and thereby also the hydrolysis constants (K
1) have been calculated from the absorbance at 392.8 nm, thepH-value and the initial concentrations of theN-bromo compound and the bromide. The following compounds have been investigated:N-bromo-succinimide:K
1=2.2·10–6, 1,3-dibromo-5,5-dimethylhydantoin:K
1=1.7·10–5,N-bromoacetamide:K
1=1.8·10–6,N-bromo-monochloroacetamide: 5.2·10–6,N-bromo-dichloroacetamide:K
1=8.9·10–6 andN-bromo-trichloroacetamide:K
1=1.8·10–5. The precision of the method, which is mainly suited for weak hydrolizingN-bromocompounds (K
1<10–4) are discussed and the overall error of the calculated values was found to be in the range of ±5–12%. The reactivities in aqueous solution of the most frequently usedN-bromo compounds are compared by means of the calculated HOBr equilibrium concentrations. The differences to be expected on the basis of the latters are at concentrations >10–5 mol/l rather great, while they can be neglected in very dilute solutions (-10–6 mol/l). 相似文献
16.
Cationic Five‐Coordinate Bis(guanidinato)silicon(IV) Complexes with SiN4El Skeletons (El=S,Se): “Heterolytic Activation” of S−S and Se−Se Bonds
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Felix M. Mück Johannes A. Baus Dr. Christian Burschka Prof. Dr. Reinhold Tacke 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(17):5830-5834
The donor‐stabilized silylene [iPrNC(NiPr2)NiPr]2Si ( 2 ) reacts with PhEl?ElPh (El=S, Se) to form the respective cationic five‐coordinate bis(guanidinato)silicon(IV) complexes {[iPrNC(NiPr2)NiPr]2SiSPh}+PhS? ( 4 ) and {[iPrNC (NiPr2)NiPr]2SiSePh}+PhSe? ( 5 ). Compounds 4 and 5 were characterized by crystal structure analyses and NMR spectroscopic studies in the solid state. 相似文献
17.
Stepan S. Basok Igor A. Schepetkin Andrei I. Khlebnikov Anatoliy F. Lutsyuk Tatiana I. Kirichenko Liliya N. Kirpotina Victor I. Pavlovsky Klim A. Leonov Darya A. Vishenkova Mark T. Quinn 《Molecules (Basel, Switzerland)》2021,26(8)
Synthetic and natural ionophores have been developed to catalyze ion transport and have been shown to exhibit a variety of biological effects. We synthesized 24 aza- and diaza-crown ethers containing adamantyl, adamantylalkyl, aminomethylbenzoyl, and ε-aminocaproyl substituents and analyzed their biological effects in vitro. Ten of the compounds (8, 10–17, and 21) increased intracellular calcium ([Ca2+]i) in human neutrophils, with the most potent being compound 15 (N,N’-bis[2-(1-adamantyl)acetyl]-4,10-diaza-15-crown-5), suggesting that these compounds could alter normal neutrophil [Ca2+]i flux. Indeed, a number of these compounds (i.e., 8, 10–17, and 21) inhibited [Ca2+]i flux in human neutrophils activated by N-formyl peptide (fMLF). Some of these compounds also inhibited chemotactic peptide-induced [Ca2+]i flux in HL60 cells transfected with N-formyl peptide receptor 1 or 2 (FPR1 or FPR2). In addition, several of the active compounds inhibited neutrophil reactive oxygen species production induced by phorbol 12-myristate 13-acetate (PMA) and neutrophil chemotaxis toward fMLF, as both of these processes are highly dependent on regulated [Ca2+]i flux. Quantum chemical calculations were performed on five structure-related diaza-crown ethers and their complexes with Ca2+, Na+, and K+ to obtain a set of molecular electronic properties and to correlate these properties with biological activity. According to density-functional theory (DFT) modeling, Ca2+ ions were more effectively bound by these compounds versus Na+ and K+. The DFT-optimized structures of the ligand-Ca2+ complexes and quantitative structure-activity relationship (QSAR) analysis showed that the carbonyl oxygen atoms of the N,N’-diacylated diaza-crown ethers participated in cation binding and could play an important role in Ca2+ transfer. Thus, our modeling experiments provide a molecular basis to explain at least part of the ionophore mechanism of biological action of aza-crown ethers. 相似文献
18.
Terence R. Jones Richard F. Betteridge David R. Newell Ann L. Jackman 《Journal of heterocyclic chemistry》1989,26(5):1501-1507
The synthesis of N3-methyl-10-propargyl-5,8-dideazafolic acid ( 1b ) is described. Ring closure of methyl-5-methylanthranilate with chloroformamidine hydrochloride gave a high yield of pure 2-amino-4-hydroxy-6-methylquinazoline treatment of which with iodomethane/sodium hydroxide provided the corresponding 3-methylquinazoline (6) which was converted to its 2-pivaloylamino derivative. This synthetic approach, next involving functionalisation of the 6-methyl group, was not further pursued because of difficulty encountered in removing the pivaloyl group. Methyl 5-methylanthranilate was treated with p-toluenesulfonyl chloride and the product then N-methylated. The tosyl group was cleaved with hydrogen bromide/phenol and the resulting methylamine ring-closed with chloroformamidine hydrochloride to provide 2-amino-1,4-dihydro-1,6-dimethyl-4-oxoquinazoline ( 11 ). The 2-pivaloylamino derivative of 11 was prone to hydrolytic deamination when attempts were made to remove the pivaloyl group and further elaboration of this heterocycle, with the intention of obtaining N1-methyl-10-propargyl-5,8-dideazafolic acid was, too, not attempted. Di-t-butyl N-(4-propargylamino)benzoyl)-L-glutamate was therefore prepared and coupled with 2-amino-6-bromomethyl-4-hydroxyquinazoline hydrobromide. The resulting antifolate diester was N-monomethylated. Removal of the t-butyl groups with trifluoracetic acid afforded the target compound 1b and its structure was proved by degradation to the quinazoline 6 . Its IC50 for L1210 thymidylate synthase (TS) was 26 μM; the control value for 10-propargyl-5,8-dideazafolic acid ( 1a ) was 0.02 μM. Thus the substitution of the lactam hydrogen in 1a by a methyl group reduced the TS inhibition by 1300-fold. Compound 1b was poorly cytotoxic to L1210 cells in culture (ID50 > 100 μM). An unperturbed lactam group in this class of antifolate is important for binding to TS. 相似文献
19.
Dr. Pei Jen Tiong Laura R. Groom Dr. Eric Clot Prof. Dr. Philip Mountford 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(13):4198-4216
We report a detailed study of the reactions of the Ti?NNCPh2 alkylidene hydrazide functional group in [Cp*Ti{MeC(NiPr)2}(NNCPh2)] ( 8 ) with a variety of unsaturated and saturated substrates. Compound 8 was prepared from [Cp*Ti{MeC(NiPr)2}(NtBu)] and Ph2CNNH2. DFT calculations were used to determine the nature of the bonding for the Ti?NNCPh2 moiety in 8 and in the previously reported [Cp2Ti(NNCPh2)(PMe3)]. Reaction of 8 with CO2 gave dimeric [(Cp*Ti{MeC(NiPr)2}{μ‐OC(NNCPh2)O})2] and the “double‐insertion” dicarboxylate species [Cp*Ti‐{MeC(NiPr)2}{OC(O)N(NCPh2)C(O)O}] through an initial [2+2] cycloaddition product [Cp*Ti{MeC(NiPr)2}{N(NCPh2)C(O)O}], the congener of which could be isolated in the corresponding reaction with CS2. The reaction with isocyanates or isothiocyanates tBuNCO or ArNCE (Ar=Tol or 2,6‐C6H3iPr2; E=O, S) gave either complete NNCPh2 transfer, [2+2] cycloaddition to Ti?Nα or single‐ or double‐substrate insertion into the Ti?Nα bond. The treatment of 8 with isonitriles RNC (R=tBu or Xyl) formed σ‐adducts [Cp*Ti{MeC(NiPr)2}(NNCPh2)(CNR)]. With ArF5CCH (ArF5=C6F5) the [2+2] cycloaddition product [Cp*Ti{MeC(NiPr)2}{N(NCPh2)C(ArF5)C(H)}] was formed, whereas with benzonitriles ArCN (Ar=Ph or ArF5) two equivalents of substrate were coupled in a head‐to‐tail manner across the Ti?Nα bond to form [Cp*Ti{MeC(NiPr)2}{N(NCPh2)C(Ar)NC(Ar)N}]. Treatment of 8 with RSiH3 (R=aryl or Bu) or Ph2SiH2 gave [Cp*Ti{MeC(NiPr)2}{N(SiHRR′)N(CHPh2)}] (R′=H or Ph) through net 1,3‐addition of Si? H to the N? N?CPh2 linkage of 8 , whereas reaction with PhSiH2X (X=Cl, Br) led to the Ti?Nα 1,2‐addition products [Cp*Ti{MeC(NiPr)2}(X){N(NCPh2)SiH2Ph}]. 相似文献
20.
The influence of a substituent at the hydroximo function of the lactam analogue 1 on the inhibition of β- and α-glucosidases is evaluated. In contrast to 1 , the O-alkyl oximes 5 , 6 , 9 , and 10 are selective inhibitors of β-glucosidases. Alkylation of the D -gluconohydroximo-1,5-lactam 19 with the triflate 12 , or condensation of the thiogluconolactam 20 with the hydroxylamines 14 or 18 afforded the benzylated cellobioside analogues 21 and 23 , respectively. The O-alkyl oximes 33 and 39 were prepared similarly (Scheme 3). Deprotection afforded the cellobioside analogues 5 and 6 , and the O-alkyl oximes 9 and 10 . The lactam O-alkyl oximes 5 , 6 , 9 , and 10 are strong inhibitors of the β-glucosidase from C. saccharolyticum (IC50=0.3 – 8 μM ) and, with exception of the dodecyl analogue 9 (IC50=2 μM ), moderate-to-weak inhibitors of β-glucosidases from sweet almond (IC50=60 – 1000 μM ; see Table). In contrast to the strong inhibition of α-glucosidase from brewer's yeast by 1 (Ki=2.9 μM ), the ethers 5 , 6 , and 10 are weak inhibitors of this enzyme (IC50 between 2500 and >5000 μM ). Similarly, the D -galactohydroximo-1,5-lactam 7 is a potent inhibitor of the α-galactosidase from coffee beans and of the β-galactosidases from bovine liver and E. coli (Ki=5, 10, and 0.1 μM , resp.), while the lactoside analogue 8 is a strong inhibitor of the E. coli β-galactosidase (Ki=0.1 μM ), but a moderate-to-weak inhibitor of coffee-bean α-galactosidase and bovine-liver β-galactosidase (Ki=250 μM and IC50=2500 μM , resp.). The galacto-configured lactam oximes 7 and 8 are good inhibitors of the β-glucosidase isolated from C. saccharolyticum (Ki=2.5 and 3.3 μM , resp.). 相似文献