Tetrahydro Derivatives Research Articles

IDN5706 Inhibits Synovial Inflammation via Inducing M2 Polarization of Synovial Macrophages in Osteoarthritis Rats

Introduction: IDN5706 is a tetrahydro derivative of hyperforin. In this study, we aimed to explore the effect of IDN5706 on synovial macrophages in osteoarthritis (OA) rats and the underlying mechanisms. Methods: OA rats were employed for the in vivo experiments, and RAW264.7 cells were employed for the in vitro experiments. Histopathological changes in synovium were examined using hematoxylin-eosin staining. Cell apoptosis in synovium was assessed by TUNEL staining. Macrophage polarization was determined by immunohistochemical analysis and flow cytometry. The mRNA expression and protein level of genes were detected by qRT-PCR and Western blot. The efferocytosis of macrophages was assessed by flow cytometry. Results: IDN5706 reversed the increased CD86-positive cells (M1 macrophages) and decreased CD206-positive cells (M2 macrophages), both in synovium and synovial fluid of OA rats. The in vitro experiments further confirmed the promotion effect of IDN5706 on M2 macrophages, accompanied by the elevated Arg-1 and reduced iNOS. Also, the upregulated p-mTOR in synovium and synovial fluid of OA rats were reversed by IDN5706, and the decreased M1 macrophages and increased M2 macrophages induced by IDN5706 were reversed by the mTOR activator. IDN5706 enhanced the efferocytosis of IL-4-treated RAW264.7 cells, and the animal experiments further revealed the involvement of efferocytosis in the improvement of OA by IDN5706. Conclusions: IDN5706 enhanced the efferocytosis of synovial macrophages by inducing M2 polarization via inhibiting p-mTOR, thus suppressing synovial inflammation and OA development, providing a theoretical basis for IDN5706 as a clinical drug for inflammatory diseases.

Stability of human stress hormones and stress hormone metabolites in wastewater under oxic and anoxic conditions.

Levels in wastewater of human stress biomarkers, such as cortisone (E), cortisol (F), tetrahydrocortisone (THE), and tetrahydrocortisol (THF) may serve as indicators of population wellbeing and overall health. This study examined the stability of these biosignature compounds in wastewater to inform on their applicability for use in wastewater-based epidemiology (WBE). Wastewater from two undisclosed U.S. municipalities were fortified with the above four biomarkers of stress to a concentration of 10 ppb, and their decay was studied at three temperatures (15, 25, and 35 °C) over 24 h in oxic and anoxic conditions. Samples were analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS) in conjunction with the isotope dilution method for absolute quantitation. Results demonstrated short-term persistence (24 h) of biomarkers at low temperatures (15 °C), and accelerating kinetics of decay that were positively correlated with temperature increases. Among the four biomarkers evaluated, the tetrahydro derivatives were the most long-lived sewage-borne stress biomarkers and these are recommended as prime analytical targets for use in WBE when tracking population stress. Statistical analyses using a non-parametric Wilcoxon test further revealed no significant differences (p > 0.05) between oxic and anoxic decay rates for all stress biomarkers in wastewater from all study locations, regardless of the prevailing temperature regime. This negative finding is worthy of reporting because it suggests the feasibility of straightforward modeling of stress hormone decay, irrespective of whether the sewerage system monitored contains fully filled, pressurized pipes or partially filled gravity flow pipes, whose filling level, and with it its redox conditions, are known to fluctuate over time with water use and storm events.

Gas chromatography-mass spectrometry based steroid metabolomics in women with different phenotypes of polycystic ovarian syndrome and normal body weight

Objective: to study the steroid metabolomics in women with normal body weight and various PCOS phenotypes by gas chromatography-mass spectrometry (GC-MS). Materials and methods: forty-eight(48)women with PCOS aged 25±0,3 yearswith a BMI less than 25 kg/m2 were examined. The control group (CG) consisted of twenty-five (25) healthy women aged 26±0,6 years with a BMI of 23 (21-24) kg/m2. Immunoassays were used to determine the levels of hormones in serum. Urinary steroid profiles (USP) were studied by GC-MS method. Statistical data processing was performed using the software system STATISTICA for WINDOWS (ver. 10). Results: the article provides an analysis of the metabolism of androgens, glucocorticoids and progestogens in women with different phenotypes of polycystic ovary syndromeaccording to gas chromatography-mass spectrometry. Summary: the urinary excretion of androstenedione metabolites was increased in PCOS patients with androgen excess and anovulation (A and B phenotypes), dehydroepiandrosterone metabolites - in PCOS patients with androgen excess (A, B and C phenotypes). PCOS women with phenotype C showed raised urinary excretion of 11-oxo-pregnanetriol, pregnanetriol and 17-hydroxypregnanolone, a decrease in the ratios of the sum of tetrahydro derivatives of cortisol and cortisone to these progestogens, as well as determination of tetrahydro-21-deoxycorticol and nonclassical 5-ene-pregnenes according to GC-MS data. In fact, it indicated to deficiency of the 21-hydroxylase enzyme in these patients. It was found PCOS patients with androgen excess (A, B and C phenotypes) had the signs of insufficient 3β-hydroxysteroid dehydrogenase activity. PCOS women with phenotype A were revealed deficiency of 11β-hydroxysteroid dehydrogenase (type 1).

Synthesis and further transformations of 8-chloro-3,4-dihydroisoquinoline

Two procedures for the synthesis of barely accessible 8-chloro-3,4-dihydroisoquinoline were investigated. The first approach is based on a directed ortho-lithiation of N-pivaloyl meta-chlorophenylethylamine, followed by formylation and subsequent ring closure under acidic conditions. In the second, more advantageous variant, the N-hydroxyethyl ortho-chlorobenzylamine intermediate undergoes a Friedel-Crafts reaction, and the resulting tetrahydro derivative is oxidized with N-bromosuccinimide. The 8-chloro-3,4-dihydroisoquinoline key intermediate is then applied in Suzuki reactions to give various 8-aryl-3,4-dihydroisoquinolines, which are finally treated with alkyl or aryllithiums to give 1-substituted 8-aryl-1,2,3,4-tetrahydroisoquinolines. These novel 1,2,3,4-tetrahydroisoquinoline derivatives can be used as building blocks in the synthesis of potential drug candidates.

Biotransformation of Bicyclic Sesqui- and Diterpene 1,2-dials and Their Derivatives by the Fungus, Aspergillus niger

Microbial biotransformation of naturally occurring pungent sesquiterpene 1,2-dials, polygodial and cinnamodial, and a diterpene 1,2-dial, sacculatal as well as their tetrahydro derivatives was carried out by using Aspergillus niger. The pungent polygodial and sacculatal are toxic against A. niger not to produce any metabolites while A. niger biotransformed cinnamodial to the lactonized products in small amount. On the other hands, the dihydroxy derivatives of the former two dialdehydes were bioconverted by the same fungus to give hydroxy-, oxo-, carboxylic- and epoxy-products. The stereostructures of each metabolite and their metabolic pathways were described.

Synthesis of masked 2-amino-6-methyl-4-oxo-4H-pyran-3-carbaldehydes

Acetoacetylation of (1,3-dimethylbenzimidazol-2-ylidene)-, (3-methylbenzothiazol-2-ylidene)-, and (3,4-dimethylthiazol-2-ylidene)acetonitriles with 2,2,6-trimethyl-4H-1,3-dioxin-4-one was found to yield appropriate C-acylation products. Treatment of the obtained products with perchloric acid afforded 2-(2-amino-6-methyl-4H-pyran-4-one-3-yl)substituted quaternary azolium salts. Their reduction with sodium borohydride yielded the corresponding dihydro (in the case of benzoazoles) or tetrahydro (in the case of thiazole) derivatives, which were shown to be synthetic equivalents of the title aldehyde.

9,10-Dihydrophenanthrene with Two Spiro(dibenzocycloheptatriene) Units: A Highly Strained Caged Hydrocarbon Exhibiting Reversible Electrochromic Behavior.

The title dispiro hydrocarbon 1 was designed as a new electrochromic material. This multiply clamped hexaphenylethane-type electron donor was prepared from 2,2′-diiodobiphenyl via biphenyl-2,2′-diylbis(dibenzotropylium) 22+ salt. X-ray analysis of 1 revealed a highly strained structure as reflected by an elongated “ethane” bond [bond length: 1.6665(17) Å] and nearly eclipsed conformation. The weakened bond was cleaved upon two-electron oxidation to regenerate the deeply colored dication 22+. The reversible interconversion between 1 and 22+ is accompanied not only by a drastic color change but also by C–C bond formation/cleavage. Thus, the voltammogram showed a pair of well-separated redox waves, which is characteristic of “dynamic redox (dyrex)” behavior. The tetrahydro derivative of 1 with two units of spiro(dibenzocycloheptadiene), which suffers from more severe steric congestion, was also prepared. The crystallographically determined bond length for the central C–C bond [1.705(4) Å] is greatest among the values reported for 9,9,10,10-tetraaryl-9,10-dihydrophenanthrene derivatives.

Cyclopentadienones via a tandem C-cyclopropylnitrone cyclization-cycloreversion sequence.

Aldonitrones derived from spiro[2.4]hepta-4,6-diene-1-carbaldehyde and its benzo analog undergo a tandem uncatalyzed intramolecular cyclopropane-nitrone cyclization-5,6-dihydro-1,2-oxazine cycloreversion to give cyclopentadienones. Similarly, the NH-nitrone generated in situ from spiro[cyclopropane-1,1'-indene]carbaldehyde oxime leads to benzocyclopentadienone (1H-inden-1-one) by the same mechanism. DFT calculations are in favor of a concerted yet highly asynchronous pathway for the cyclizations. Control experiments with the dihydro and tetrahydro derivatives show that the spirocyclopentadiene unit is essential for the success of the reaction, invoking spiroconjugative effects for increased cyclopropane reactivity.

Cobalt Encapsulated in N-Doped Graphene Layers: An Efficient and Stable Catalyst for Hydrogenation of Quinoline Compounds

Porous nitrogen-doped graphene layers encapsulating cobalt nanoparticles (NPs) were prepared by the direct pyrolysis process. The resulting hybrids catalyze the hydrogenation of diverse quinoline compounds to access the corresponding tetrahydro derivatives (THQs), important molecules present in fine and bulk chemicals. Near-quantitative yields of the corresponding THQs were obtained under optimized conditions. Notably, various useful substituted quinolines and other biologically important N-heteroarenes are also viable. The enhanced stability of the catalyst is ascribed to the encapsulation structure, which can enormously reduce the extent of leaching of base metals and protect metal NPs from growing larger. The achieved success in the encapsulation of metal NPs within graphene layers opens an avenue for the design of highly active and reusable heterogeneous catalysts for more challenging molecules.

New Synthesis of Isoindolo[2,1–b]isoquinolines. Preparation and Aqueous Bioavailability of its Silica Nanoparticles Hybrid System

In this paper we report a new strategy for the synthesis of isoindolo[2,1-b]isoquinolines. N-(1,2- Diphenylethyl)acetamides prepared from the corresponding deoxybenzoins were used as starting material. Double cascade cyclization of the amides promoted by oxalyl chloride and stannyl chloride afforded the oxidized isoindolo[ 2,1-b]isoquinolinone derivatives, which by reduction with a BH3·THF complex gave the 5,7,11b,12- tetrahydroisoindolo[2,1-b]isoquinolines 1b and 1d. Cyclization and reduction were also carried out in one-pot reaction improving the overall yield. DFT structural analysis of the tetrahydro derivatives showed a constrained and planar structure similar to that of camptothecin. SiO2 nanoparticles of 1b (1b-SiNP) were also prepared. This hybrid material provides a very good bioavailability for these compounds in aqueous systems. Keywords: Alkaloid, aza-heterocyclic, cascade reaction, conformational analysis, drug delivery, isoquinolone, oxalyl chloride, toposiomerase- 1.

Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases

The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins using NAD+ as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with β-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused >1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50=2nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2.

Easy synthesis of new series of pteridine analogs: di- and tetra-hydropyrimido[4,5-d]pyrimidines via 5-pyrimidinecarbaldehydes

Pyrimidine-5-carbaldehyde derivatives, of easy acce ss, were selected as precursors for the synthesis of mimic pteridine derivatives 5,6-dihydr opyrimido(4,5-d)pyrimidines and 5,6,7,8- tetrahydropyrimido(4,5-d)pyrimidines via 4-amino-(5-aminomethyl)pyrimidine intermediates. Straightforward procedures allow a quick access to these compounds. The dihydro derivatives were prepared means of a final cyclocondensation ca rried out with orthoesters, catalysed by acid and assisted by microwaves irradiation under solven t free conditions. The final cyclo- condensation with carbonyl compounds forming the tetrahydro derivatives was done under mild conditions, in which stereochemical induction was c arried out on the building of this skeleton, and stereochemistry assignments corroborated by theoretical calculations.

Synthesis of new fused penta- and hexacyclic polynitrogen systems from 1H-benzimidazol-2-ylacetonitrile

In recent time, fused polynitrogen heterocycles attract interest as promising pharmacologically active compounds exhibiting pronounced antiviral, immunosuppressive, antitumor, and other properties [1]. In continuation of studies directed toward searching for biologically active compounds in the series of nitrogen-containing heterocycles [2], the present communication reports on the synthesis of a derivative of novel 8H-pyrido[1′′,2′′ : 1′,2′]pyrimido[5′,4′ : 5,6]pyrido[1,2-a]benzimidazole heterocyclic system, as well of a tetrahydro derivative of the known benzimidazo[1,2-a]naphtho[2,1-g][1,8]naphthyridine system [3]. 1H-Benzimidazole-2-ylacetonitrile (I), being a C,N-binucleophile, is known to react with heterocyclic o-chloro aldehydes to give polycyclic compounds via tandem nucleophilic substitution pattern [3]. Analogous reactions of nitrile I with o-chloro aldehydes II and III in DMF afforded new fused polycyclic polyaza heterocycles IV and V, respectively. The product structure was confirmed by elemental analysis and IR and H NMR spectroscopy.

Synthesis of Some New 2-Mercapto/Hydrizino 5, 6, 7, 8 - Tetrahydro Quinazoline Derivatives as In-Vitro Anthelimentic Agents

A new series of substituted 5, 6, 7, 8 tetrahydro quinazoline derivative has been synthesized from a mixture of methyl/ethylacetoacetate with different substituted aromatic/ hetero aromatic aldehydes. Then treated with aminoguanidines / thiourea afforded 2-hydrizino substituted 5, 6, 7, 8-tetrahydro quinazoline (D1-8)/ 2-mercapto substituted 5, 6, 7, 8-tetrahydro quinazoline derivatives (E1-8). The structures of newly synthesized compounds were confirmed by spectral data (IR, H 1

Absolute Configuration and Conformational Analysis of Brevipolides, Bioactive 5,6-Dihydro-α-pyrones from Hyptis brevipes

The (6'S)-configuration of brevipolides A-J (1-10), isolated from Hyptis brevipes, was established by X-ray diffraction analysis of 9 in conjunction with Mosher's ester analysis of the tetrahydro derivative 11 obtained from both geometric isomers 8 and 9 as well as by chemical correlations. The structure of the new brevipolide J (10) was characterized through NMR and MS data as having the same 6-heptyl-5,6-dihydro-2H-pyran-2-one framework possessing the cyclopropane moiety of all brevipolides but substituted by an isoferuloyl group instead of the p-methoxycinnamoyl moiety found in 8 and 9. Conformational analysis of these cytotoxic 6-heptyl-5,6-dihydro-α-pyrones was carried out on compound 9 by application of a protocol based on comparison between experimental and DFT-calculated vicinal (1)H-(1)H NMR coupling constants. Molecular modeling was used to correlate minimum energy conformers and observed electronic circular dichroism transitions for the isomeric series of brevipolides. Compounds 7-10 exhibited moderate activity (ED(50) 0.3-8.0 μg/mL) against a variety of tumor cell lines.

ChemInform Abstract: A Highly Efficient and Enantioselective Access to Tetrahydroisoquinoline Alkaloids: Asymmetric Hydrogenation with an Iridium Catalyst.

AbstractThe iridium hydrido complex in combination with elemental iodine allows the preparation of tetrahydro derivatives with high levels of enantioselectivity.

Synthesis of novel thienonorbornylpurine derivatives

The synthesis and antiviral evaluation of 6-amino- and 6-chloro-9-(exo-bicyclo[2.2.1]hept-2yl)-9H-purine derivatives with thiophene and tetrahydrothiophenes annelated to a norbornane moiety are described. The key step in the synthesis of derivatives with the symmetrically annelated thiophene was the Mitsunobu reaction of endo-4-thiatricyclo[5.2.1.02,6]deca-2,5-dien-8-ol with 6-chloropurine. The key alcohol was obtained by DDQ mediated aromatization of the corresponding tetrahydro derivatives, which were used for the preparation of the target tetrahydrothieno analogs. The key intermediate for the synthesis of derivatives with the asymmetrically annelated thiophene was 8-exo-azido-3-thiatricyclo[5.2.1.02,6]deca-2(6),4-diene, which was prepared from 5-exo-azido[2.2.1]heptan-2-one by aldol condensation with O-ethyl S-(2-oxoethyl) carbonodithioate, deprotection and cyclization. The target compounds were obtained by the construction of the purine base on an amine, which was obtained by LAH reduction of the key azide. The synthesized compounds were evaluated for antiviral and cytostatic activity.

Synthesis and evaluation of tetrahydro β-carboline derivatives as anticancer agents

Synthesis and evaluation of tetrahydro β-carboline derivatives as anticancer agents

Transformation of (±)-lavandulol and (±)-tetrahydrolavandulol by a fungal strain Rhizopus oryzae

Biotransformation of an irregular monoterpene alcohol, (±)-lavandulol [(±)-5-methyl-2-(1-methylethenyl)-4-hexen-1-ol] (I) and its tetrahydro derivative, (±)-tetrahydrolavandulol [(±)-2-isopropyl-5-methylhexan-1-ol] (II) were studied using a soil isolated fungal strain Rhizopus oryzae. Five metabolites, 2-((3,3-dimethyloxiran-2-yl)methyl)-3-methylbut-3-en-1-ol (Ia), 2-methyl-5-(prop-1-en-2-yl)hex-2-ene-1,6-diol (Ib), 2-methyl-5-(prop-1-en-2-yl)hexane-1,6-diol (Ic), 2-(3-methylbut-2-enyl)-3-methylenebutane-1,4-diol (Id), 5-methyl-2-(2-methyloxiran-2-yl)hex-4-en-1-ol (Ie) have been isolated from the fermentation medium and characterized with lavandulol as a substrate. When tetrahydrolavandulol used as a substrate, two metabolites 2-isopropyl-5-methylhexane-1,5-diol (IIa) and 2-isopentyl-3-methylbutane-1,3-diol (IIb) have been isolated from the fermentation medium. Biotransformation studies with R. oryzae clearly indicate that the organism initiates the transformation either by hydroxylation at allylic methyl groups or epoxidation of double bond. GC and GCMS analyses indicated that both (R)- and (S)-enantiomers of I and II have been transformed into corresponding hydroxylated or epoxy derivatives, when racemic I and II were used as substrates.

A Highly Efficient and Enantioselective Access to Tetrahydroisoquinoline Alkaloids: Asymmetric Hydrogenation with an Iridium Catalyst

The iridium hydrido complex in combination with elemental iodine allows the preparation of tetrahydro derivatives with high levels of enantioselectivity.