Branched-chain sucroses: Synthesis and Wittig reaction of the 1′-aldehydo derivative of sucrose

The reaction of 2,3,4,3′,4′-penta-O-acetylsucrose (1) with 3.3 mol. equiv. of tert-butyldiphenylsilyl chloride in pyridine in the presence of 4-dimethylamino-pyridine gave the 6,1′,6′-tris(tert-butyldiphenylsilyl) derivative 2 (27%) and the 6,6′-bis(tert-butyldiphenylsilyl) derivative (67%). Oxidation of the HO-1′ in 3 with methyl sulphoxide and trifluoroacetic anhydride gave the 1′-aldehydo derivative 5, which reacted with the stabilised Wittig reagent (Ph₃PCHCO₂Et) to give the 1′-ethoxycarbonylmethylene derivative 6. Deacetylation of the hepta-acetate 7 of 6 with methanolic sodium methoxide was accompanied by a Michael addition reaction to give 2,1′-anhydro-1′-methoxycarbonylmethylsucrose.     

Estrogen effects on MMP-13 and MMP-14 regulation of left ventricular mass in Dahl salt-induced hypertension

Background:Female Dahl salt-sensitive (DS) rats fed a low-salt diet develop hypertension at 6 months of age. Ovariectomy at 2 months of age accelerates the development of hypertension, and estrogen replacement delays it. Although acute pressure overload induces structural changes in the left ventricle (LV) further effects of gradual hypertension on LV remodeling have not been examined in the DS rat model.Objective: The purpose of this study was to test the hypothesis that aging and estrogen loss in hypertensive DS rats are accompanied by changes in LV remodeling.Methods: Four groups of DS rats were examined: young intact, middle-aged (MA) intact, MA ovariectomized (MA-OVX), and MA-OVX with 17β-eestradiol (E₂) supplementation (MA-OVX+E²). Myocardial matrix metalloproteinases (MMPs),tissue inhibitors of metalloproteinases (TIMPs),and extracellular matrix (ECM) proteins were assessed by immunoblotting.Results: Each of the 4 groups comprised 6 animals. Mean (SEM) LV mass was significantly greater in the MA-intact and the MA-OVX groups (1257 [31] mg and 1199 [25] mg, respectively; both, P < 0.05) compared with the young-intact group (697 [6] mg). LV mass in the MA-OVX+E₂ group was significantly lower compared with the MA-intact and MA-OVX groups (both, P < 0.05), suggesting that estrogen may attenuate LV remodeling.Fibronectin and collagen III and IV concentrations increased significantly in the MA-intact and MA-OOVX groups (all, P < 0.05),indicating increased fibrosis. Multiple MMPs also increased in the MA-intact an nd MA-OVX rats, including MMP-3, -7, -99, -113, and -114, and all TIMPs. In contrast, estrogen attenuated fibrosis by increasing MMP-8 concentrations and increasing collagen III fragments. From good-fit regression modeling, MMP-13 and MMP-14 concentrations correlated positively with LV mass for the MA-intact and MA-OVX groups, respectively.Conclusions: Gradual hypertension stimulated ECM turnover by increasing both MMP/TIMP production and ECM degradation.Estrogen loss or gain resulted in a shift in MMP profiles, suggesting that MMP-13 and MMP-14 may be differentially regulated in postmenopausal hypertension.     

Synthesis and antiprotozoal activity of 2,5-bis[amidinoaryl]thiazoles

Seven novel diamidino 2,5-bis(aryl)thiazoles (5a–g) were synthesized and evaluated against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f.). The diamidines were obtained directly from the corresponding bis-nitriles (4a–g) by the action of lithium bis(trimethylsilyl)amide. The bis-nitriles 4a–f were synthesized in four steps starting with the Stille coupling of 2-tributyltinthiazole with the appropriate cyanoaryl halide. The bis-nitrile 5g was obtained by the palladium facilitated coupling of the mixed tin-silyl reagent 2-trimethylsilyl-5-trimethyltinthiazole with 2-bromo-5-cyanopyridine. The amidoxime potential prodrugs 6a–e, 6g were obtained by the reaction of hydroxylamine with the bis-nitriles. O-Methylation of the amidoximes gave the corresponding N-methoxyamidines 7a–c, 7e, 7g. The diamidines showed strong DNA binding affinity as reflected by ΔT_m measurements. Four of the diamidines 5a, 5b, 5d and 5e were highly active in vitro against P. f. giving IC₅₀ values between 1.1 and 2.5 nM. The same four diamidines showed IC₅₀ values between 4 and 6 nM against T. b. r. The selectivity indices ranged from 233 to 9175. One diamidine 5a produced one of four cures at an ip dose of 4 × 5 mg/kg in the STIB900 mouse model for acute African trypanosomiasis. The amidoxime and N-methoxyamidine of 5a were the only produgs to provide cures (1/4 cures) in the same mouse model on oral dosage at 4 × 25 mg/kg.     

Analysis of permethylated hexopyranosyl-2-acetamido-2-deoxyhexitols by g.l.c.-m.s.

The major product obtained on acetonation of d-mannose with a 2-molar excess of isopropenyl methyl (or ethyl) ether is 4,6-O-isopropylidene-α-d-mannopyranose (3a), the product of kinetic acetonation: a larger excess of the reagent leads, to the 2,3:4,6-diisopropylidene acetal (6). The course of the reaction and side-products formed were examined in detail. The 1,2,3-triacetate of 3a was deacetonated to give α-d-mannopyranose 1,2,3-triacetate; similar reactions were performed on the β anomers. The 1-acetate of the diacetal 6 could be selectively deacetonated to give 1-O-acetyl-2,3-O-isopropylidene-α-d-mannopyranose. The reactions provide access to protected derivatives of d-mannose, and partially acylated derivatives, having modes of substitution different from those obtainable by classical acetonation procedures conducted under conditions of thermodynamic control.     

Syntheses and pharmacokinetic evaluations of four metabolites of 2-(4-(2-((1H-benzo[d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis-(methylthio)pyridin-3-yl)acetamide hydrochloride [K-604], an acyl-CoA:cholesterol O-acyltransferase-1 inhibitor

We synthesized and identified four metabolites of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT)-1 inhibitor, K-604 (1). Two of the metabolites M1 and M2, were prepared from 1 using a combination reagent of hydrogen peroxide and sodium tungstate with either phosphoric acid or trifluoroethanol as the solvent to control the regioselectivity. Upon exposure of 4b to tert-butyl hypochlorite at −78 °C, the monosulfoxidation afforded synthetic intermediate of M3 in excellent yield. The efficient synthesis of M4 was established. The in vitro metabolic study exhibited a high clearance value (720 μL/min/mg protein) of 1 using human liver microsomes. We orally administered a single dose of 10 mg/kg of 1 to monkeys because the in vitro metabolic patterns are quite similar. Fortunately, the drug concentration of 1 was much higher than those of M1, M2, M3 and M4.     

Modified colorimetric ninhydrin methods for peptidase assay

Four colorimetric procedures suitable for the determination of peptidase activity on peptides having a free α- or ε-amino group are described. Two of the methods (A and B) are modifications of the conventional ninhydrin method described by S. Moore and W. H. Stein ((1948) J. Biol. Chem.176, 367–388; (1954) Ibid.211, 907–913); the heating time is shortened to 5 min at 100°C and the pH of the buffer in the reagent is lowered to 4.0. Method A differs from method B in buffer concentration. The other two methods (C and D) are modifications of the Cd-ninhydrin method described by A. P. Tsarichenko ((1966) Nauch. Tr. Krasnodar. Gos. Pedagog. Inst.70, 86–88, as cited in Chem. Abs.67, 79479c); the water content in the reagent is reduced to $\text{1}\text{20}$ of the original reagent and the sample is heated for 5 min at 84°C. Method C differs from method D in the ratio of sample to reagent. In contrast to the free amino acids which are sufficiently colored, various peptides and amino acid derivatives except for the glycylpeptides give only a faint color with these methods. These four methods are not only useful for the determination of peptidase activity on peptides (e.g., Leu-Gly and tert-butyloxycarbonyl-glycyl-lysyl-leucine), but are also useful for the determinations of amidase activity on amino acid amides (e.g., Leu-NH₃) and esterase activity on amino acid esters (e.g., tyrosine ethyl ester).     

Effects of bismuth subsalicylate and calcium-ammonium nitrate on ruminal in vitro fermentation of bahiagrass hay with supplemental molasses

There is a need to increase efficiency of beef production. Decreasing losses of CH₄ and improving byproduct utilization are popular strategies. Two feed additives were tested to find potential solutions. Three randomized complete block design experiments were performed using batch culture systems to evaluate the effects of bismuth subsalicylate (BSS) and calcium-ammonium nitrate (CAN) on in vitro ruminal fermentation of bahiagrass hay and supplemental molasses. The first experiment contained four treatments: (1) basal substrate; (2) basal substrate with 0.75% urea (DM basis); (3) basal substrate with 1.2% CAN and 0.38% urea (DM basis); and (4) basal substrate with 2.4% CAN (DM basis). Treatments 2, 3, and 4 were isonitrogenous. The second experiment had a 4 × 3 factorial arrangement of treatments with 4 concentrations of BSS (0.00, 0.33, 0.66, and 1.00%; DM basis) and 3 concentrations of CAN (0.0, 1.2, and 2.4%; DM basis). The third experiment had the following treatments: (1) basal substrate; (2) basal substrate with 0.05% BSS (DM basis); (3) basal substrate with 0.10% BSS (DM basis); and (4) basal substrate with 0.33% BSS (DM basis). For all experiments, basal substrate consisted of Pensacola bahiagrass hay (Paspalum notatum Flüggé; 80% substrate DM) and molasses (20% substrate DM). All data were analyzed using the MIXED procedure of SAS. In Exp. 1, in vitro organic matter (OM) digestibility (IVOMD) was linearly reduced (P < 0.001) with the inclusion of CAN, and CH₄, in mmol/g OM fermented, was decreased linearly (P < 0.001). The volatile fatty acid (VFA) profile was not impacted by the inclusion of nonprotein nitrogen (NPN) or CAN (P > 0.05). In Exp. 2, except for CH₄ production (P < 0.05), there were no BSS × CAN interactions. Linear reductions in total gas production (P < 0.001), IVOMD (P < 0.001), and total concentration of VFA (P = 0.007) were observed with the inclusion of BSS up to 1%. The inclusion of BSS decreased H₂S production in a quadratic manner (P = 0.024). In Exp. 3, IVOMD was not impacted by the inclusion of BSS (P > 0.05); however, production of H₂S was linearly decreased (P = 0.004) with the inclusion of BSS up to 0.33%. In conclusion, in vitro fermentation was negatively impacted by the inclusions of BSS, up to 1%, and CAN, up to 2.4%; however, BSS decreased production of H₂S when included up to 0.33% without impeding fermentation, while CAN decreased CH₄ production.     

Reaction of methanesulphonyl chloride-N,N-dimethylformamide with partially esterified derivatives of sucrose

Treatment of sucrose 2,3,3′,4′,6-penta-acetate (1) with methanesulphonyl chloride-N,N-dimethylformamide (reagent A) gave the 1′,4,6′-trichloride 2, the 1′-O-formyl-4,6′-dichloride 3, the 4,6′-dichloride 4, and the 1′,4-di-O-formyl-6′-chloride 5. De-esterification of 3 afforded the unsubstituted 4,6′-dichloride 6 which, on acetylation, gave the corresponding hexa-acetate 7, also prepared by acetylation of 4. In compounds 2, 3, and 4, substitution at C-4 by chloride ion occurred with inversion of configuration. The structure of 5 was confirmed by conversion into the known 6′chloro-6′-deoxysucrose hepta-acetate by de-esterification followed by acetylation. Treatment of sucrose 1′,2,3,3′,4′,6′-hexa-acetate (10) with the reagent gave the 4,6-dichloride 11 and 4-O-formyl-6-chloride 12. The formyl group in 12 was selectively removed by using an anion-exchange resin to give 16. De-esterification of 12 with methanolic sodium methoxide gave 6-chloro-6-deoxysucrose (13) which, on acetylation and benzoylation, afforded the hepta-acetate 14 and the hepta-benzoate 15, respectively. Alternatively, 15 was prepared by the reaction of 1′,2,3,3′,4,4′,6′-hepta-O-benzoylsucrose with reagent A. Treatment of 14 with sodium methoxide in methanol followed by acetylation gave 3,6-anhydrosucrose hexa-acetate (24). Reaction of sucrose 2,3,3′,4,4′-pentabenzoate (17) with reagent A gave the known 1′,6,6′-trichloro-1′,6,6′-trideoxysucrose pentabenzoate (18) and 1′-O-formyl-6,6′-dichloride 19. Treatment of 19 with anion-exchange resins selectively removed the formyl group to give 20. The structure of 20 was confirmed by conversion into the 1′-chlorosulphate-6,6′-dichloride (21). Treatment of sucrose 1′,2,3,3′,4,4′-hexabenzoate (22) with reagent A gave the expected 6,6′-dichloride (23).     

Two crystalline pentofuranosyl bromides: tri-O-(p-nitrobenzoyl)-β-D-ribofuranosyl bromide and tri-O-(p-nitrobenzoyl)-α,β-D-xylofuranosyl bromide

Methyl α,β-D-ribofuranoside was p-nitrobenzoylated to give methyl tri-O-(p-nitrobenzoyl)-β-D-ribofuranoside (2),and this was treated with HBr in acetic acid to give tri- O-(p-nitrobenzoyl)-β-D-ribofuranosyl bromide (3). Bromide 3 could be converted into 2,5-anhydro-3,4,6-tri-O-(p-nitrobenzoyl)-D-allononitrile (4) with Hg(CN)₂, or hydrolyzed to 2,3,5-tri-O-(p-nitrobenzoyl)-D-ribose (5). On p-nitro- benzoylation, 5 gave tetra-O-(p-nitrobenzoyl)-β-D-ribofuranose (6). The synthesis of tri-O-(p-nitrobenzoyl)-α-β-D-xylofuranosyl bromide (11) started with methyl 3,5-O-isopropylidene-β-D-xyldfuranoside (7), which was p-nitrobenzoylated to give ester 8; this was then hydrolyzed, and the product p-nitrobenzoylated to give methyl tri-O-(p-nitrobenzoyl)-β-D-xylofuranoside (10) which, on treatment with HBr in CH₂Cl₂, afforded the desired bromide (11). Nucleophilic replacement with Hg(CN)₂ afforded 2,5-anhydro-3,4,6-tri-O-(p-nitrobenzoyl)-D-gulononitrile (12).     

2-Thiophenyltellurium derivatives: Alternative synthetic routes and structural characterization

Grignard reagent prepared from 2-thiophenyl bromide in THF consumes elemental tellurium readily at room temperature and provides a route to obtain bis(2-thiophenyl)ditelluride, Tpn₂Te₂ (1, Tpn = 2-C₄H₃S) in good yield. It can also thiophenylate aryltellurium(II) bromides, producing solutions of mixed aryl(heteroaryl)tellurides, which when chlorinated give crystalline aryl(heteroaryl)tellurium(IV) dichlorides, ArTpnTeCl₂ (Ar = 1-C₁₀H₇, Npl; 2,4,6-Me₃C₆H₂, Mes). Oxidative addition of α-bromo-N,N-diethylacetamide to (2-thiophenyl)tellurium(II) bromide, gave the mixed alkyl(heteroaryl)tellurium(IV) dibromide, (Et₂NCOCH₂)TpnTeBr₂. Ditelluride 1 can be detellurated by electrolytic copper to the bis(2-thiophenyl)telluride, Tpn₂Te (2). Chemical shifts, δ(¹H, ¹³C and ¹²⁵Te) for (2-thiophenyl)tellurium(IV) halides are reported. Crystal structures of Tpn₂TeBr₂ (2b), Tpn₂TeI₂ (2c) and Mes(Tpn)TeCl₂ (2e) have been determined unambiguously. In the case of 2e, steric repulsion of the mesityl ligand counters the tellurium lone pair repulsion to widen the equatorial C-Te-C angle to the extent of 108°. In the crystal lattices of 2b and 2c, the intermolecular Te?X secondary bonds give rise to an interesting tetrameric supramolecular architecture with S₂ symmetry that defies the stereochemical activity of the lone pair on the central tellurium atom.     

Synthesis and pharmacological evaluation of optically pure,novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists

A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT_2B and 5-HT₇ receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT_2B (K_i = 5.1 nM) and 5-HT₇ (K_i = 1.7 nM) receptors with high selectivity over 5-HT_2A, 5-HT_2C, α₁, D₂ and M₁ receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.     

Synthesis and reactions of α- and β-d-glucopyranosyluronic esters of amino acids

The synthesis of the fully benzylated α- and β-d-glucopyranosyluronic esters of 1-benzyl N-benzyloxycarbonyl-l-aspartic and -glutamic acids and N-(tert-butoxycarbonyl)-l-phenylalanine, followed by hydrogenolysis, afforded the respective anomers of the 1-O-acyl-d-glucopyranuronic acids 2, 7, and 12. Esterification of both anomers of the N-acetylated derivatives of 2 and 7 by diazomethane was accompanied by glycosyl-bond cleavage, and, in the case of the α anomers, with concomitant 1→2 acyl migration to give, after O-acetylation, the 2-O-acyl O-acetyl methyl ester derivatives 5 and 10, respectively. Similarly, 12α yielded methyl 1,3,4-tri-O-acetyl-2-O-[N-(tert-butoxycarbonyl)-l-phenylalanyl]-d-glucopyranuronate and an analogue having a furanurono-6,3-lactone structure. Esterification of the C-5 carboxyl group, in 1-O-acyl-α-d-glucopyranuronic acids by methanol in the presence of the BF_3^?-MeOH reagent (1–1.5 equiv.) proceeded without acyl migration. By using this procedure, followed by acetylation, the N-acetylated derivative of 7α afforded methyl 2,3,4-tri-O-acetyl-1-O-(1-methyl N-acetyl-l-glutam-5-oyl)-α-d-glucopyranuronate, and 12α gave methyl 2,3,4-tri-O-acetyl-1-O-(N-acetyl-l-phenylalanyl)-α-d-glucopyranuronate; the formation of the latter involved cleavage of the tert-butoxycarbonyl group by BF₃, followed by N-acetylation in the next step.     

Greater Combined Reductions in Hba1C ≥1.0% and Weight ≥5.0% with Semaglutide Versus Comparators in type 2 Diabetes

Objective: Semaglutide is a glucagon-like peptide 1 (GLP-1) analog for the once-weekly treatment of type 2 diabetes (T2D). In the global SUSTAIN clinical trial program, semaglutide demonstrated superior glycated hemoglobin (HbA_1c) and body weight reductions versus comparators. This post hoc analysis compared the proportion of patients achieving combined reductions in glycemia and body weight versus comparators.Methods: A total of 5,119 subjects with T2D in the phase 3 SUSTAIN 1 through 5 and 7 trials, from 33 countries, were included in this post hoc analysis. Subjects received subcutaneous semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg, insulin glargine, dulaglutide 0.75 or 1.5 mg). The main endpoint was a composite of ≥1.0% HbA_1c reduction and ≥5.0% weight loss at end of treatment.Results: Significantly greater proportions of subjects achieved the composite endpoint with semaglutide 0.5 (25 to 38%) and 1.0 mg (38 to 59%) versus comparators (2 to 23%). More subjects treated with semaglutide versus comparators achieved ≥1.0% HbA_1c reductions (58 to 77% and 75 to 83% for semaglutide 0.5 and 1.0 mg versus 12 to 68%) and ≥5.0% weight loss (37 to 46%, 45 to 66% versus 4 to 30%). Proportions of subjects achieving targets were significantly higher with semaglutide 1.0 versus 0.5 mg in four of five trials. Semaglutide was well tolerated, with a safety profile similar to other GLP-1 receptor agonists.Conclusion: Significantly more subjects achieved both ≥1.0% HbA_1c reduction and ≥5.0% weight loss with once-weekly subcutaneous semaglutide treatment versus comparators in the SUSTAIN trials. A dose-dependent effect was observed with semaglutide.Abbreviations: AE = adverse event; CV = cardiovascular; ER = extended release; GLP-1 = glucagon-like peptide 1; GLP-1 RA = glucagon-like peptide 1 receptor agonist; HbA_1c = glycated hemoglobin; OAD = oral antidiabetic drug; sc = subcutaneous; T2D = type 2 diabetes     

New carboxamides bearing benzenesulphonamides: Synthesis,molecular docking and pharmacological properties

Ten new derivatives of benzenesulphonamide bearing carboxamide functionality were synthesized and investigated for their in vitro antimicrobial, antioxidant and in vivo anti-inflammatory activities. Compound 9d inhibited carrageenan induced rat-paw oedema at 93.81, 88.79 and 86.09% at 1 h, 2 h and 3 h administration respectively. In the antimicrobial activity, compound 9a (6.54, 6.69 and 6.64 mg/mL) was most potent against S. aureus, B. subtilis and C. albicans respectively, compound 9e (6.45 and 6.46 mg/mL) was most active against P. aeruginosa and A. niger respectively while compound 9i (6.24 mg/mL) was most active against E. coli. Only compound 9a (IC₅₀ 0.3052 mg/mL) had comparable activity with Vitamin C (IC₅₀ 0.2090 mg/mL) in the antioxidant assay.     

cis-Dichloroplatinum (II) complexes with aminomethylnicotinate and -isonicotinate ligands

6-Aminomethylnicotinic acid (1a) and 2-aminomethylisonicotinic acid (1b) were each reacted with K₂PtCl₄ in aqueous 1 M HCl to give the corresponding N,N-chelated cis-dichloroplatinum(II) complexes 2. These were converted into amides 3 via their mixed anhydrides by treating them first with ethyl chloroformate and then with the respective 1° or 2° amine. The analogous 6-aminomethylnicotinic acid ester complexes 7 were obtained by reaction of the preformed ligands with K₂PtCl₄.     

Hydrogenolysis of benzylidene acetals of 1,6-anhydro-β-d-galactopyranose derivatives with the LiAlH4—AlCl3 reagent

Benzylidenation of 1,6-anhydro-β-d-galactopyranose (1) and its 2-O-acetyl (2) and 2-O-allyl (3) derivatives under various conditions afforded mixtures of 1,6-anhydro-exo- and -endo-3,4-O-benzylidene-β-d-galactopyranose (4 and 5) and the2-O-acetyl (6 and 7) and 2-O-allyl (8 and 9) derivatives, respectively. Hydrogenolysis of the exo (4 and 8) or the endo (5 and 9) derivatives with the LiAlH₂—AlCl₃ reagent gave only the 3-O-benzyl derivatives (10 and 11).     

Preparation of novel (Z)-4-ylidenebenzo[b]furo[3,2-d][1,3]oxazines and their biological activity

A reaction of 2-acetyl-3-acylaminobenzo[b]furans (9d–o) with Vilsmeier (VM) reagent afforded a mixture of (E)- and (Z)-{(E)-2-aralkenylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylidene}acetaldehydes (5) with a characteristic exo-formylmethylene group on the oxazine ring. The Z-isomer was more stable than the E-isomer. The Z-isomers ((Z)-5) were reacted with phosphonate reagents under two different conditions to obtain various butadiene derivatives (12) containing benzo[b]furo[3,2-d][1,3]oxazine skeleton. Typical compounds (5 and 12) were evaluated for their anti-osteoclastic bone resorption activity, antagonistic activity for the cysLT1 receptor and growth inhibitory activity for MIA PaCa-2 and MCF-7. Compounds 12f and 12j showed potent anti-osteoclastic bone resorption activity comparable to E₂ (17β-estradiol).     

Hydrolysis of neutral phosphate and phosphonate esters catalysed by Co2+-chelates of tris-imidazolyl phosphines

The hydrolysis of two neutral phosphate esters, (tris-2-pyridylphosphate and tris-p-nitrophenylphosphate, 5 and 4 respectively) and a phosphonate ester (ethyl-p-nitrophenylmethylphosphonate (6)) were studied in the presence of Co²⁺-complexes of two tris- imidazolylphosphines. In the hydrolyses of both 5 and 6, the Co²⁺-complex of bis-[4,5-diisopropyl- imidazol-2-yl]imidazole-2-yl phosphine (2) appears to act as the anionic form, generated by ionization of a Co²⁺-bound H₂O having a pK_a of ～8 at 37 °C in 80% ethanol-H₂O. On the other hand, the Co²⁺-complex of bis-[4,5-diisopropylimidazol-2-yl]-4(5)- hydroxyethylimidazol-2-yl phosphine (3) catalyses the hydrolyses of 5 and 6 with an activity which increases linearly with pH. In this case, the active form of Co²⁺:3 has a pK_a in excess of 8.3 which apparently obtains from ionization of the Co²⁺- associated hydroxyethyl group. Evidence is presented that Co²⁺:3 functions as a general base catalyst in the hydrolysis of 5.     

Synthesis and reactions of 1′,2:4,6-di-o-isopropylidene-sucrose

The reaction of sucrose with a combination of 2,2-dimethoxypropane, N,N-dimethylformamide, and toluene-p-sulphonic acid (reagent A) gave, after acetylation followed by chromatography, 1′,2:4,6-di-O-isopropylidenesucrose tetra-acetate (1) in 15% yield. The structure of 1 was determined on the basis of p.m.r. and mass spectrometry, and by chemical transformations. Treatment of 1 with aqueous acetic acid afforded sucrose 3,3′,4′,6′-tetra-acetate 2. Reacetalation of 2 using reagent A gave 1 in 80% yield. The p.m.r. spectrum of 2 confirmed the presence of hydroxyl groups at C-2 and C-4. The following sequence of reactions showed that the remaining two hydroxyl groups were located at C-6 and C-1′. Selective tritylation of 2 gave 1′,6-di-O-tritylsucrose 3,3′,4′,6′-tetra-acetate (3) as the minor, and 6-O-tritylsucrose 3,3′,4′,6′-tetra-acetate (4) as the major, product. When tritylation was carried out under forcing conditions, 2 gave 3 as the major product. Acetylation of 4 afforded 6-O-tritylsucrose hepta-acetate. Mesylation of 2 gave the tetramethanesulphonate 5, which afforded the 6-dcoxy-6-iodo derivative 6 on treatment with a refluxing solution of sodium iodide in butanone. Treatment of 3 with methanesulphonyl chloride in pyridine gave the disulphonate 7, which on detritylation followed by acetylation gave 2,4-di-O-methanesulphonylsucrose hexa-acetate (9). Treatment of 9 with sodium benzoate in hexamethylphosphoric triamide displaced the 4-sulphonate, with inversion of configuration, to give the galacto derivative 10.     

Synthesis and pharmacological evaluation of pyrazolo[4,3-c]quinolinones as high affinity GABAA-R ligands and potential anxiolytics

The synthesis, in vitro ligand binding study and in vivo Elevated Plus Maze test (EPM) of a series of pyrazolo[4,3-c]quinolin-3-ones (PQs) are reported. Multistep synthesis of PQs started from anilines and diethyl 2-(ethoxymethylene)malonate to give the quinolin-4-one nucleus, via the Gould-Jacobs reaction. These quinolinones were transformed to 4-chloroquinolines, which react with aryl-hydrazines affording the final compounds. PQs exhibited different potency in displacing specific [³H]Flunitrazepam binding from the benzodiazepine binding site at the γ-aminobutyric acid receptor (GABA_A-R) depending on the substitution of the pyrazoloquinolone nucleus. PCA helped determine how different substituents contributed to the differential behavior of the PQs studied. Compounds with high affinity for the GABA_A-R were tested regarding their anxiolytic properties in Wistar adult male rats using the Elevated Plus Maze (EPM). Thus, PQs with a p-methoxy phenyl group at N-1 (7b-ii and 7c-ii) displayed a remarkable anxiolytic activity at low doses (0.5–1.0?mg/kg). Meanwhile, PQs featuring an unsubstituted phenyl (7b-i) or p-fluoro phenyl group (7b-iii) at the N-1 showed anxiogenic effects in the EPM test.