Biaryls and heterobiaryls as alpha-glucosidase and protein tyrosine phosphatase inhibitors

Various 6-aryl-4-substituted-2H-pyran-2-one-3-carbonitriles (1a-d) have been synthesized as precursor for the synthesis of 3,4-dihydro-1H-isothiochroman (2a) and benzocycloalkanes (2b-e). Highly functionalized 9-thiaphenanthrene (3b) and phenanthrene (3a) have also been obtained from the reaction of 1c with thiochroman-4-one and 1-tetralone separately. Similarly 4 has been obtained by the ring transformation of 1d by 4-trifluoromethylacetophenone. Most of the synthesized compounds were evaluated for alpha-glucosidase and protein tyrosine phosphatase inhibitory activities. Some of the compounds, 2a, 3a and b and 4 displayed better alpha-glucosidase inhibitory activity compared to standard drug acarbose.     

Steroidal saponins from Smilax lebrunii.

Two new steroidal saponins, (25 R)-spirostan-3 beta-ol-6-one-3-O-[alpha-L-arabinopyranosyl (1----6)]-beta-D-glucopyranoside and (25 R)-spirostan-3 beta-ol-6-one-3-O-[beta-D-glucopyranosyl(1---4)] [alpha-L-arabinopyranosyl(1----6)]-beta-glucopyranoside, were isolated from the rhizomes of Smilax lebrunii. Their structures have been established by chemical and spectral methods.     

Polyoxypregnane glycosides from Caralluma retrospiciens

Six related polyoxypregnane glycosides were isolated and characterised from Caralluma retrospiciens leaves. The compounds were identified as 12beta-benzoyloxy-8beta,14beta-dihydroxypregn-20-one-3-O-[3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1 --> 4)-beta-D-cymaropyranosyl-(1 --> 4)-]-beta-D-cymaropyranoside], 12beta-benzoyloxy-8beta,14beta-dihydroxypregn-20-one-3-O-[beta-D-glucopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1 --> 4)-beta-D-cymaropyranosyl-(1 --> 4)-beta-D-cymaropyranoside], 12beta-benzoyloxy-8beta,14beta-dihydroxypregn-20-one-3-O-[beta-D-glucopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-galactopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-galactopyranoside], 12beta-benzoyloxy-8beta,14beta-dihydroxypregn-20-one-3-O-[beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-galactopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-galactopyranoside], 12beta-benzoyloxy-11alpha-isovaleroyloxy-8beta,14beta-dihydroxypregn-20-one-3-O-[beta-D-glucopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-galactopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-galactopyranoside], and 12beta-benzoyloxy-11alpha-isovaleroyloxy-8beta,14beta-dihydroxypregn-20-one-3-O-[beta-D-glucopyranosyl (1 --> 4)-3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1 --> 4)-beta-D-cymaropyranosyl-(1 --> 4)-beta-D-cymaropyranoside]. The structures were determined by detailed analysis of one- and two-dimensional NMR spectra as well as by chemical means. The compounds showed cytotoxic activities towards brine shrimp having IC50 values of 1.19 x 10(-4), 8.83 x 10(-5), 2.64 x 10(-4), 2.26 x 10(-4), 2.39 x 10(-4) and 1.70 x 10(-4) M, respectively. This is the first report of the isolation of these compounds from a natural source.     

Novel immunomodulators based on an oxazolin-2-one-4-carboxamide scaffold

A series of oxazolidin-2-one-4-carboxylic amide compounds (1a-f) were designed and synthesized as the non-phosphate S1P(1) receptor agonists. The single crystal of 1e was prepared and solved to elucidate the structure of 1a-f. EC(50) of 1a-d were about 1.1-3.6 μM in S1P(1) Redistribution? assay, and their cytotoxicity was 8-40-fold lower than FTY720. Though its S1P(1) agonist activities in vitro were about 1000-folds weaker than (S)-FTY720-P, at a dose of 10mg/Kg, the immunosuppressive effects of 1a were comparable to FTY720. So oxazolidin-2-one-4-carboxylic amide derivatives were found as potential immunomodulator, compound 1a could be considered as a lead compound, rational modifications of 1a are anticipated using medicinal chemistry techniques and molecular modeling to obtain analogs with higher affinity and better clinical therapeutic properties.     

New pregnane glycosides from Stelmatocrypton khasianum

Four new pregnane glycosides, stelmatocryptonoside A, B, C, and D (1-4), were isolated from the stems of Stelmatocrypton khasianum. On the basis of chemical and spectral data, the structures of 1-4 were established as 3beta, 16alpha-dihydroxy-pregn-5-en-20-one-16-O-beta-D-glucopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->6)]-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside; 3beta, 20-dihydroxy-pregn-5-en-20-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-->2)-beta-D-digitalopyranoside; 3beta, 16alpha-dihydroxy-pregn-5-en-20-one-16-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside; and 3beta, 16alpha-dihydroxy-pregn-5-en-20-one-16-O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside. This is the first report of pregnane glycosides with sugar chains linked at C-16 of the aglycone.     

Synthesis of bicyclic biaryls as glucose-6-phosphatase inhibitors

Biaryls, 7-naphthyl-5-s-amino-2,3-dihydrobenzo[b]thiophene-4-carbonitriles (3a-e), 8-(1-naphthyl)-6-s-amino-isothiochroman-5-carbonitriles (6a-d), 4-(1-naphthyl)-2-s-aminobezocycloalkene-1-carbonitriles (6e-j), 8-naphthyl-6-s-amino-2-ethyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrle (6k-n), 1-naphthyl-3-s-amino-10H-9-thia-phenantherene-4-carbonitriles (8a-e) and 1-(1-naphthyl)-3-s-amino-9,10-dihydrophenantherene-4-carbonitriles (8f-i) have been prepared through carbanion induced ring transformation reactions of 6-naphthyl-3-cyano-4-s-amino-2H-pyran-2-ones (1) from respective ketones (2, 5, and 7). These compounds have been evaluated for their glucose-6-phosphatase inhibitory activity and only 6a, c, j, m, c, d, h displayed significant inhibition of the glucose-6-phosphatase.     

中国南海侧扁软柳珊瑚中孕甾烷类化学成分的研究(英文)

从南海侧扁软柳珊瑚Subergorgia suberosa的二氯甲烷-甲醇提取物中首次分离鉴定了8个孕甾烷类化合物,经波谱鉴定为3β-O-palmitoyl-pregn-5-ene-20-one-3-ol (1),3β-O-palmitoyl-5α-pregn-20-one-3-ol (2),5α-pregn-1-ene-3,20-dione (3),3β,5α-pregn-20-one-3-ol (4),3β-pregn-5-ene-20-one-3-ol (5),3β,5β-pregn-20-one-3-ol (6),5β-pregn-3,20-dione (7),pregn-4-ene-3,20-dione (8).其中化合物1,2为新化合物.     

Regioselective halogenation of some 2,3-anhydro pyrimidine nucleosides with dilithium tetrahalocuprates.

The reaction of 1-(2,3-anhydro-5-O-trityl-beta-D-lyxofuranosyl)-2-O-methyluracil (1a) and its thymine analogue (1b) with dilithium tetrahalocuprate (Li2CuX4) revealed excellent to perfect regioselectivity, yielding 2,2'-anhydro-3'-halonucleosides (2a-d), while the same reactions with 2,3-anhydro uracil and thymine nucleosides (4a,b) gave arabinosyl (5a-d) and xylosyl halohydrins (6a-d) with the respective product ratio of 7:3 to 8:2. compounds 5 and 6 were isolated as the 2-O-(7) and 3- O-mesyl derivatives (8).     

Novel side reactions accompanying activation and aminolysis of N-benzoyl-2-alkylserines

2-Phenyl-4-alkyl-4-hydroxymethyl-1,3-oxazolones (2a-d) have been identified as side products accompanying activation of N-benzoyl-2-alkylserines (1a-d). Oxazolones 2a-d in the presence of amine rearrange subsequently to corresponding 4-alkyl-2-phenyl-4,5-dihydro-1,3-oxazole-5 carboxylic acids (4a-d) at a 20-68% yield.     

Synthesis and anti-HBV activity of thiouracils linked via S and N-1 to the 5-position of methyl beta-D-ribofuranoside

Reverse nucleoside derivatives of 2-(methylsulfanyl)uracils 6a-d were prepared by treating of the sodium salt of 2-(methylsulfanyl)uracils (5a-d) with methyl 2,3-O-isopropylidene-5-O-p-toluenesulfonyl-beta-D-ribofuranoside (2). The alkylation of 2-thiouracils 4a-d with methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside (3) afforded the corresponding S-ribofuranoside derivatives 8a-d. Deisopropylidenation of 6a-d and 8a-d afforded the corresponding deprotected derivatives 7a-d and 9a-d, respectively. The Anti-HBV activity of selected compounds was studied.     

Syntheses and Biological Evaluation of Alkanediamines as Antioxidant and Hypolipidemic Agents

A new series of compounds belonging to N,N′- [bis (1-aryl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkanediamines (2–5a–f) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds namely 2c, 2e, 4c, 5b, 5c, 5e and 5f exhibit potent antioxidant activity. These compounds have also been evaluated for hypolipidemic activity.     

Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines

The key dinitrile intermediates 4a-d were synthesized by reaction of phenacyl bromide 1 and the appropriate 2-amino-5-bromopyridines to yield 3a-d. Suzuki coupling of 3a-d with 4-cyanophenylboronic acid yielded the 2,6-bis(4-cyanophenyl)-imidazo[1,2-a]pyridine derivatives 4a-d. The bis-amidoximes 5a-d, obtained from 4a-d by the action of hydroxylamine, were converted to the bis-O-acetoxyamidoximes which on catalytic hydrogenation in a mixture of ethanol/ethyl acetate gave the acetate salts of 2,6-bis[4-(amidinophenyl)]-imidazo[1,2-a]pyridines 7a-d. In contrast, catalytic hydrogenation of the bis-O-acetoxyamidoxime of 5a in glacial acetic acid gave the saturated analogue 2,6-bis[4-(amidinophenyl)]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine 8. O-Methylation of the amidoximes 5a-d gave the N-methoxyamidines 6a-d. The diamidines showed strong DNA binding affinity, were very active in vitro against T. b. r. exhibiting IC(50) values between 7 and 38nM, but were less effective against P. f. with IC(50) values between 23 and 92nM. Two of the diamidines 7c and 7d were slightly more active than furamidine but less active than azafuramidine in the T. b. r. STIB900 mouse model. Only one prodrug 6b showed moderate activity in the same mouse model.     

Synthesis of some novel 6-benzyl(or substituted benzyl)-2-beta-D-glucopyranosyl-1,2,4-triazolo[4,3-b][1,2,4]triazines as potential antimicrobial chemotherapeutics

Glucosidation of the new 8-amino-6-benzyl(or substituted benzyl)-2,8-dihydro-1,2,4-triazolo[4,3-b][1,2,4]triazin-7(3H)-ones (3a-d) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide 4 gave the corresponding N-glucosides 5a-d. Chemical transformations leading to new functionalities have also been achieved to give compounds 7-12. Antimicrobial activity of compounds 5a-c against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli is described.     

Isolation and Identification of 1-Ribosyl Pyridone Nucleosides from Human Urine

Abstract

1-Ribosylpyridin-4-one-3-carboxamide with lesser amounts of 1-ribosylpyridin-2-one-5-carboxamide have been isolated quantitatively from human urine using ion exchange column chromatography. Absorption spectra and mass spectrometry were used in the identification.     

Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives of naproxen

Some 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a-f and 5a-d) have been synthesized by cyclisation of 4-amino-5-[1-(6-methoxy-2-naphthyl)ethyl]-3-mercapto-(4H)-1,2,4-triazole (3) with various substituted aromatic acids and aryl/alkyl isothiocyanates, through a single step reaction. The target compounds were pharmacologically evaluated for their anti-inflammatory and analgesic potentials by known experimental models. Several of these showed significant activity. Very low ulcerogenic index was observed for potent compounds.     

Highly potent cell differentiation-inducing analogues of 1alpha,25-dihydroxyvitamin D3: synthesis and biological activity of 2-methyl-1,25-dihydroxyvitamin D3 with side-chain modifications

Eight 2-methyl substituted analogues of 20-epi-22R-methyl-1alpha,25-dihydroxyvitamin D3 (5) and 20-epi-24,26,27-trihomo-22-oxa-1alpha,25-dihydroxyvitamin D3 (6: KH-1060) were convergently synthesized. Preparation of the CD-ring portions with modified side chains of 5 and 6, followed by palladium-catalyzed cross-coupling with the A-ring enyne synthons (20a-d), (3S,4S,5R)-, (3S,4R,5R)-, (3S,4S,5S)- and (3R,4R,5S)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-methyloct-1-en-7-yne, afforded two sets of four A-ring stereoisomers of 20-epi-2,22-dimethyl-1,25-dihydroxyvitamin D3 (7a-d) and 20-epi-24,26,27-trihomo-2-methyl-22-oxa-1,25-dihydroxyvitamin D3 (8a-d). The biological profiles of the hybrid analogues were assessed in terms of affinity for vitamin D receptor (VDR) and HL-60 cell differentiation-inducing activity in comparison with the natural hormone. The combined modifications of the A-ring at the 2-position and the side chain yielded analogues with high potency.     

Chiral O-(Z-alpha-aminoacyl) sugars: convenient building blocks for glycopeptide libraries

1,2:3,4-Di-O-isopropylidene-alpha-D-galactopyranose (2), 1,2:5,6-di-O-isopropylidene-d-glucose (5), and 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (7) are efficiently O-acylated in 78-96% yields with readily available N-(Z-alpha-aminoacyl)benzotriazoles 1a-e, 1d+1d' under microwave irradiation to give chiral 3a-d, 4, 6a-d, 8a,b and diastereomeric mixtures (3d+3d'), (6a+6a'), and (6d+6d'). The original chirality was retained as evidenced by HPLC. The diisopropylidene protecting groups were removed from compounds 3a,d, 6d to give the free O-(Z-alpha-aminoacyl) sugars 9a,b, 10.     

Synthesis and antiproliferative evaluation of amide-containing flavone and isoflavone derivatives

Certain amide-containing flavone and isoflavone derivatives were synthesized and evaluated for their antiproliferative activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with H(2)SO(4) and NaN(3) (Schmidt reaction). The preliminary assays indicated that the inhibitory activity against the growth of NCI-H661 decreased in an order of linked chromophore flavone-6-yl 16a-d>flavone-7-yl 17a-d>flavone-3-yl 15a-d and isoflavone-7-yl 18a-d. Among these flavone-6-yl derivatives, N-(4-methoxyphenyl)-2-(4-oxo-2-phenyl-4H-chromen-6-yloxy)acetamide (16c) was the most potent with a GI(50) value of 0.84 microM. The inhibitory activity against the growth of NPC-TW01 decreased in an order of linked chromophore flavone-6-yl 16a-d>isoflavone-7-yl 18a-d>flavone-7-yl 17a-d>flavone-3-yl 15a-d. Flavone-6-yl derivatives 16a-d demonstrated significant inhibitory activities against the growth of NPC-TW01 cell with an average GI(50) value of 0.84 microM. The oxime derivatives 1 and 2 caused accumulation of NPC-TW01 cell in G(2)/M phase which were distinct from that of their amide isomers 16b and 16c, respectively, which induced cell-cycle arrest in G(0)/G(1) phase followed by apoptosis. Therefore, the antiproliferative mechanism of flavone derivatives was affected not only by the phenyl benzopyran-4-one pharmacophore but also by the peripheral substituents.     

The degradation of beta-sitosterol by Pseudomonas sp. NCIB 10590 under aerobic conditions

The bacterial degradation of beta-sitosterol by Pseudomonas sp NCIB 10590 has been studied. Major biotransformation products included 24-ethylcholest-4-en-3-one, androsta-1,4-diene-3,17-dione, 3-oxochol-4-en-3-one-24-oic acid and 3-oxopregn-4-en-3-one-20-carboxylic acid. Minor products identified were 26-hydroxy-24-ethylcholest-4-en-3-one, androst-4-ene-3,17-dione, 3-oxo-24-ethylcholest-4-en-26-oic acid, 3-oxochola-1,4-dien-3-one-24-oic acid, 3-oxopregna-1,4-dien-3-one-20 carboxylic acid and 9 alpha-hydroxyandrosta-1,4-diene-3,17-dione. Studies with selected inhibitors have enabled the elucidation of a comprehensive pathway of beta-sitosterol degradation by bacteria.     

Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles 14a-e, 15a-e, 17a-c, and 18a-d have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 6-quinolinyl pyrazole analogue 14b inhibited ALK5 phosphorylation with IC(50) value of 0.022 μM and showed 84% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.