[A_(15)Asn,A_(17)Pro,A_(21)Ala]-胰岛素的体内外生物活性

对胰岛素的研究使得许多生命科学中的重要问题被认识．然而对于胰岛素结构和功能关系,仍有许多不清楚的地方．在胰岛素Ａ链的Ｎ端和Ｃ端各有一个螺旋区：Ａ２－８和Ａ１２－１８．杨士珍［１］的研究表明：缺失Ａ１２－１８肽段的Ａ链类似物虽然能和天然Ｂ链重组,但其重组产物只保留了天然胰岛素的约６％的体内外生物活性．这说明Ａ１２－１８对胰岛素的生物活性十分重要．但是这一结果还不能说明是Ａ１２－１８螺旋还是Ａ１２－１８肽段对胰岛素的生物活性十分重要．根据Ｃｈｕｏ－Ｆａｓｍａｎ法,在含有Ａｓｎ和Ｐｒｏ的肽段中不能形成…     

The biodistribution of [75Se]bis-[β-(N,N,N-trimethylamino)ethyl]selenide diiodide in adult guinea pigs

The biodistribution of [⁷⁵Se]BISTAES was studied in guinea pigs. A higher concentration of radioactivity was observed in articular cartilage than in other tissues or organs. A minimal amount of radioactivity was found in the blood, muscle and bone. The compound was excreted rapidly in urine. The target to background ratios were encouraging. [⁷⁵Se]BISTAES has potential as an articular cartilage imaging agent and further studies in osteoarthritic animals are merited.     

Antagonists of 5-HT₆ receptors. Substituted 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines-Synthesis and 'structure-activity' relationship

Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT(6) receptors with little difference between angular or linear shape of the tricyclic core, the angular species being only slightly more potent. The angular representative of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines, 5, can be considered as more favorable candidate for further development as it shows only weak 5-HT(2B) blocking activity (IC(50)=6.16 μM as compared with IC(50)=1.8 nM for 5-HT(6) receptors) and very low hERG potassium channel blocking potency (IC(50)=54.2 μM). The linear analog, 11, is less favorable as while showing no binding to the 5-HT(2B) receptor at concentrations of up to 10 μM, it exhibits quite a high potency to block the hERG channel (IC(50)=0.5 μM).     

Conformational Studies of Dextran [α-(1⇒6)-D-Glucan]

Abstract

A theoretical conformational study of dextran, a (l?6)-linked α-D-glucan polysaccharide, has been made to allow an explicit comparison with earlier results on pustulan, the corresponding (1 ?6)-linked β-D-glucan. The nonbonded, torsional and hydrogen bond contributions to potential energy were calculated as a function of rotational angles φ, ψ, and ω The (φ, ψ, ω)-space of the disaccharide and of helices contain many local energy minima with very small energy differences. A comparison of (1?6)-α-D-glucans with (1?6)-β-D-glucans indicates significant differences in conformational behavior. Specifically, our results shed light on the fact that dextran does not gel, whereas pustulan does. The difference in tendency to gel may be related to the fact that dextran has no particularly favored conformations with structural regularity whereas pustulan does.     

Chemotherapeutic Evaluation of Clotrimazole [Bay b 5097, 1 (o-Chloro-α-α-Diphenylbenzyl) Imidazole]

Clotrimazole has a broad spectrum of activity against yeast and filamentous fungi in vitro and also in vivo when given orally or parenterally to experimentally infected mice and when administered orally or topically to infected guinea pigs. In vitro a distinct inoculum effect has been observed with a number of strains of Candida and Torulopsis; minimal inhibitory concentrations have tended to increase with increased incubation time. With prolonged incubation times, resistance can be developed to clotrimazole in vitro, but this resistance is readily reversible upon passage in drug-free broth. The degree of in vivo activity of clotrimazole against Candida depends on the severity of infection used. Orally it appears to be more effective when administered by gavage than when given mixed in the diet. Pretreatment with the agent may decrease its efficacy because of drug inactivation. Against dermatophytes, clotrimazole has a degree of activity similar to griseofulvin when given orally, but it is less active than tolnaftate topically in cutaneous infection of Trichophyton mentagrophytes in guinea pigs. In vitro, but not in vivo, some gram-positive and gram-negative bacteria are inhibited by low concentrations of clotrimazole.     

[B_1Ala,B_2Ala,B_3Lys]-胰岛素的制备和生物活性(英文)

本文报道了胰岛素分子中Ｂ１～３序列（Ｐｈｅ－Ｖａｌ－Ａｓｎ）为Ａｌａ－Ａｌａ－Ｌｙｓ取代的胰岛素类似物制备及其生物性质。［Ｂ１Ａｌａ,Ｂ２Ａｌａ,Ｂ３Ｌｙｓ］－胰岛素仍保留天然胰岛素的全部体内活性和受体结合能力,但体外促脂肪生成活性和免疫活性分别只为胰岛素的７０％和０．８８％。本文还就胰岛素Ｂ链Ｎ端肽段对其结构和功能的影响进行了讨论。     

Synthesis, cytotoxic activities and cell cycle arrest profiles of naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione glycosides

Naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (NPCD) is known to be a very potent and selective cyclin D1-CDK4 inhibitors and could induce strong G1 phase arrest in breast tumor cell lines. In this work, the synthesis of five NPCD glycosides and their cytotoxic activities against eight tumor cell lines are presented, as well as the investigation of their cell cycle arrest profiles. The results showed that the introduction of a sugar moiety onto NPCD did not affect much of their cytotoxic activities, while the subtle structure of the sugar moiety affected the underlying mechanism strongly. In addition, NPCD showed distinct cell-cycle arrest profiles in BxPC3 prostate cells and MCF-7 breast cells, while NPCD glycosides shared similar cell cycle arrest profiles in MCF-7 and BxPC3 cells, which also indicated that not only the indolocarbazole framework as well known before but the sugar moiety can have a profound impact on the mechanism of action for these types of compounds.     

Enantioselective enzymatic acetylation of racemic [4-[4α,6β (E)]]-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

Summary A chiral compound [4R-[4,6ß(E)]]-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one (R-(+)-1) was prepared by the lipase-catalysed stereoselective acetylation of racemic 1 in an organic solvent. Chiral R-(+)-1 is a hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitor and a potential anticholesterol drug candidate. Among various lipases evaluated, lipase PS-30 from Pseudomonas species efficiently catalysed acetylation of the undesired enantiomer of racemic 1 to yield the S-(–)-acetylated product 2 and unreacted desired R-(+)-1. A reaction yield of 48 mol% and an optical purity of 98% were obtained for R-(+)-1 when the reaction was conducted in toluence as solvent in the presence of isopropenyl acetate as acyl donor. Lipase PS-30 was immobilized on Accurel polypropylene (PP) and the immobilized enzyme was reused (five cycles) in the acetylation reaction without loss of enzyme activity, productivity, or optical purity of the R-(+)-1. The enzymatic acetylation process was scaled-up to 501 and a 640-l volume (preparative batches) at a substrate concentration of 4 g/l. R-(+)–1 was recovered from the preparative batches in 68–71% recovery yield with 98.5% gas chromatography homogeneity index and 98.5% optical purity. The S-(–) acetate 2 produced by the acetylation reaction was enzymatically hydrolysed by lipase PS-30 in a biphasic system to prepare the corresponding S-(–)-1.Correspondence to: R. N. Patel     

Synthesis and characterization of [Pt(COD)Cl(NO3)] and [Pt(COD)(NO3)2] and the use of [Pt(COD)Clx(NO3)2−x] in the preparation of cis[Pt(PPh3)2Clx(NO3)2−x] (x=0, 1, 2) and [Pt(PPh3)3L](NO3) (L=Cl,NO3)

[Pt(COD)Cl₂] (COD=1,5-cyclooctadiene) is a versatile starting material for the synthesis of Pt(II) compounds. The preparations of the new compounds [Pt(COD)Cl(NO₃)], [Pt(COD)(NO₃)₂] and [Pt(PPh₃)₃(NO₃)](NO₃) and also of the known compounds cis[Pt(PPh₃)₂Cl₂], cis [Pt(PPh₃)₂Cl(NO₃)], cis[Pt(PPh₃)₂(NO₃)₂] and [Pt(PPh₃)₃Cl](NO₃)are reported. The compounds are characterized by elemental analysis, ³¹P{¹H} NMR spectroscopy and IR spectroscopy.     

Synthesis and in vivo evaluation of [18F]N-(2-benzofuranylmethyl)-N'-[4-(2-fluoroethoxy)benzyl]piperazine, a novel σ1 receptor PET imaging agent

N-(2-Benzofuranylmethyl)-N'-[4-(2-fluoroethoxy)benzyl]piperazine (6, σ(1)K(i)=2.6 nM) was radiolabeled with fluorine-18 to provide a potential σ(1) receptor radioligand for use in positron emission tomography (PET). Radiofluorination of the appropriate tosylate precursor furnished [(18)F]6 with a specific activity of 45 GBq/μmol, in an average radiochemical yield of 18% and greater than 98% radiochemical purity. MicroPET imaging in Papio hamadryas baboon brain revealed [(18)F]6 uptake consistent with σ receptor distribution, and specificity for σ receptors was demonstrated in a haloperidol pre-treated animal. [(18)F]6 possesses suitable properties for PET imaging of σ(1) receptors, and further investigation of this σ(1) receptor tracer is warranted.     

Protective Group-Free Syntheses of (±)-Frontalin, (±)-endo-Brevicomin, (±)-exo-Brevicomin,and (±)-3,4-Dehydro-exo-brevicomin: Racemic Pheromones with a 6,8-Dioxabicyclo[3.2.1]octane Ring

Protective group-free syntheses of four racemic pheromones with a 6,8-dioxabicyclo[3.2.1]octane ring were achieved in five or six steps from commercially available (±)-3-butyn-2-ol (6) and 2-alkenyl halides or 2-alken-1-ol by employing Lewis acid-catalyzed acetalization of δ, ε-epoxy ketones as the key reaction. (±)-Frontalin (1) was prepared in a 25% overall yield in five steps from methallyl chloride (5a), (±)-endo-brevicomin (2) was prepared in a 23% overall yield in five steps from (E)-2-pentenyl bromide (5b), and (±)-exo-brevicomin (3) and (±)-3,4-dehydro-exo-brevicomin (4) were both prepared in a 4% overall yield in six steps based on (Z)-2-penten-1-ol (12).     

Synthesis of novel spiro[pyrazolo[4,3-d]pyrimidinones and spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-diones and their evaluation for anticancer activity

An efficient and novel method for the preparation of spiro[pyrazolo[4,3-d]pyrimidin]-7′(1′H)-ones by the condensation of 4-amino-1-methyl-3-propylpyrazole-5-carboxamide with ketones under mild conditions using catalytic InCl₃ was reported. This method has been extended for the synthesis of novel spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-dione which are having potential applications in medicinal chemistry. All the synthesized compounds were evaluated for their anti-proliferative properties in vitro against cancer cell lines and several compounds were found to be active. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.     

Protective group-free syntheses of (±)-frontalin, (±)-endo-brevicomin, (±)-exo-brevicomin, and (±)-3,4-dehydro-exo-brevicomin: racemic pheromones with a 6,8-dioxabicyclo[3.2.1]octane ring

Protective group-free syntheses of four racemic pheromones with a 6,8-dioxabicyclo[3.2.1]octane ring were achieved in five or six steps from commercially available (±)-3-butyn-2-ol (6) and 2-alkenyl halides or 2-alken-1-ol by employing Lewis acid-catalyzed acetalization of δ, ε-epoxy ketones as the key reaction. (±)-Frontalin (1) was prepared in a 25% overall yield in five steps from methallyl chloride (5a), (±)-endo-brevicomin (2) was prepared in a 23% overall yield in five steps from (E)-2-pentenyl bromide (5b), and (±)-exo-brevicomin (3) and (±)-3,4-dehydro-exo-brevicomin (4) were both prepared in a 4% overall yield in six steps based on (Z)-2-penten-1-ol (12).     

Synthesis of [1-[2′,5′-bis-O-(t-Butyldimethylsilyl)-β- L-ribofuranosyl] thymine]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (L-TSAO-T)

Abstract

Derivatives of TSAO-T based upon pentofuranose sugars with the L-configuration have been prepared and evaluated as inhibitors of HIV-1 induced cytopathicity.     

N-Phenyl-N′-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as novel inhibitors of VEGFR and FGFR kinases

We have recently reported the discovery of pyrrolo[3,2-d]pyrimidine derivatives 1a and 1b as potent triple inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and Tie-2 kinases. To identify compounds having strong inhibitory activity against fibroblast growth factor receptor (FGFR) kinase, further modification was conducted using the co-crystal structure analysis of VEGFR2 and 1b. Among the compounds synthesized, urea derivative 11l having a piperazine moiety on the terminal benzene ring showed strong inhibitory activity against FGFR1 kinase as well as VEGFR2 kinase. A binding model of 11l complexed with VEGFR2 suggested that the piperazine moiety forms additional interactions with Ile1025 and His1026.     

亚鳞木属[Sublepidodendron (Nathorst) Hirmer, 1927]的研究述评

亚鳞木属广泛分布于世界早石炭世地层中,其模式种奇异亚鳞木不但被视为欧美植物区泥盆纪末与石炭纪初之交的标志种,而且在中国还广泛出现于晚泥盆世,因此也被作为中国晚泥盆世晚期(法门期)植物化石组合带的首要成员。然而,由于以往亚鳞木属单凭叶座等外部形态性状来定义,所以人们对它的认识仍然局限于茎器官属,这妨碍了对亚鳞木属的真正分类位置和演化谱系的认识。文章通过对亚鳞木植物研究历史的回顾,分析了与其相关的古植物学家的分类观点,并从中发现了一些有待解决的问题。结合亚鳞木属的两个种无锝亚鳞木和松滋亚鳞木的解剖学和生殖器官的研究,作者得出以下主要认识：1)历史上的亚鳞木属缺乏明确的定义和必要的生物学属性研究;2)亚鳞木属的定义需要重新厘定;3)无锡亚鳞木和松滋亚鳞木的解剖、生殖结构以及松滋亚鳞木和模式种奇异亚鳞木的分枝构造表明,亚鳞木属与石炭纪比较进化的鳞木目(或广义水韭目)中的木本石橙檀物关系更近,而与传统所认为的泥盆纪原始鳞木目中草本石松植物的关系较远。因此,文章将亚鳞木科和亚鳞木属从原始鳞木目中分离出来,归入广义的水韭目。亚鳞木属种的广泛出现进一步证实,石炭纪比较进化的木本石松植物在晚泥盆世(距今约3．7亿年)已经演化成功,木本石松植物中假单轴分枝的组构类型在同一时期业已形成。亚鳞木属可能代表了系统发育上比较高级的木本石松植物的一个演化支系或鳞木科的祖先类群之一。     

Synthesis and evaluation of (S,S)-N,N′-bis-[3-(2,2′,6,6′-tetramethylbenzhydryloxy)-2-hydroxy-propyl]-ethylenediamine (S2824) analogs with anti-tuberculosis activity

In order to identify new and potent candidate drugs to treat tuberculosis, a library of compounds was screened, and (S,S)-N,N′-bis-[3-(2,2′,6,6′-tetramethylbenzhydryloxy)-2-hydroxy-propyl]-ethylenediamine (S2824) was identified as a hit in the screen. This research discusses our efforts to synthesize and test 30 analogs of this hit for activity against Mycobacterium tuberculosis. Two compounds with homopiperazine ring possess high in vitro activity against drug sensitive and resistant M. tuberculosis with MICs 0.78–3.13 μg/mL (or 1.22–4.88 μM).     

RNA Modified Uridines VI: Conformations of 3-[3-(S)-Amino-3-Carboxypropyl]Uridine (acp3U) from tRNA and 1-Methyl-3-[3-(S)-Amino-3-Carboxypropyl]Pseudouridine (m1acp3Ψ) from rRNA

Abstract

The conformation of chemically synthesized acp³U is 60& 3′-endo, gauche⁺, whereas that of m¹acp³Ψ is 60& 2′-endo, gauche⁺. We conclude that the difference in conformation probably imparts important local structures to their respective tRNA and rRNA.     

Metabolism of O,O-Dipropyl S-[2-(2′-Methyl-1′-piperidinyl)-2-oxo-ethyl] Phosphorodithioate (C 19 490) in Paddy Rice

The fate of O,O-dipropyl S-[2-(2′-methyl-1′-piperidinyl)-2-oxo-ethyl] phosphorodithioate (C 19 490, piperophos) was followed in greenhouse-grown rice after application of 1.6 kg/ha ¹⁴C-labeled C 19 490 into the paddy water. At maturity the shoots contained 2.5 ppm and the hulled grains 0.16 ppm ¹⁴C-C 19 490 equivalents. Small amounts of unchanged C 19 490 were found in the shoots but none in the grains.

The main metabolites found were:- 2-(2′-methyl-1′-piperidiny])-2-oxo-ethane sulfonic acid, 2-(2?-methyl-1?-piperidinyl)-2-oxo-ethanoic acid and a fraction of polar unknown substances. O,O-Dipropyl S-[2-(2?-methyl-1′ -piperidinyl)-2-oxo-ethyl] phosphorothioate, 2-(2?-methyl-1?-piperidinyl)- 1-methyl-sulfinyl-2-oxo-ethane, 2-(2?-methyl-1?-piperidinyl)-1-methyl-sulfonyl-2-oxo- ethane, 2-methyl-piperidine and CO₂ were found in smaller amounts.