Synthesis of L-3′-Hydroxymethylribonucleosides

Abstract

The target compounds were synthesized via the key intermediate carbohydrate 8, which was synthesized by first selectively protecting the 1′ - and 2′- hydroxyl groups followed by selective tosylation of the 5′ -hydroxyl group to obtain compound 3. The tosyl moiety was then replaced by a benzyl ether to obtain 4. Compound 4 underwent Dess-Martin oxidation to afford the ketone 5. Compound 5 was subjected to Wittig olefination to afford the alkene 6 followed by regioselective hydroboration to obtain 7. Compound 7 was fully acetylated using acetic acid, acetic anhydride and sulfuric acid to obtain the key intermediate 8.     

MOLECULAR AND PHARMACOLOGICAL CHARACTERISATION OF THE MSH-R ALLELES IN SWISS CATTLE BREEDS

ABSTRACT

The coat colour in mammals is determined by the relative amounts of eumelanin (black/brown) and phaeomelanin (red/yellow), produced in melanocytes, which are controlled by melanocyte stimulating hormone receptor (MSH-R). Melanocyte stimulating hormone receptor is activated by α-melanocyte-stimulating hormone (α-MSH). Stimulated MSH-R activates adenylyl cyclase (AC), thereby increasing the amount of cyclic AMP in the cell, which activates the enzyme tyrosinase resulting in eumelanin synthesis. In this study the complete coding sequences of five alleles of the MSH-R gene found in Holstein, Red Holstein, Simmental, and Brown Swiss cattle were cloned into a mammalian expression vector and transfected into human embryonic kidney (HEK) 293 cells. The expressed receptors were analyzed for their ability to increase intracellular cAMP in response to stimulation by α-MSH. The recessive red allele (e) found in Red Holstein and Simmental and the dominant black allele (E^D) found in Holstein were unresponsive to a wide range of α-MSH concentrations. Two alleles from Brown Swiss (E^d1, E^d2) and one allele found in the Simmental breed (e^f) responded to stimulation by α-MSH in a dose-dependent manner. When compared to E^d1 and E^d2, the cells transfected with the e^f MSH-R allele, however, reached the corresponding intracellular cAMP concentrations at a 10-fold higher concentration of α-MSH. In conjunction with the mode of inheritance of coat colour, the results indicate that the e MSH-R allele is a non-functional receptor, E^D is constitutively activated receptor, and E^d1 and E^d2 are hormonally activated receptors. The delay in e^f MSH-R response may explain the similarity between the e and e^f phenotypes.     

A Convenient Synthesis of Acyclic Adenosines with an Unsaturated Side Chain by Modification of 9-(2,3-O-Isopropylidene-D-Ribityl)Adenine

Abstract

In expectation of discovering their antiviral activity, acyclic adenosine derivatives 7, 11, 12, and 16 were designed as analogs of neplanocin A (NPA) and L-eritadenine which are strong inhibitors of S-adenosyl-L-homocysteine hydrolase. The 1′,5′-seco-analog of 4′-deoxymethyl-NPA (DHCA) 7 was synthesized by dideoxygenation of 9-(2,3-O-isopropylidene-D-ribityl)adenine (2). Acyclic DHCA analogs 11 and 16 were obtained by Wittig reaction of the aldehyde 3 with Ph₃P=CHCO₂Et and Ph₃P=CHCN, respectively. Hydrolysis of the ester 11 afforded a vinylog of L-eritadenine 12. The synthesized acyclic nucleosides 7, 10, and 11 were evaluated for antiviral activity, however, none of them showed any significant antiviral activity.     

Nucleosides. 140. Stereoselectivity of the Reaction of 1-(2,3-Anhydro-5-O-Benzoyl-β-D-Lyxofuranosyl) Uracil with Ammonium Azide. Isolation and Characterization of 2-Azido-Xylo-Nucleoside Derivatives

Abstract

The composition of the products of reaction of 1-(2,3-anhydro-5-O-benzoyl-β-D-lyxofuranosyl)uracil (1) with NH₄N₃ was studied by a reverse-phase HPLC system which was found to separate the 3-azido-arabino 2 and 2-azido-xylo 3 isomers that were formed. The use of a 10:1 ratio of NH ₄ N ₃ to 1 in refluxing EtOH was found to minimize ring opening at C-2 (7%). The higher stereoselectivity of ring opening produced by using a large excess of NH ₄ N ₃ was suppressed by conducting the reaction in DMF. Preventing the escape of the NH ₃ by-product only resulted in debenzoylation. The isolation of pure, crystalline 3 was achieved by reverse-phase preparative HPLC. Separation from the arabino isomer was also effected by debenzoylation and selective acetonide formation with the xylo isomer, which allowed facile isolation of the latter by normal phase chromatography. Hydrolysis of the acetonide 7 provided unprotected 2-azido-xylo nucleoside 6, which was also obtained by NaOMe treatment of 3. The mechanistic basis for the stereoselectivity of epoxide opening is discussed.     

Thiosugars. X. Novel Nucleoside Analogues Derived from 4-Thio-L-lyxofuranose

Abstract

1-O-Acetyl-2,3,5-tri-O-benzyl-4-thio-L-lyxofuranose 1 was transformed into O-benzyl- and O-acetyl-protected 1-(4-thio-L-lyxofuranosyl) nucleoside derivatives by use of the TMSOTf method. Debenzylation with boron tribromide or deacetylation with sodium methoxide yielded the corresponding pyrimidine (7–11, 17, 18, 26 and 27) and purine (29 and 34) nucleoside analogues. The anomeric configurations were determined by NMR spectroscopy and, in the case of the 5-halo- (7–9) and nitrouridine derivative 11 and the 6-methylcytidine derivative 27, by X-ray structural analyses. – The unprotected nucleosides were not antivirically inhibitory at 250 µM.     

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by ¹H NMR, ¹³CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1–S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1–S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with K_is in the range of 1.79?±?0.22–2.73?±?0.08?nM against hCA I and in the range of 1.72?±?0.58–11.64?±?5.21?nM against hCA II, respectively.     

Plant growth regulators and Axl and immune checkpoint inhibitors from the edible mushroom Leucopaxillus giganteus

ABSTRACT

A novel compound, (R)-4-ethoxy-2-hydroxy-4-oxobutanoic acid (1), and six known compounds (2–7) were isolated from the fruiting bodies of the wild edible mushroom Leucopaxillus giganteus. The planar structure of 1 was determined by the interpretation of spectroscopic data analysis. The absolute configuration of 1 was determined by comparing specific rotation of the synthetic compounds. In the plant regulatory assay, the isolated compounds (1–7) and the chemically prepared compounds (8–10) were evaluated their biological activity against the lettuce (Lactuca sativa) growth. Compounds 1 and 3–10 showed the significant regulatory activity of lettuce growth. 1 showed the strongest inhibition activity among the all the compounds tested. In the lung cancer assay, all the compounds were assessed the mRNA expression of Axl and immune checkpoints (PD-L1, PD-L2) in the human A549 alveolar epithelial cell line by RT-PCR. Compounds 1–10 showed significant inhibition activity against Axl and/or immune checkpoint.     

Formation Mechanism of the Free Radical Product and Its Precursor by the Reaction of Dehydro-L-ascorbic Acid with Amino Acid

During the formation of radical A (2) and its precursor (tris(2-deoxy-2-L-ascorbyl)amine, 1) by the reaction of dehydroascorbic acid (DHA) with amino acid, ascorbic acid (AsA) and the reduced red pigment (3) were newly identified, in addition to scorbamic acid (SCA) and the red pigment (4), as intermediate products. The addition of AsA to the DHA-amino acid reaction, as well as to the DHA-SCA reaction, greatly increased the formation of 3 and 1. The reaction of AsA with 4 gave rapidly 3, followed by the gradual production of 1. From these results, a reaction pathway is proposed that 3 formed by the reduction of 4 with AsA is a key intermediate and its condensation with DHA followed by reduction with AsA might produce 2 and 1.     

Synthesis of Optically Pure (R)-4a-Methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone and Its Transformation into (+)-7-Hydroxycostal

A novel synthesis of the enone 12 starting from (+)-dihydrocarvone (3) and its transformation into (+)-7-hydroxycostal (1) are described. The ketone 10, obtained from 4 through a four-step sequence was converted to 12 by acid-catalyzed elimination and subsequent regioselective hydrogenation. Alternatively, the methoxyhydroperoxide 13 generated by the ozonolysis of 4 was subjected to the Criegee rearrangement, providing a mixture of 10 and 14, which on acid treatment, gave 11. Transformation of 12 into 19 was accomplished via a five-step reaction sequence. The reaction of 19 with the lithium alkoxide of 2-lithio-2-propenol afforded (+)-7-hydroxycostol (2), whose oxidation with manganese dioxide gave rise to (+)-7-hydroxycostal (1).     

Synthesis of 3-fluoro-6-S-(2-S-pyridyl) nucleosides as potential lead cytostatic agents

The 3-deoxy-3-fluoro-6-S-(2-S-pyridyl)-6-thio-β-d-glucopyranosyl nucleoside analogs 7 were prepared via two facile synthetic routes. Their precursors, 3-fluoro-6-thio-glucopyranosyl nucleosides 5a-e, were obtained by the sequence of deacetylation of 3-deoxy-3-fluoro-β-d-glucopyranosyl nucleosides 2a-e, selective tosylation of the primary OH of 3 and finally treatment with potassium thioacetate. The desired thiolpyridine protected analogs 7a-c,f,g were obtained by the sequence of deacetylation of 5a-c followed by thiopyridinylation and/or condensation of the corresponding heterocyclic bases with the newly synthesized peracetylated 6-S-(2-S-pyridyl) sugar precursor 13, which was obtained via a novel synthetic route from glycosyl donor 12. None of the compounds 6 and 7 showed antiviral activity, but the 5-fluorouracil derivative 7c and particularly the uracil derivative 7b were endowed with an interesting and selective cytostatic action against a variety of murine and human tumor cell cultures.     

Chemical constituents isolated from Paeonia lactiflora roots and their neuroprotective activity against oxidative stress in vitro

The methanolic extract of Paeonia lactiflora roots significantly protected primary cultures of rat cortical cells exposed to oxidative stress induced by H₂O₂. Seven monoterpenes, paeonilactone-B (1), paeonilactone-C (2), paeoniflorigenone (3), benzoylpaeoniflorin (4), paeoniflorin (5), oxypaeoniflorin (6) and albiflorin (7), were isolated by bioactivity-guided fractionation and further separation using chromatographic techniques. Among them, compounds 2 and 4 significantly protected primary cultures of rat cortical cells against H₂O₂-induced neurotoxicity.     

Microbial transformation of hydrocortisone by two fungal species Fusarium fujikuroi PTCC 5144 and Rhizomucor pusillus PTCC 5134

Abstract

This paper examines the biotransformation of hydrocortisone (1) by Fusarium fujikuroi and Rhizomucor pusillus. These species have not previously been tested for hydrocortisone biotransformation. The metabolites produced during hydrocortisone biotransformation by these two fungi were 11β,17α,20β,21-tetrahydroxypregn-4-en-3-one (2) and 11 β-hydroxyandrost-4-en-3,17-dione (3). Chemical structures were determined by spectroscopic methods. A time course study revealed that the disappearance of hydrocortisone was accompanied by the formation of metabolites 2 and 3. Metabolite 2 was produced as the major metabolite with high yield but the transformation to metabolite 3 was considerably lower, as determined by HPLC.     

Theoretical mechanistic study of the reaction of the methylidyne radical with methylacetylene

A detailed doublet potential energy surface for the reaction of CH with CH₃CCH is investigated at the B3LYP/6-311G(d,p) and G3B3 (single-point) levels. Various possible reaction pathways are probed. It is shown that the reaction is initiated by the addition of CH to the terminal C atom of CH₃CCH, forming CH₃CCHCH 1 (1a,1b). Starting from 1 (1a,1b), the most feasible pathway is the ring closure of 1a to CH₃–cCCHCH 2 followed by dissociation to P ₃ (CH₃–cCCCH+H), or a 2,3 H shift in 1a to form CH₃CHCCH 3 followed by C–H bond cleavage to form P ₅ (CH₂CHCCH+H), or a 1,2 H-shift in 1 (1a, 1b) to form CH₃CCCH₂ 4 followed by C–H bond fission to form P ₆ (CH₂CCCH₂+H). Much less competitively, 1 (1a,1b) can undergo 3,4 H shift to form CH₂CHCHCH 5. Subsequently, 5 can undergo either C–H bond cleavage to form P ₅ (CH₂CHCCH+H) or C–C bond cleavage to generate P ₇ (C₂H₂+C₂H₃). Our calculated results may represent the first mechanistic study of the CH + CH₃CCH reaction, and may thus lead to a deeper understanding of the title reaction.     

Nucleosides. LIV1 Synthesis and Properties of 3′-Azido- and 2′,3′-Dideoxy-6,7-diphenyllumazine Nucleosides

Abstract

The best approach for the synthesis of1-(3-azido-2,3-dideoxy-β-D-erythro-pento-furanosyl)lumazine (5) and its 6,7-dimethyl- (4) and 6,7-diphenyl derivatives (3) has been found in the interconversion of the corresponding 1-(2-deoxy- β-threo-pentofuranosyl)-lumazines. Monomethoxytritylation at the 5′-position (1 7, 3 4, 4 9) followed by mesylation at the 3′-OH group and subsequent nucleophilic displacement by lithium azide afforded 1 9, 2 9 and 4 7 which were deprotected by acid treatment to give 3–5 in good yields. The syntheses of 1-(2,3-dideoxy-β-D-glycero-pentofuranosyl)-6,7-diphenyllumazine (6) and its 6,7-dimethyl derivative (7) were achieved from 1-(2-deoxy-β-D-erythro-pentofuranosyl)-6,7-diphenyllumazine and the corresponding 6,7-dimethyllumazine (2 6) via their 5′-O-p-toluoyl- (2 0, 3 0), and 3′-deoxy-3′-iodo derivatives (2 4, 3 1) to form, after radical dehalogenation and final deprotection, 6 and 7. The newly synthesized lumazine nucleosides have been characterized by elemental analyses, UV-and NMR spectra.     

Nucleosides. LXV. Synthesis of New Pteridine–N8–Nucleosides

A general synthetic approach to various isoxanthopterin‐nucleosides starting from 6‐methyl‐2‐methylthio‐4(3H), 7(8H)‐pterdinedione (1) has been developed. Ribosylation with 1‐O‐acetyl‐2,3,5‐tri‐O‐benzoyl‐β‐d‐ribofuranose via the silyl‐method led to 2 and reaction with 1‐chloro‐2‐deoxy‐3,5‐di‐O‐p‐toluoyl‐α‐d‐ribofuranose using the DBU‐method afforded 28. Protection of the amide function at O⁴ by benzylation to 5 and by a Mitsunobu reaction with 2‐(4‐nitrophenyl)ethanol to 29 gave soluble intermediates which can be oxidized to the corresponding 2‐methylsulfonyl derivatives 8 and 30, respectively. Nucleophilic displacement reactions of the highly reactive 2‐methylsulfonyl functions by various amines proceeded under mild conditions to isoxanthopterin‐N₈‐ribo‐ (11–17) and 2′‐deoxyribomucleosides (31–33). Debenzylation can be achieve by Pd‐catalyzed hydrogenation (9 to 19) and cleavage of the npe‐protecting group (31, 32 to 34, 35) works well with DBU by β‐elimination.     

CYP 17 and CYP 19 Inhibitors. Evaluation of Fluorine Effects on the Inhibiting Activity of Regioselectively Fluorinated 1-(Naphthalen-2-ylmethyl)imidazoles

Regioselectively fluorinated 1-(naphth-2-ylmethyl)imidazoles 1a–h have been synthesized starting from the corresponding (naphth-2-yl)methanols (2). 2a–d have been obtained by LiAlH4-promoted reduction of fluorinated 1-methyl-2-naphthaldehydes. The latter were easily prepared in fairly good overall yields by ceric ammonium nitrate (CAN)-promoted oxidative addition of the suitable 3-(fluoroaryl)-1-trimethylsilyloxy-1-butenes to ethyl vinyl ether in methanol followed by cyclization of the resulting acetals in strongly acidic medium in the presence of DDQ. 2e–h were prepared by LiAlH4-promoted reduction of the corresponding fluorinated methyl 2-naphthoates. The latter were more profitably obtained by reacting the suitable benzyl bromide with the sodium salt of dimethyl 2-(2,2-dimethoxyethyl)malonate in DMF followed by demethoxycarbonylation and acid catalysed cyclization of the resulting acetals. Compared with the non-fluorinated parent compounds 1i–l, fluorinated 1-(naphth-2-yl)methylimidazoles 1a–h turned out to be potent inhibitors of CYP17 and CYP19 enzymes. The most active inhibitor of CYP17 is 1c, whereas CYP19 is strongly inhibited by 1b, 1e, and 1g. Interestingly, 1g is a potent dual inhibitor also being very active towards CYP19.     

2,2′-Anhydro-4′-Thionucleosides: Precursors for 2′-Azido- and 2′-Chloro-4′-thionucleosides and for a Novel Thiolane to Thietane Rearrangement

Abstract

2,2′-Anhydro-4′-thio-β-and α-nucleosides 9 and 10 have been prepared by an in situ 4-thio-1,2-glycal addition route. They undergo ring-opening by azide or chloride ion to give, after deprotection, the 2′-substituted-4′-thionucleosides 13 and 14, whereas reactions with cyanide or fluoride sources lead to the unsaturated nucleosides 17 or 18, depending upon conditions. An unexpected and clean rearrangement to the thietane 23 occurs on treatment of uracil derivative 20 with DAST.     

DNA sequence-specific ligands: XIV. Synthesis of fluorescent biologically active dimeric bisbenzimidazoles DB(3, 4, 5, 7, 11)

Five fluorescent symmetrical dimeric bisbenzimidazoles DB(n) containing four 2,6-substituted benzimidazole cores and differing in the length of the oligomethylene linker between two bisbenzimidazole rings (n = 3, 4, 5, 7, 11) have been synthesized. The ability of the dimeric bisbenzimidazoles to form complexes with the double-stranded DNA has been shown by spectral methods. Upon binding to the double-stranded DNA, DB(n) are localized in the narrow groove. The data on the inhibition of the DNA methyltransferase Dnmt3a by DB(n) indicate that dimeric bisbenzimidazoles DB(3) and DB(11) site-specifically bind to the oligonucleotide duplex.     

A Convenient Method for the Synthesis of 2-(β-D-Glycopyranosylthio) Pyridines

Abstract

Treatment of piperidinium salts of dihydropyridinethiolates 3 with glycosyl bromides 4 in dry acetone provides a convenient and high yielding synthesis of 1,4-dihydro-3-cyanopyridine thioglycosides 5. The structures of 5 were confirmed by oxidation as well as by ¹H NMR and ¹³C NMR spectral analysis.     

苦槛蓝叶中的黄酮类化合物

为了解苦槛蓝(Myoporum bontioides A.Gray)的化学成分,采用色谱分离技术从苦槛蓝叶片中分离得到11个黄酮类化合物。通过波谱分析,他们的结构分别鉴定为:桔皮素(1)、甜橙素(2)、5,4′-二羟基-6,7,8,3′-四甲氧基黄酮(3)、4′,5,7,8-四甲氧基黄酮(4)、去甲基川陈皮素(5)、5-羟基-6,7,3′,4′-四甲氧基黄酮(6)、3′,4′,5,6,7,8-六甲氧基黄酮(7)、二氢山柰酚(8)、木犀草素(9)、3′,4′,5,7-四羟基-3-甲氧基黄酮(10)和芹黄素(11)。除化合物9之外,其他化合物均为首次从苦槛蓝叶片中分离得到。孢子萌发法测定结果表明,化合物1,2,8和9对香蕉炭疽菌(Colletotrichum musae)具有较好的抑菌活性。这为苦槛蓝叶片中有效成分的利用提供了理论依据。