抗真菌药物的研究VI.C-端含MEDP的寡肽的合成和抗白念珠菌活性

目的:寻找高效低毒的抗真菌化合物。方法和结果:根据违法传递概念设计合成了12个碳端含有MEDP(N³-[(2R,3R)-4-methoxyepoxysucinyl]-L-2,3-diaminopropanoicacid)的二肽和三肽(1～12),均系新化合物。结论:体外抗白念珠菌实验表明:有些二肽三肽体外实验显示了较强的抑菌活性,其中Val MEDP的活性最强,其MMIC为45nmol·mL^-1,较母体MEDP提高960倍。     

Synthesis and biological properties of N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid dipeptides, a novel group of antimicrobial agents

A series of dipeptides with N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), the irreversible inhibitor of glucosamine-6-phosphate synthetase from bacteria and fungi, have been synthesized and their antibacterial and antifungal properties in vitro evaluated. The results demonstrate that these peptides inhibit the growth of a number of the tested microorganisms, especially pathogenic fungus Candida albicans. The results of competitive antagonism studies indicate specific peptide transport of the peptides via peptide permeases as drug delivery system and gives evidence for the high selectivity of the action upon the cells, as a result of the inhibition of generation of glucosamine.     

Antimicrobial properties of N3-(iodoacetyl)-L-2,3-diaminopropanoic acid-peptide conjugates

Six peptide conjugates consisting of either norvaline, methionine, or lysine and N3-(iodoacetyl)-L-2,3-diaminopropanoic acid--a strong, irreversible inactivator of bacterial and fungal glucosamine-6-phosphate synthase--were synthesized and their antibacterial and antifungal activities were evaluated. Antimicrobial potencies of these peptides were correlated with their transport and cleavage rates inside the cells. Bacteriolysis of Bacillus pumilus cells and inhibition of [14C]glucose incorporation into cell-wall polysaccharides of Candida albicans as a result of glucosamine 6-phosphate inactivation were also observed. Reversal of growth inhibitory effect of these peptides by N-acetylglucosamine in bacteria and fungi suggests the effective delivery of N3-iodoacetyl-L-2,3-diaminopropanoic acid into the cell by a peptide-transport system.     

吡咯并嘧啶类化合物的合成及其抑制JAK3激酶活性的研究

目的设计合成吡咯并嘧啶类化合物并研究其抑制JAK3激酶的活性。方法以4-氯-7H-吡咯并[2,3-d]嘧啶为原料,经过取代、氨基脱保护和N-酰化反应合成两类(Ⅰa和Ⅰb)吡咯并嘧啶类化合物,经体外细胞试验测定其对JAK3激酶的抑制活性。结果设计并合成了8个新化合物,结构经1H-NMR和HR-MS确证。初步活性测试结果显示Ⅰa-1和Ⅰb-3对JAK3的抑制强度与阳性对照药tofacitinib相近。结论目标化合物对JAK3依赖的DAUDI细胞抑制活性较好,对非JAK3依赖的BT-20细胞抑制作用弱。     

Synthesis of inhibitors of the meso-diaminopimelate-adding enzyme from Escherichia coli

In order to obtain inhibitors of the meso-diaminopimelate-adding enzyme, which participates in the biosynthesis of bacterial peptidoglycan, several N^α -propionyl-dipeptides of the general formula Pr-l -Ala-ambo-Xaa-OH were synthesized. Xaa represented methionine S,S-dioxide, methionine S-oxide, methionine sulfoximine, and 2-amino-4-phosphonobutyric acid, i.e. transition state analogs of glutamine synthetase and γ-glutamyl-cysteine synthetase, which catalyze the same type of reaction as our target enzyme. After synthesis, the diastereoisomers were separated by preparative HPLC or t.l.c.; those containing methionine derivatives could be identified thanks to previously synthesized reference compounds. After preincubation with the meso-diaminopimelate-adding activity from Escherichia coli. the ld diastereoisomers displayed moderate inhibitory effects, whereas the ll ones were inefficient. The best inhibition was obtained with one diastereoisomer of Pr-l -Ala-ζ-2-amino-4-phosphonobutyrate, presumably the ld one. A chloromethylketone derivative Pr-l -Ala-d -Glu(CH₂Cl)-OH, potential affinity labeler of the meso-diaminopimelate-adding enzyme, was also synthesized. In the assay with preincubation, this compound behaved as the best inhibitor.     

Oxazepines and Thiazepines,XXV: Chemical Transformations of 2,3-Dihydro-1,5-benzothiazepin-4(5H)-ones

2,3-Dihydro-1,5-benzothiazepine-4(5H)-thiones 13-22 were prepared by the reaction of the appropriate 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones with Lawesson's reagent. N-Acyl ( 23-25 ) and N-alkyl ( 26-28 ) derivatives have also been synthesized. Oxidation with 3-chloroperoxybenzoic acid afforded sulfoxides 29-32 , and sulfones 33-40 were obtained by using H₂O₂ as an oxidizing agent.     

Synthesis and antimicrobial activity of new pyridine derivatives-I

2-Amino substituted benzothiazoles 2a–l and 2-chloropyridine-3-carboxylic acid 3 were used to prepare 2-[N-(substitutedbenzothiazolyl)amino]pyridine-3-carboxylic acids (4a–l) in 2-ethoxy ethanol. Acid chlorides (5a–l) were condensed with 2-hydroxyethyl piperazine (6) and 2,3-dichloropiperazine (7) to prepare amide derivatives 2-[N-(substituted benzothiazolyl)amino]pyridin-3-yl(4-(2-hydroxyethyl)piperazin-1-yl)methanones (8a–l) and 2-[N-(substituted benzothiazolyl) amino]pyridin-3-yl(2,3-dichloropiperazine-1-yl)methanones (9a–l), respectively. The structures of new compounds have been established on the basis of elemental analysis and spectral (IR, ¹H NMR, and Mass spectra) studies. The in vitro antimicrobial activity was screened for all the synthesized compounds. Variable and modest activity were observed against the investigated strains of bacteria and fungi.     

The in vitro N-oxygenation of N-tert.alkyl-substituted benzamidine

Studies of the N-Oxygenation of N-(tert.Alkyl)benzamidines in vitro N-tert.Butyl- and N-tert.octylbenzamidine ( 1a and b ) and their potential N-oxygenated metabolites, the amidoximes 2a and b , have been synthesized and characterized. N-tert.Butylbenzamidine 1a is N-oxygenated to the amidoxime 2a by aerobic incubation with non-induced microsomal fractions of rabbit liver homogenates and NADPH. This transformation supports the hypothesis that benzamidines undergo N-oxygenation by the cytochrome P-450 enzyme system when N-dealkylation is not possible (absence of hydrogen atoms in α-position to the amidine nitrogen atoms).     

含有替加氟的卵磷脂类似物设计、合成及抗癌活性

目的合成含有替加氟的以卵磷脂类似物作载体的缀合物,并测定其生物活性。方法将替加氟转化为羟烷基衍生物,六乙基亚磷酰三胺作磷酰化试剂,与羟烷基替加氟、1-十六烷基甘油及硫作用,经一锅法合成得到环甘油硫代磷脂羟烷基替加氟缀合物,通过三乙胺对环甘油硫代磷脂替加氟缀合物开环得到标题产物。结果得到新化合物9个(2a～c,3a～c,4a～c),其结构经IR,NMR和元素分析确证。结论体外活性测定表明,化合物4a对人体膀胱癌细胞的抑制效果比替加氟好。     

Structure–activity study of fluorine or chlorine-substituted cinnamic acid derivatives with tertiary amine side chain in acetylcholinesterase and butyrylcholinesterase inhibition

In this study, a series of new fluorine or chlorine-substituted cinnamic acid derivatives that contain tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results show that almost all the derivatives containing tertiary amine side chain (compounds 4a–9d ) exhibit moderate or potent activity in AChE inhibition. By contrast, their parent compounds (compounds 3a–3f ) in the absence of tertiary amine moitery exhibit poor inhibitory activity against AChE. For the compounds containing pyrroline or piperidine side chain, the bioactivity in AChE inhibition is much intense than those containing N,N-diethylamino side chain. The chlorine or fluorine substituted position produces a significant effect on the bioactivity and selectivity in AChE inhibition. Most of the compounds that contain para-substituted fluorine or chlorine exhibit potent activity against AChE and poor activity against BChE, while ortho-substituted analogs show the opposite effect. It is worth noticing that the compounds containing N,N-diethylamino side chain are exceptions to this pattern. Among the newly synthesized compounds, compounds 6d are the most potent in AChE inhibition (IC₅₀ = 1.11 ± 0.08 μmol/L) with high selectivity for AChE over BChE (selectivity ratio: 46.58). An enzyme kinetic study of compounds 6d suggests it produces a mixed-type inhibitory effect in AChE.     

Enzymatic synthesis of [1‐14C‐N‐acetyl,P18O2] cytidine monophosphate neuraminic acid

A method for the enzymatic synthesis of [1‐¹⁴C‐N‐acetyl, P¹⁸O₂] cytidine monophosphate neuraminic acid (CMP‐NeuAc) is described. Central to the synthesis of [1‐¹⁴C‐N‐acetyl, P¹⁸O₂]CMP‐NeuAc was the enzymatic preparation of [γ‐P¹⁸O₃]ATP for use in a reaction with uridine kinase and cytidine to provide 5′‐[P¹⁸O₃]CMP. The [1‐¹⁴C‐N‐acetyl, P¹⁸O₂]CMP‐NeuAc isotopomer was then synthesized from a reaction involving nucleoside monophosphate kinase, pyruvate kinase and CMP‐NeuAc synthetase. The isolated reaction yield was 35%. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and Evaluation of Biological and Antitumor Activities of Tetrahydrobenzothieno[2,3‐d]Pyrimidine Derivatives as Novel Inhibitors of FGFR1

A series of tetrahydrobenzothieno[2,3‐d]pyrimidine derivatives were designed, synthesized, and evaluated as inhibitors of FGFR1. These analogs were synthesized via Gewald's reaction under mild conditions. The structures of the synthesized compounds were characterized by spectroscopic data (IR, ¹H NMR and MS). Their antitumor activities were evaluated against H460, A549 and U251 cell lines in vitro. Results revealed that the tested compounds showed moderate antitumor activities. Structure–activity relationship analyses indicated that compounds with an aromatic ring substituted in the C‐2 position or with larger molecules such as 3g , 4c , and 7 were more effective than others. The compound, 3g (78.8% FGFR1 inhibition at 10 μ m ), was identified to have the most potent antitumor activities, with IC₅₀ values of 7.7, 18.9, and 13.3 μ m against the H460, A549, and U251 cell lines, respectively. Together, the results suggested that tetrahydrobenzothieno[2,3‐d]pyrimidine derivatives may serve as a potential agent for the treatment of FGFR1‐mediated cancers.     

Substituted 2-[(2-Oxo-2H-[1,2,4]triazino [2,3-c]quinazolin-6-yl)thio]acetamides with Thiazole and Thiadiazole Fragments: Synthesis,Physicochemical Properties,Cytotoxicity, and Anticancer Activity

The series of novel N-R-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]acetamides with thiazole and thiadiazole fragments in a molecule were obtained by alkylation of potassium salts 1.1–1.4 by N-hetaryl-2-chloroacetamides and by aminolysis of activated acids 2.1–2.4 with N,N’-carbonyldiimidazole (CDI). The structures of compounds were determined by IR, ¹H NMR, MS, and EI-MS analysis. The results of cytotoxicity evaluated by the bioluminescence inhibition of bacterium Photobacterium leiognathi, Sh1 showed that the compounds have considerable cytotoxicity. The synthesized compounds were tested for anticancer activity in NCI against 60 cell lines. Among the highly active compounds 3.1, 3.2, and 6.5, 2-[(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]-N-(1,3-thiazol-2-yl)acetamide (3.1) was found to be the most active anticancer agent against the cell lines of colon cancer (GI₅₀ at 0.41–0.69 μM), melanoma (GI₅₀ 0.48–13.50 μM), and ovarian cancer (GI₅₀ 0.25–5.01 μM). The structure-activity relationship (SAR-analysis) was discussed.     

Synthesis and Cytotoxic Activity of Novel Amidine Analogues of Bis(2‐chloroethyl)amine

Novel nitrogen mustard agents 7 – 12 involving 4‐(N,N‐bis(2‐chloroethyl)aminophenyl)propylamine linked to a 5‐(4‐N‐alkylamidinophenyl)‐2‐furancarboxylic acid moiety by the formation of an amide bond have been synthesized, characterized, and evaluated for their in‐vitro cytotoxic activity against MDA‐MB‐231 and MCF‐7 human breast cancer cells. Evaluation of the cytotoxicity of 7 – 12 employing a MTT assay and inhibition of [³H]thymidine incorporation into DNA demonstrated that these compounds exhibit remarkable cytotoxic effects in comparison with 4‐[bis(2‐chloroethyl)amino]benzenebutanoic acid. Compounds 7 and 9 , which possess a cationic amidine and 4,5‐dihydro‐1H‐imidazol function moiety are approximately ten times more potent than 4‐[bis(2‐chloroethyl)amino]benzenebutanoic acid. The new compounds were evaluated as DNA topoisomerase II inhibitors. The cytotoxicity of the compounds 7 – 12 correlates with their DNA‐binding affinities and their relative potency as topoisomerase II inhibitors.     

Anticandidal properties of N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid oligopeptides

Tri-, tetra-, and pentapeptides containing N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), an inactivator of glucosamine 6-phosphate synthase of fungal origin (a key enzyme in the biosynthesis of macromolecular components of the fungal cell wall) have been synthesized and investigated as anticandidal agents. Structure-activity relationships of a series of peptides revealed that tripeptides were generally more active than the other peptides examined. In this study, the lysyl peptide, Lys-Nva-FMDP has been found to be the most active compound in the series.     

Anticonvulsant and Monoamine Oxidase Inhibitory Activities of some Triazene N1-Oxides

Thirty-three N ³-2-, -3- or -4-substituted aryl-N ¹-(alkyl/aryl/substituted aryl)-triazene N ¹-oxides were synthesized and evaluated for their anticonvulsant and monoamine oxidase (MAO) inhibitory activities. Most of the compounds exhibited MAO inhibitory activity in vitro, and kinetic studies conducted with N ³-4-chlorophenyl-N ¹-methyltriazene N ¹-oxide, the most potent inhibitor, showed that the inhibition is non-competitive in nature. The MAO inhibiting activity of the compounds correlated well with their anticonvulsant effect against maximal electroshock-induced seizures in rats. Acute toxicity studies indicate that the compounds have a wide margin of safety.     

The Hypolipidemic Activity of a Series of 2,3-Dihydrophthalazine-l,4-dione Derivatives in Rodents

A series of substituted 2,3-dihydrophthalazine-l,4-dione derivatives as well as the corresponding N,N-diaminophthalamides were prepared and were demonstrated to have potent hypolipidemic activity, lowering both serum triglyceride and cholesterol levels significantly at 20 mg/kg/day after 16 days of dosing in CF₁ male mice. The parent compound, 2,3-dihydrophthalazine-l,4-dione, lowered serum cholesterol 51% and serum triglyceride 43%. 2-(2-Carboxyethyl)-2,3-dihydrophthalazine-l,4-dione demonstrated the best hypocholesterolemic activity, with a 66% reduction after 16 days. The 2-(p-chlorophenyl) derivative demonstrated good activity (>40% reduction) in both screens, as did the 6-methyl-2,3-dihydrophthalazine-l,4-dione derivative. Of the amides, 4-methyk N,N-diaminophthalamide demonstrated the best hypolipidemic activity, affording a greater than 40% reduction. 2,3-Dihydrophthalazine-l,4-dione was found to inhibit the enzyme activity of acetyl CoA synthetase, ATP-dependent citrate lyase, sn-glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and mitochondrial citrate exchange of liver. In mice after 16 days of dosing, there was a reduction of cholesterol, triglycerides, neutral lipids, and phospholipids in the liver. Cholesterol and neutral lipids were reduced in rat chylomicrons, very low-density lipoproteins, and low-density lipoproteins. The cholesterol content of the high-density lipoprotein fraction was slightly elevated, but reductions in the triglycerides and phospholipids were observed in this lipoprotein fraction. ³H-Cholesterol distribution studies showed a lower concentration in the major organs and plasma, with a higher ³H-cholesterol content in the stomach and large intestine.     

Synthesis and Evaluation of 3-Fluoro-2-piperazinyl-5,8,13-trihydro-5-oxoquino[1,2-a][3,1]benzoxazine-6-carboxylic Acids as Potential Antibacterial Agents

3-Fluoro-2-piperazinyl-5,8,13-trihydro-5-oxoquino[1,2-a][3,1]-benzoxazine-6-carboxylic acids were designed and synthesized as potential DNA gyrase inhibitors and antibacterial agents. The design rationale rests on the proposition made by Ohta and Koga that in order for N₁-aryl substituted quinolones to posses antibacterial activity the N₁-aryl ring should be oriented out of the plane of the quinolone ring. α-[Bis(methylthio)methylene]-2,4,5-trifluoro-β-oxobenzenepropanoic acid tert-butyl ester ( 6 ) obtained by the treatment of 2,4,5-trifluoro-β-oxobenzenepropanoic acid tert-butyl ester ( 5 ) with carbon disulfide and methyl iodide in the presence of cesium carbonate was used as a key intermediate, yielding tert-butyl 2,3-difluoro-5,8,13-trihydro-5-oxoquino[1,2-a][3,1]benzoxazine-6-carboxylate ( 8 ) upon treatment with 2-aminobenzyl alcohol. The coupling of 8 with piperazines followed by the hydrolysis of the ester under acidic conditions afforded the desired product ( 3 ). Contrary to expectation, both compounds ( 3a,b ) were, however, devoid of antibacterial activity, suggesting that for N₁-aryl substituted quinolones to exhibit antimicrobial activity important structural feature(s) other than the conformational requirement of the N₁-aryl ring with respect to the quinolone nucleus should also be satisfied.     

Synthesis and elastase inhibition activities of novel aryl,substituted aryl,and heteroaryl oxime ester derivatives

Fifteen novel aryl, substituted aryl and heteroaryl γ‐hydroxy‐ ( 2a–e ), γ‐methoxyimin o‐ (3a–e ), and γ‐benzyloxyimino‐ ( 4a–e ) butyric acid methyl esters were investigated for their enzyme inhibition, and the synthesis of 10 compounds ( 3a–e , 4a–e ) is given in this study. The other five compounds ( 2a–e ) were synthesized before in another study. Compounds 3a–e and 4a–e were synthesized in this work as original compounds and characterized by ¹H and ¹³C NMR, IR, mass, and elemental analyses. Their (E/Z)‐isomerisation ratios were analyzed by ¹H and ¹³C NMR. All of them are of pure (E)‐configuration. Due to the literature survey, the elastase inhibition activity was not studied for these compounds. Elastase inhibition ability was investigated in this work for five γ‐hydroxy‐ ( 2a–e ), five γ‐methoxy‐ ( 3a–e ), and five γ‐benzyloxyimino‐ ( 4a–e ) butyric acid methyl esters. All these 15 compounds showed elastase inhibition activity. Compound 2b was the best one and exhibited a better activity than the standard ursolic acid whereas compound 2a worked like the standard. All these compounds can be novel elastase inhibitor agents in the pharmaceutical and cosmetic industries.