离子液体中6-羟基-2(1H)-喹啉酮的合成

研究了对甲氧基苯胺经溴化、酰化和Heck反应在离子液体中合成6-羟基-2(1H)-喹啉酮的方法。对甲氧基苯胺与离子液体[bmim]Br3发生选择性溴化反应,以98.2%的收率得到质量分数为99.5%的2-溴-4-甲氧基苯胺;2-溴-4-甲氧基苯胺与丙烯酰氯发生酰化反应,以95.7%的收率得到N-(2-溴-4-甲氧基苯基)丙烯酰胺;在离子液体、醋酸钯、碳酸钾和1,3-双(二苯基膦)丙烷反应体系中,N-(2-溴-4-甲氧基苯基)丙烯酰胺顺利地发生分子内Heck反应,以91.5%的收率得到6-羟基-2(1H)-喹啉酮。该方法原料易得,反应条件易控制,收率高,离子液体可以重复使用,对环境友好。     

离子液体中6-羟基-2(1H)-喹啉酮的合成研究

研究了对甲氧基苯胺经溴化、酰化和Heck反应在离子液体中合成6-羟基-2(1H)-喹啉酮的方法。对甲氧基苯胺与离子液体[bmim]Br3发生选择性溴化反应,以98.2%的收率得到质量分数为99.5%的2-溴-4-甲氧基苯胺;2-溴-4-甲氧基苯胺与丙烯酰氯发生酰化反应,以95.7%的收率得到N-(2-溴-4-甲氧基苯基)丙烯酰胺;在离子液体、醋酸钯、碳酸钾和1,3-双(二苯基膦)丙烷反应体系中,N-(2-溴-4-甲氧基苯基)丙烯酰胺顺利地发生分子内Heck反应,以91.5%的收率得到6-羟基-2(1H)-喹啉酮。该方法原料易得,反应条件易于控制,反应收率高,离子液体可以重复使用,对环境友好。     

离子液体中6-羟基-3,4-二氢-2(1H)-喹啉酮的合成

研究了离子液体[bmim]Cl-AlCl3催化4-甲氧基苯胺与丙烯酰氯反应一锅法合成6-羟基-3,4-二氢-2(1H)-喹啉酮,并用IR、1HNMR和元素分析对其结构进行确证。在[bmim]Cl-AlCl3介质中,4-甲氧基苯胺与丙烯酰氯发生酰化反应生成N-(4-甲氧基苯基)丙烯酰胺。而后在[bmim]Cl-AlCl3和酰化反应产生的HCl协同作用下,经过分子内Friedel-Crafts烷基化和脱甲基化反应,以89.6%的产率得到6-羟基-3,4-二氢-2(1H)-喹啉酮。离子液体[bmim]Cl-AlCl3作为催化剂和反应介质可以回收利用,重复使用5次目标产物的产率无明显降低。     

4-羟基-3-甲氧基肉桂酸衍生物的除草活性测定

[目的]天然产物4-羟基-3-甲氧基肉桂酸是新型除草剂创制的先导化合物,为了评价其衍生物的除草活性。[方法]试验采用平皿法测定了以4-羟基-3-甲氧基肉桂酸为母体合成的26种衍生物对拟南芥的抑制作用。[结果]17种衍生物具有不同程度的除草活性,其中2-(4-羟基-3-甲氧基亚苄基)丙二酸二乙酯、N-(4-氟苯基)-3-(4-羟基-3-甲氧基苯基)丙烯酰胺、3-溴-4-羟基-5-甲氧基肉桂酸3种衍生物除草活性较高,对拟南芥的抑制中浓度(IC50)分别为9.90、7.53、6.93 mg/L。[结论]4-羟基-3-甲氧基肉桂酸衍生物是开发新型除草剂的重要来源,为新型除草剂的创制奠定了一定的理论基础。     

Development of an (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114] carba analogue inhibitor for murine γ-aminobutyric acid transporter type 4

A series of GABA uptake inhibitors related to (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114], the most potent mGAT4 inhibitor known so far, were synthesized and biologically evaluated for their inhibitory potency at the four GABA uptake transporters mGAT1-4 stably expressed in HEK-293 cell lines. New analogues were developed with potencies that are similar to or slightly higher than those of current mGAT4 inhibitors, but with distinctly improved chemical stability. (S)-Nipecotic acid derivatives possessing a 2-[1-(4-methoxy-2-methylphenyl)-1,1-bis(4-methoxyphenyl)methoxy]ethyl (DDPM-859) or a 4,4,4-tris(4-methoxyphenyl)but-2-en-1-yl moiety (DDPM-1457) were found to exhibit pIC(50) values of 5.78 and 5.87, respectively. Thus, as mGAT4 inhibitors, these compounds compare well with (S)-SNAP-5114 (pIC(50) =5.71), but are far more stable than the latter. Moreover, DDPM-859 displays a more favorable subtype selectivity for mGAT4 versus mGAT3 than does (S)-SNAP-5114.     

Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl(3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC₅₀ = 36.05 µM in the series, while benzyl{3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC₅₀ = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure–activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.     

水溶性萘酰亚胺氢离子荧光分子探针的合成及性能

4 溴 1,8 萘酐与羟乙氧基乙胺反应合成了中间体N 羟乙氧基乙基 4 溴 1,8 萘酰亚胺。用该中间体分别与哌嗪、甲基哌嗪和羟乙基哌嗪反应 ,合成了 4 哌嗪基、4 (甲基哌嗪 )基和 4 (羟乙基哌嗪 )基 1,8 萘酰亚胺衍生物 (NP - 1、NP - 2和NP - 3)。这 3种化合物具有较好的水溶性 ,其水溶液的荧光强度随溶液由碱性到酸性变化 ,荧光强度增加在 5 0倍以上。NP - 1、NP - 2和NP - 3的pK′a值分别为 8 5、7 6和 6 7。     

3-(2,8,9-三氧杂-5-氮杂-1-锗三环[3.3.3.0]十一烷基)-3-(4-羟基-3-甲氧基苯基)丙酸的合成

以氧化锗、次亚磷酸钠、浓盐酸为原料经氧化还原反应合成三氯锗仿,三氯锗仿再与阿魏酸经麦克尔加成反应得到3-三氯锗基-3-(4-羟基-3-甲氧基苯基)丙酸,然后与甲醇钠反应生成3-三甲氧锗基-3-(4-羟基-3-甲氧基苯基)丙酸,再与三乙醇胺发生烷基转移反应生成标题化合物.     

Synthesis and Structure-Activity Relationships of 3-Arylisoquinolone Analogues as Highly Specific hCES2A Inhibitors

Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3-arylisoquinolones 3 h [3-(4-(benzyloxy)-3-methoxyphenyl)-7,8-dimethoxyisoquinolin-1(2H)-one] and 4 a [3-(4-(benzyloxy)-3-methoxyphenyl)-4-bromo-7,8-dimethoxyisoquinolin-1(2H)-one] were found to have potent inhibitory effects on hCES2A (IC₅₀=0.68 μΜ, K_i=0.36 μΜ) and excellent specificity (more than 147.05-fold over hCES1 A). Moreover, 4 a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3 h , with an IC₅₀ value of 0.41 μΜ. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3 h and 4 a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure−activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity.     

N,N-二甲基色胺衍生物合成研究

以四氢呋喃和对氰甲基盐酸苯肼 (Ⅹ )为主要原料合成了色胺衍生物N ,N 二甲基 2 { 5 [(3 氨基 1,2 ,4 口恶二唑 5 基 )甲基 ] 1 氢 吲哚 3 基 }乙胺 (Ⅶ )。四氢呋喃和氯化氢反应 ,得到4 氯丁醇 ( ) ,产率为 6 2 % ;用氯铬酸吡啶盐氧化得 4 氯丁醛 ( ) ,产率为 6 1% ;经缩醛化得 4 氯丁醛缩甲醇 ( ) ,产率为 5 6 % ;用二甲胺取代得 4 (N ,N 二甲胺基 )丁醛缩甲醇(Ⅸ ) ,产率为 86 % ;Ⅸ与Ⅹ经环化得N ,N 二甲基 2 [5 (氰甲基 ) 1氢 吲哚 3 基 ]乙胺 (Ⅺ ) ,产率为 76 % ;Ⅺ经酯化得N ,N 二甲基 2 [5 (乙酯甲基 ) 1氢 吲哚 3 基 ]乙胺 (Ⅻ ) ,产率为 82 % ;Ⅻ与羟基硫酸胍缩合得产物 (Ⅶ ) ,产率为 6 6 %。     

The Synthesis of 1,2-Diarylpropane-1,3-Diols via the Ivanoff Reaction

Abstract

The synthesis of two β-1 lignol dimers, 1,2-bis-(4-hydroxy-3-methoxyphenyl)-i,3-propanediol (Via) and l-(3-ethoxy-4-hydroxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)-1,3-propanediol (VIb) was performed using the Ivan off Reaction in the key synthetic step. The erythro forms of Via and b were isolated as crystalline solids in yields of approximately 15%, while the threo isomers were obtained as oils. The ratio of threo: erythro isomers was approximately 3:1.     

Oxidation of the α-tocopherol model compound 2,2,5,7,8-pentamethyl-6-chromanol in the presence of alcohols

Oxidation of the vitamin E model compound, 2,2,5,7,8-pentamethyl-6-chromanol (1b) byt-butyl hydroperoxide in chloroform has been studied in the presence of ethanol, heptanol and cholesterol. In the absence of an alcohol, the major products were the spirodimer (13b) and spirotrimer (14b) of 1b, together with 1H,2,3-dihydro-3,3,5,6,9,10,11a(R)-heptamethyl-7a(S)-(3-hydroxy-3-methylbutyl)-pyrano[2,3-a] xanthene 8(7aH), 11(11aH) dione (6b). In the presence of ethanol, heptanol and cholesterol, the major products were 5-ethoxymethyl-2,2,7,8-tetramethyl-6-chromanol (16b), 5-heptoxymethyl-2,2,7,8-tetramethyl-6-chromanol (17) and 5-cholesteroxymethyl-2,2,7,8-tetramethyl-6-chromanol (18). However, when water was present in a homogeneous reaction, the most rapidly formed product was 2-(3-hydroxy-3-methylbutyl)-3,5,6-trimethyl-1,4-benzoquinone (5b). Compounds 13b, 14b, 16b, 17 and 18 are formedvia a quinone methide intermediate, and compound 5b is formedvia a phenoxylium ion. The phenoxylium species appears to be the preferred intermediate when water is present, whereas the quinone methide species is prefered in the absence of water.     

阿达帕林的合成工艺研究

以1-金刚烷醇、4～溴苯酚为原料,在浓硫酸催化下制得2-（1-金刚烷基）-4-溴苯酚,产物再用硫酸二甲酯甲基化得到2-（1-金刚烷基）-4-溴苯甲醚,2-（1-金刚烷基）～4-溴苯甲醚的格氏化产物再与6-溴-2-萘甲酸甲酯反应,制得6～[3-（1-金刚烷基）-4-甲氧基苯基]-2-萘甲酸甲酯,该产品在氢氧化钠作用下皂化...     

Highly Selective and Potent Human β-Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design,Synthesis, X-ray Structure and Structure–Activity Relationship Studies

Herein we present the design, synthesis, and biological evaluation of potent and highly selective β-secretase 2 (memapsin 1, beta-site amyloid precursor protein cleaving enzyme 2, or BACE 2) inhibitors. BACE2 has been recognized as an exciting new target for type 2 diabetes. The X-ray structure of BACE1 bound to inhibitor 2 a {N³-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)propyl]amino]propyl]-5-[methyl(methylsulfonyl)amino]-N¹-[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide} containing a hydroxyethylamine isostere was determined. Based on this structure, a computational docking study was performed which led to inhibitor 2 a -bound BACE2 models. These were used to optimize the potency and selectivity of inhibitors. A systematic structure–activity relationship study led to the identification of determinants of the inhibitors’ potency and selectivity toward the BACE2 enzyme. Inhibitors 2 d [N³-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)pentyl]amino]propyl]-N¹-methyl-N¹-[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide; K_i=0.031 nm , selectivity over BACE1: ≈174 000-fold] and 3 l [N¹-((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N³,5-dimethyl-N³-((R)-1-phenylethyl)isophthalamide; K_i=1.6 nm , selectivity over BACE1: >500-fold] displayed outstanding potency and selectivity. Inhibitor 3 l is nonpeptide in nature and may pave the way to the development of a new class of potent and selective BACE2 inhibitors with clinical potential.     

阿魏酸异辛酯的一锅法合成

用香兰素、丙二酸二乙酯、异辛醇、冰醋酸为主要原料,以甘氨酸为催化剂,经Knoenenagel缩合反应,一锅法合成了阿魏酸异辛酯。研究了原料摩尔比、甘氨酸用量、反应时间等对阿魏酸异辛酯收率的影响。结果表明,最佳反应条件:香兰素6.08g(0.04mol),n(丙二酸二乙酯)/n(香兰素)=1.4,n(甘氨酸)/n(香兰素)=0.15,n(异辛醇)/n(丙二酸二乙酯)=12,反应时间8h,在该条件下目标产物阿魏酸异辛酯产率达75.2%。用核磁共振波谱及红外光谱对所得目标产物进行了表征。     

(5R,6S)-2-(4-甲氧基)苯基-6-[(1R)-叔丁基二甲基硅氧乙基]-青霉烯-3-羧酸乙酯的合成

以(3R,4R)-3-[(1R)-叔丁基二甲基硅氧乙基]-乙酰氧基氮杂环丁-2-酮(4AA)为原料,经取代、酰化、Wittig反应,合成了标题化合物,化合物结构经 1HNMR、IR、元素分析和质谱表征.     

龙眼核中的神经酰胺和脑苷脂的分离和鉴定

研究龙眼(Dimocarpus longan Lour.)果核的化学成分,采用硅胶柱色谱对龙眼果核石油醚提取物和体积分数95%乙醇提取物进行分离,并利用理化性质和光谱数据鉴定化合物的结构。从龙眼果核的提取物中分离得到一组混合神经酰胺(化合物1、2)和一组混合脑苷脂(化合物3～6),结构鉴定为Rel-(3S,4S,5S)-3-[(2'R)-2'-羟基二十二酰胺]-4-羟基-5-[(4″Z)-十四烷-4″-烯]-2,3,4,5-四氢呋喃(1)、Rel-(3S,4S,5S)-3-[(2'R)-2'-羟基二十四酰胺]-4-羟基-5-[(4″Z)-十四烷-4″-烯]-2,3,4,5-四氢呋喃(2)、1-O-(β-D-吡喃葡萄糖基)-(2S,3S,4R,8E)-2-(2'-羟基二十四酰胺)-8-十八烯-1,3,4-三醇(3)、1-O-(β-D-吡喃葡萄糖基)-(2S,3S,4R,8Z)-2-(2'-羟基二十四酰胺)-8-十八烯-1,3,4-三醇(4)、1-O-(β-D-吡喃葡萄糖基)-(2S,3S,4R,8E)-2-(2'-羟基二十二酰胺)-8-十八烯-1,3,4-三醇(5)、1-O-(β-D-吡喃葡萄糖基)-(2S,3S,4R,8Z)-2-(2'-羟基二十二酰胺)-8-十八烯-1,3,4-三醇(6)。     

Design,Synthesis, and Biological Evaluation of Tetrahydro-α-carbolines as Akt1 Inhibitors That Inhibit Colorectal Cancer Cell Proliferation

A series of densely functionalized THαCs were designed and synthesized as Akt1 inhibitors. Organocatalytic [3+3] annulation between indolin-2-imines 1 and nitroallylic acetates 2 provided rapid access to this pharmacologically interesting framework. In vitro kinase inhibitory abilities and cytotoxicity assays revealed that compound 3 af [(3S*,4S*)-4-(4-bromo-2-fluorophenyl)-9-methyl-3-nitro-1-tosyl-2,3,4,9-tetrahydro-1H-pyrido[2,3-b]indole] was the most potent Akt1 inhibitor, and mechanistic study indicated that compound 3 af suppressed the proliferation of colorectal cancer cells via inducing apoptosis and autophagy. Molecular docking suggested that the indole fragment of 3 af was inserted into the hydrophobic pocket of Akt1 protein, and the H-bond between 3 af and residue Lys179 also contributed to the stable binding. This article provides an efficient strategy to design and synthesize biologically important compounds as novel Akt1 inhibitors.     

碘化苯乙烯吡啶盐的制备与晶体结构

通过碘化1, 4-二甲基吡啶盐与3-甲氧基苯甲醛反应,得到了一种碘化苯乙烯吡啶盐,即碘化4-[3′-(甲氧基)苯乙烯基]-N-甲基吡啶盐,并通过红外、元素分析、氢谱、电喷雾质谱和X单晶衍射仪对其进行分析与表征,结果表明,该化合物属单斜晶系,空间群P21/c,晶胞参数a=6.848 5(16) nm,b=19.707(4) nm,c=10.831(3) nm,α=90°,β=91.069(9)°,γ=90°,Z=4,Dc=1.605 g/cm3,V=1461.5(6) nm3,μ=2.180 mm-1,F(000)=696。     

Antiproliferative activity, cell-cycle dysregulation, and cellular differentiation: salicyl- and catechol-derived acyclic 5-fluorouracil O,N-acetals against breast cancer cells

Herein we report the preparation and biological activity of three compounds with the general formula 1-[2-(5-substituted-2-hydroxybenzyloxy)-1-methoxyethyl]-5-fluorouracil. A catechol-derived compound such as 1-[3-(2-hydroxyphenoxy)-1-methoxypropyl]-5-fluorouracil and two salicyl-derived compounds such as (Z)-1-[4-(2-hydroxyphenyl)-1-methoxybut-3-enyl]-5-fluorouracil [(Z)-11] and its dihydrogenated derivative 1-[4-(2-hydroxyphenyl)-1-methoxybutyl]-5-fluorouracil were prepared to complete the set of six O,N-acetals. The most active compound against the MCF-7 breast cancer cell line was (Z)-11: IC(50)=9.40+/-0.64 microM. Differentiated breast cancer cells generate fat deposits in the cytoplasm. MCF-7 cells treated with (Z)-11 underwent an increase in lipid content relative to control cells after three days of treatment. Our results suggest that there may be significant potential advantages in the use of this new differentiating agent for the treatment of breast cancer.