共查询到20条相似文献,搜索用时 15 毫秒
1.
Grzywacz P Plum LA Sicinski RR Clagett-Dame M DeLuca HF 《Archives of biochemistry and biophysics》2007,460(2):274-284
The discovery of 2-methylene-19-nor-1alpha,25-dihydroxyvitamin D3 (2MD) as a bone selective and bone anabolic form of vitamin D has stimulated an investigation of structure/function of bone selectivity. Four new 2-substituted-19-norvitamin D analogs 3-6 have been developed to study the structure-activity relationship at C-25. As predicted, removing the 25-hydroxy group (compound 3) from the very potent analog 2MD and its 2-methyl derivatives (5 and 6) dramatically reduces in vitro activities, but biological potency is nearly fully restored in vivo likely due to in vivo 25-hydroxylation. The introduction of a methyl group at C-25 (compound 4) that blocks in vivo 25-hydroxylation reduces biological activity both in vitro and in vivo. However, analog 4 retains bone selectivity making it interesting as a possible therapeutic for bone loss diseases. 相似文献
2.
Synthesis and antiviral activities of novel N-1 alkyl substituted pyrimidines, 1-[(2-hydroxyethoxy)methyl]-5-vinyluracil (5), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-vinyluracil (6), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl]-5-vinyluracil (7) are reported. Compounds 6 and 7 were potent inhibitors of DHBV in cell culture, in contrast, all of the compounds described were devoid of activity against TK(+) HSV-1 and TK(-) HSV-1. 相似文献
3.
The bacterial degradation of flavonoids. Oxidative fission of the A-ring of dihydrogossypetin by a Pseudomonas sp 总被引:2,自引:0,他引:2 下载免费PDF全文
Cell-free extracts prepared from a Pseudomonas sp., grown on (+)-catechin, oxidized dihydrogossypetin (3',4',5,7,8-pentahydroxyflavanonol) by cleaving the A-ring to form oxaloacetic acid from C-5, C-6, C-7 and C-8 together with 5-(3,4-dihydroxyphenyl)-4-hydroxy-3-oxovalero-delta-lactone. The structure of this lactone was confirmed by synthesis of related phenylvalerolactones. 相似文献
4.
Borzilleri RM Cai ZW Ellis C Fargnoli J Fura A Gerhardt T Goyal B Hunt JT Mortillo S Qian L Tokarski J Vyas V Wautlet B Zheng X Bhide RS 《Bioorganic & medicinal chemistry letters》2005,15(5):1429-1433
A versatile synthesis of the suitably functionalized pyrrolo[2,1-f][1,2,4]triazine nucleus is described. SAR at the C-5 and C-6 positions of the 4-(3-hydroxy-4-methylphenylamino)pyrrolo[2,1-f][1,2,4]triazine template led to compounds with good in vitro potency against VEGFR-2 kinase. Glucuronidation of the phenol group is mitigated by incorporation of a basic amino group on the C-6 side chain of the pyrrolotriazine nucleus. 相似文献
5.
Sirisoma N Kasibhatla S Nguyen B Pervin A Wang Y Claassen G Tseng B Drewe J Cai SX 《Bioorganic & medicinal chemistry》2006,14(23):7761-7773
A series of 4-anilino-2-(2-pyridyl)pyrimidines has been discovered as a new class of potent inducers of apoptosis using a cell-based HTS assay. Compound 5a was found to arrest T47D cells in G2/M and induced apoptosis. SAR studies showed that a small and electron-donating group at the meta-position of the anilino ring is important for activity. A 20-fold increase in potency, from hit compound 4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (5a) to lead compound 4-(2,5-dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (5l), was obtained through the SAR studies. Compound 5l is highly active with an EC50 value of 18 nM in the caspase activation assay in T47D breast cells. Interestingly, 5a and other meta-mono-substituted compounds were active against T47D cells but were not active against H1299 and HT29 cells, while 5l and other 2,5-disubstituted compounds were active against all the three cells. In a tubulin polymerization assay, compound 5l inhibited tubulin polymerization with an IC50 value of < 0.5 microM, while 5a was not active up to 50 microM. 相似文献
6.
A number of progesterone derivatives, having a 17 alpha-acetoxy group and various functions at C-3 and C-6, interact at the cardiac glycoside (CG) binding site, using [3H]ouabain in a radioligand binding assay (RBA) with membranes from dog myocardium. We now report on results of structure-activity studies concerned with modification of the A and B rings as they influence potency in the RBA. Some progesterone derivatives with 5 alpha- or 5 beta-stereochemistry show weak receptor competing activity. Among the congeners highest potency is associated with the presence of C-4 or C-4,6 unsaturation and a C-6 substituent (CH3, Cl, Br) whose importance appears to reside in its steric rather than electronic character. The C-3 function may be carbonyl, 3 beta-hydroxy or 3 beta-acetoxy when associated with C-4 or C-4,6 unsaturation. In compounds with other substituents that promote activity, C-6 alpha substitution with -CH3, -Cl, or -Br strongly enhances activity; -F, -OCH3, carbonyl, or the unsubstituted compound promotes weak binding; and -OC2H5, -OAc, -OCOOCH3, or -OH eliminates binding activity. Receptor interaction with the double bond at C-4, but not C-5, appears to be particularly important for binding. The most potent analog identified thus far is chlormadinone acetate (17 alpha-acetoxy-6-chloropregna-4,6-diene-3,20-dione), which has 1/20 the potency of ouabain in the RBA. Studies to determine optimal structural requirements for CG-receptor binding by these hormonal steroid congeners, in conjunction with appropriate biological assays, may provide insight into the nature of a putative endogenous counterpart, lead to a better understanding of the mode of action of the CG and yield CG-like compounds with superior therapeutic properties. 相似文献
7.
Nicholas A. Meanwell Owen B. Wallace Haiquan Fang Henry Wang Milind Deshpande Tao Wang Zhiwei Yin Zhongxing Zhang Bradley C. Pearce Jennifer James Kap-Sun Yeung Zhilei Qiu J.J. Kim Wright Zheng Yang Lisa Zadjura Donald L. Tweedie Suresh Yeola Fang Zhao Sunanda Ranadive Brett A. Robinson Pin-fang Lin 《Bioorganic & medicinal chemistry letters》2009,19(7):1977-1981
The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore. 相似文献
8.
Allelochemicals of the tropical weed Sphenoclea zeylanica 总被引:1,自引:0,他引:1
Hirai N Sakashita S Sano T Inoue T Ohigashi H Premasthira C Asakawa Y Harada J Fujii Y 《Phytochemistry》2000,55(2):131-140
Nine plant growth inhibitors were isolated from the tropical weed Sphenoclea zeylanica, which shows allelopathic properties. Those compounds hitherto not reported from any plant source were the isomers of cyclic thiosulfinate, (1S,3R,4R)-(+)- and (1R,3R,4R)-(+)-4-hydroxy-3-hydroxymethyl-1,2-dithiolane-1-oxides, and (2R,3R,4R)-(-)- and (2S,3R,4R)-(+)-4-hydroxy-3-hydroxymethyl-1,2-dithiolane-2-oxides. These were named zeylanoxide A, epi-zeylanoxide A, zeylanoxide B and epi-zeylanoxide B, respectively. The absolute configurations at C-3 and C-4 were elucidated by chemical synthesis of both enantiomers from L- and D-glucose. Two of the inhibitors were secologanic acid and secologanoside. and three other inhibitors were by known secoiridoid glucosides formed as artifacts during extraction with methanol. The cyclic thiosulfinates and secoiridoid glucosides completely inhibit the root growth of rice seedlings at 3.0 mM. While the specific activity of the inhibitors was not high, since they accumulated to circa 0.61% S. zelanica by dry weight, this suggests that the inhibitors are nervertheless potent allelochemicals in this weed. 相似文献
9.
10.
Microbiological degradation of bile acids. Metabolites formed from 3-(3a alpha-hexahydro-7a beta-methyl-1,5-dioxoindan-4 alpha-yl) propionic acid by Streptomyces rubescens. 总被引:1,自引:1,他引:0 下载免费PDF全文
1. The metabolism of 3-(3a alpha-hexahydro-7a beta-methyl-1,5-dioxoindan-4 alpha-yl)propionic acid (III), which is a possible precursor of 2,3,4,6,6a beta, 7,8,9,9a alpha,9b beta-decahydro-6a beta-methyl-1H-cyclopenta[f]quinoline-3,7-dione (II) formed from cholic acid (I) by streptomyces rubescens, was investigated by using the same organism. 2. This organism effected amide bond formation, reduction of the carbonyl groups, trans alpha beta-desaturation and R-oriented beta-hydroxylation of the propionic acid side chain and skeleton cleavage, and the following metabolites were isolated as these forms or their derivatives: compound (II), 1,2,3,4 a beta,-5,6,6a beta,7,8,9a alpha,9b beta-dodecahydro-6a beta -methylcyclopental[f][1]benzopyran-3,7-dione (IVa), (1R)-1,2,3,4a beta,5,6,6a beta,7,8,9.9a alpha,9b beta-dodecahydro-1-hydroxy-6a beta-methylcyclopenta[f][1]benzopyran-3,7-dione (IVb), (E)-3-(3aalpha-hexahydro-5 alpha-hydroxy-7a beta-methyl-l-oxo-indan-4 alpha-yl)prop-2-enoic acid (V), (+)-(5R)-5-methyl-4-oxo-octane-1,8-dioic acid (VI), 3-(4-hydroxy-5-methyl-2-oxo-2H-pyran-6-yl)propionic acid (VII) and 3-(3a alpha-hexahydro-1 beta-hydroxy-7a beta-methyl-5-oxoindan-4 alpha-yl)propionic acid (VIII). The metabolites (IVb), (V), (VI) and (VII) were new compounds, and their structures were established by chemical synthesis. 3. The question of whether these metabolites are true degradative intermediates is discussed, and a degradative pathway of compound (III) to the possible precursor of compound (VII), 7-carboxy-4-methyl-3,5-dioxoheptanoyl-CoA (IX), is tentatively proposed. The further degradation of compound (IX) to small fragments is also considered. 相似文献
11.
Dutta AK Venkataraman SK Fei XS Kolhatkar R Zhang S Reith ME 《Bioorganic & medicinal chemistry》2004,12(16):4361-4373
In a recent preliminary communication we described the development of a series of hybrid molecules for the dopamine D2 and D3 receptor subtypes. The design of these compounds was based on combining pharmacophoric elements of aminotetralin and piperazine molecular fragments derived from known dopamine receptor agonist and antagonist molecules. Molecules developed from this approach exhibited high affinity and selectivity for the D3 receptor as judged from preliminary [(3)H]spiperone binding data. In this report, we have expanded our previous finding by developing additional novel molecules and additionally evaluated functional activities of these novel molecules in the [(3)H]thymidine incorporation mitogenesis assay. The binding results indicated highest selectivity in the bioisosteric benzothiazole derivative N6-[2-(4-phenyl-piperazin-1-yl)-ethyl]-N6-propyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine (14) for the D3 receptor whereas the racemic compound 7-([2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl]-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ol (10c) showed the strongest potency. Mitogenesis studies to evaluate functional activity demonstrated potent agonist properties in these novel derivatives for both D2 and D3 receptors. In this regard, compound 7-[[4-(4-phenyl-piperazin-1-yl)-butyl]-prop-2-ynyl-amino]-5,6,7,8-tetrahydro-naphthalen-2-ol (7b) exhibited the most potent agonist activity at the D3 receptor, 10 times more potent than quinpirole and was also the most selective compound for the D3 receptor in this series. Racemic compound 10a was resolved; however, little separation of activity was found between the two enantiomers of 10a. The marginally more active enantiomer (-)-10a was examined in vivo using the 6-OH-DA induced unilaterally lesioned rat model to evaluate its activity in producing contralateral rotations. The results demonstrated that in comparison to the reference compound apomorphine, (-)-10a was quite potent in inducing contralateral rotations and exhibited longer duration of action. 相似文献
12.
K Y Hui H M Siragy E Haber 《International journal of peptide and protein research》1992,40(2):152-160
Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA)-commonly used as a substitute for the scissile-bond dipeptide to boost potency-is not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; IC50 of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, normotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect. 相似文献
13.
Takano Y Shiga F Asano J Ando N Uchiki H Fukuchi K Anraku T 《Bioorganic & medicinal chemistry》2005,13(20):5841-5863
We describe the design, synthesis, and biological properties of a novel series of 7-substituted 6-nitro-3-oxoquinoxaline-2-carboxylic acids. After designing, studying the structure-activity relationships, and evaluating the properties of various compounds, we found that 7-heterocyclic-6-nitro-3-oxoquinoxaline-2-carboxylic acids that contain a substituted phenyl group linked through urethane at the 7 position possess good alpha-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) antagonistic activity. Among the compounds tested, compound 29p (GRA-293), which has a 4-carboxy group on the terminal phenyl moiety, exhibited high potency and selectivity for the AMPA-R in vitro and good neuroprotective efficacy in vivo. It also showed good aqueous solubility. 相似文献
14.
Uricase (urate:oxygen oxidoreductase, EC 1.7.3.3) exposes a positional and steric specificity in the enzymic conversion of urate to allantoin. C-2 of urate was recovered as C-2 of allantoin. By the consecutive oxidation and hydrolysis reactions a levorotatory intermediate was formed, presumably (-)-2-oxo-4-hydroxy-4-carbohydroxy-5-ureido-imidazoline. The absorption and optical rotation dispersion spectra of the intermediate were established. In the presence of borate buffer, the intermediate was transformed to (+)-alloxanate. The decay of the former compound depends on general base and acid catalysis. RS-(+/-)-allantoin was formed by chemical decarboxylation and S-(+)-allantoin by enzymic decarboxylation. 相似文献
15.
Koichi Tsuji Hidetsugu Tsubouchi Koichi Yasumura Makoto Matsumoto Hiroshi Ishikawa 《Bioorganic & medicinal chemistry》1996,4(12):2135-2149
A series of cephalosporins, 2-isocephems, and 2-oxaisocephems with C-3′ catechol-containing (pyridinium-4-thio)methyl groups and 2-isocephems with C-7 catechol related aromatics have been prepared and evaluated for antimicrobial activity. It turns out that these compounds have highly potent activity against Gram-negative bacteria, especially resistant pathogens such as Pseudomonas aeruginosa. The most active compound of the series was (6S,7S)-7-[2-(2-aminothiazol-4-yl)-2-[(Z)-[(1,5-dihydroxy-4-pyridon-2-yl)methoxy] imino]acetamido]-3-[[[(4-methyl-5-carboxymethyl)thiazol-2-yl]thio]methyl]-8-oxo-1-aza-4-thiabicyclo [4.2.0] oct-2-ene-2-carboxylic acid which exhibited potent in vitro activity against clinically isolated P. aeruginosa and Acinetobacter baumanii which is also resistant to many anti-infectives, and good in vivo efficacy against clinically isolated P. aeruginosa.
A series of cephalosporins, 2-isocephems, and 2-oxaisocephems and C-3′ or C-7 catechol or related aromatics have been prepared and evaluated for antibacterial activity. 相似文献
16.
Antioxidant, cyclooxygenase and topoisomerase inhibitory compounds from Apium graveolens Linn. seeds 总被引:1,自引:0,他引:1
Cyclooxygenase inhibitory and antioxidant bioassay-directed extraction and purification of celery seeds yielded sedanolide (1), senkyunolide-N (2), senkyunolide-J (3), 3-hydroxymethyl-6-methoxy-2,3-dihydro-1H-indol-2-ol (4), L-tryptophan (6), and 7-[3-(3,4-dihydroxy-4-hydroxymethyl-tetrahydro-furan-2-yloxy)-4,5-dihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy]-5-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-chromen-4-one (7). The structures of compounds 1-7 were determined using spectroscopic methods. Compound 4 is reported here for the first time. At 250 pg ml(-1), compounds 1-4, 6 and 7 displayed prostaglandin H endoperoxide synthase-I (COX-I) and prostaglandin H endoperoxide synthase-II (COX-II) inhibitory activities at pH 7. The acetylated product (5) of compound 4 also inhibited COX-I and COX-II enzymes when tested at 250 microg ml(-1). Compounds 6 and 7 exhibited good antioxidant activity at concentrations of 125 and 250 microg ml(-1). Only compounds 1-3 exhibited topoisomerase-I and -II enzyme inhibitory activity at concentrations of 100, 200 and 200 microg ml(-1), respectively. 相似文献
17.
Antioxidant activity (AOA) assay-guided chemical analysis, using a rat pancreas homogenate model, of aerial parts from Eysenhardtia subcoriacea, led to isolation of the new compound subcoriacin (3-(2'-hydroxy-4',5'-methylendioxyphenyl)-6-(3'-hydroxymethyl-4'-hydroxybut-2'-enyl)-7-hydroxycoumarin) together with the known substances: (+)-catechin, (-)-epicatechin, (+)-afzelechin, eriodictyol, (+)-catechin 3-O-beta-D-galactopyranoside and quercetin 3-O-beta-D-galactopyranoside as bioactive constituents. The structure of the compound was determined from 1D and 2D NMR spectroscopic analyses. Additional known constituents were characterized. The bioactive compounds showed also moderate to strong radical scavenging properties against diphenylpicrylhydrazyl radical (DPPH). In addition, subcoriacin, (+)-catechin, (-)-epicatechin and (+)-afzelechin improved the reduced glutathione levels in rat pancreatic homogenate. 相似文献
18.
Salvati ME Balog A Shan W Rampulla R Giese S Mitt T Furch JA Vite GD Attar RM Jure-Kunkel M Geng J Rizzo CA Gottardis MM Krystek SR Gougoutas J Galella MA Obermeier M Fura A Chandrasena G 《Bioorganic & medicinal chemistry letters》2008,18(6):1910-1915
A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model. 相似文献
19.
《Phytochemistry》2012
Four homoisoflavonoids named portulacanones A−D, identified as 2′-hydroxy- 5,7-dimethoxy-3-benzyl-chroman-4-one, 2′-hydroxy-5,6,7-trimethoxy-3-benzyl-chroman-4-one, 5,2′-dihydroxy-6,7-dimethoxy-3-benzyl-chroman-4-one, and 5,2′-dihydroxy-7-methoxy-3-benzylidene-chroman-4-one, were isolated from aerial parts of the plant Portulaca oleracea along with nine other known metabolites. Their structures were established on the basis of extensive spectroscopic analyses. Portulacanones A−D is the first group of homoisoflavonoids so far reported from the family Portulacaceae. They represent a rare subclass of homoisoflavonoids in nature with a structural feature of a single hydroxyl group substituted at C-2′ rather than at C-4′ in ring B of the skeleton. Three homoisoflavonoids and the known compound 2,2′-dihydroxy-4′,6′-dimethoxychalcone selectively showed in vitro cytotoxic activities towards four human cancer cell lines. Especially 2,2′-dihydroxy-4′,6′-dimethoxychalcone showed cytotoxic activity against cell line SGC-7901 with an IC50 value of 1.6 μg/ml, which was more potent than the reference compound mitomycin C (IC50 13.0 μg/ml). 相似文献
20.
Tao ZF Li G Tong Y Chen Z Merta P Kovar P Zhang H Rosenberg SH Sham HL Sowin TJ Lin NH 《Bioorganic & medicinal chemistry letters》2007,17(15):4308-4315
A new series of potent tricyclic pyrazole-based Chk1 inhibitors are described. Analogues disubstituted on the 6- and 7-positions show improved Chk1 inhibition potency compared with analogues with a single substituent on either the 6- or 7-position. Based on the lead compound 4'-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol (2), detailed SAR studies on the 6- and 7-positions were performed. 3'-morpholin-4'-yl-propoxy, pyridin-4'-ylmethoxy, pyridin-3'-ylmethoxy, 2'-(5'-ethyl-pyridin-2'-yl)-ethoxy, pyridin-2'-ylethoxy, (6'-methyl-pyridin-2'-yl)-propoxyethoxy, 2',3'-dihydroxyl-1'-yl-propoxy, and tetrahydro-furan-3'-yloxy have been identified as the best groups on the 6-position when the 7-position is substituted with methoxyl group. Pyridin-2'-ylmethoxy and pyridin-3'-ylmethoxy have been identified as the best substituents at the 7-position while the 6-position bearing methoxyl group. These compounds significantly potentiate the cytotoxicity of DNA-damaging antitumor agents in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and the camptothecin-induced S checkpoints, suggesting that their potent biological activities are mechanism-based through Chk1 inhibition. 相似文献