The synthesis of 18beta-glycyrrhetinic acid derivatives which have increased antiproliferative and apoptotic effects in leukemia cells

18beta-Glycyrrhetinic acid (GA), 3beta-hydroxyl-11-oxo-olean-12-ene-29-oic acid, has been found to inhibit growth and to induce apoptosis in cancer cells. Through structural modification, 16 GA derivatives (12 novel compounds) with modified structures at the C(3) and C(29) positions were synthesized. The antiproliferative effects and apoptosis induction abilities of these compounds were determined in human leukemia HL-60 cells. The replacement of the hydroxyl group of GA with a carbonyl group or an oxime group at C(3) position does not influence the antiproliferative effect. However, the antiproliferative and apoptosis induction abilities of the compounds with a replaced alkoxyimino group at position C(3) and a free C(29) carboxyl group are markedly increased.     

Studies on the Chemical Constituents of Annona squamosa(5)

From the seeds of Annona squamosa L.,three compounds were obtained,in which compounds i and 2 are known compounds,i.e. bullatacin and annonin I,respectively.Compounds 3 is a new non -adjacent bis -tetrahydrofuranyl annonaceous acetogenin,named squamostatin C.Based on the analysis of IR MS,1H NMR and 13 C NMR spectra,the structure of compound 3 was elucidated as (3).     

Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity

We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.     

雷公藤二萜类化合物精细立体结构研究

雷公藤二萜内酯类化合物在结构上有一定的相似性:它们均含有3个六元环、1个五元内酯环和1～3个二元氧环,并且具有多种生物活性。本文选择了7个具有代表性的雷公藤二萜内酯化合物并通过X衍射分析获得其三维结构数据,以已有的药理实验数据为基础,对其精细立体结构变化和生物活性关系进行了探讨。研究结果表明:雷公藤萜内酯类化合物中的A、B、C三个六元环是其活性骨架的几何依托;18位上的羰基和7～8位上的三元氧环是其活性的可能结合部位;而该类化合物的活性部位则集中在C环的取代位置上;D环不是该类化合物具有生物活性的必需骨架部分。     

Synthetic peptides as antagonists of the anaphylatoxin C3a.

Peptide compounds resembling the receptor-binding C-terminal domain of the anaphylatoxic peptide C3a were synthesized to examine two kinds of C3a antagonism: (a) specific desensitization of C3a-sensitive cells and (b) competitive binding to the C3a receptor. We used guinea-pig platelets, which express a C3a receptor and specifically release ATP upon stimulation, to evaluate the actions of the C3a analogues. The ATP liberation can be inhibited by pretreatment (i.e. desensitization) of the guinea-pig platelets with substimulatory concentrations of C3a or its analogues. Compared to C3a, several peptides were found with at least a tenfold greater difference between the required concentrations for C3a-specific half-maximal desensitization (DD50) and half-maximal platelet activation (ED50). The most potent compounds were YAAALKLAR and Fmoc-EAALKLAR (Fmoc: 9-fluorenylmethoxycarbonyl) with an ED50/DD50 of 140 +/- 28 and 80 +/- 17, respectively (mean +/- standard deviation). The ED50/DD50 of human C3a was found to be only 6 +/- 2. Some C3a derivatives were also tested in competitive binding studies for their ability to compete with C3a for receptor sites on guinea-pig platelets. Three of them were considered partial antagonists [YRRGRCGGLCLAR, YRRGRXCGGLCLAR and YRRGRXCGALCLAR (X = 6-aminohexanoyl)] because their Ki were smaller than their ED50 (Ki/ED50 = 0.6 +/- 0.3, 0.5 +/- 0.1 and 0.4 +/- 0.2, respectively). Interestingly, the last two compounds also had ED50/DD50 values greater than 60. Common to all three peptides are N-terminal arginine-rich sequences and intramolecular disulfide bridges which introduce conformational constraint.     

一氧化氮参与盐胁迫下长春花酚类代谢的调控研究

为研究外源一氧化氮(NO)调控盐胁迫下长春花中酚类化合物的响应,采用液相色谱—质谱联用(LCMS)技术靶向分析梯度浓度硝普纳(SNP)处理对盐胁迫下长春花幼苗根、茎、花、叶4个部位中酚类化合物组分及含量水平的变化。结果共鉴定出L-苯丙氨酸和18种酚类物质,C6C1类5种、C6C3类5种、C6C3C6类8种,其中原儿茶酸、绿原酸、槲皮素在长春花根、茎、花、叶4个部位中均存在;不同浓度SNP处理后长春花不同部位酚类化合物响应积累明显不同,其中C6C1和C6C3小分子酚酸类化合物主要积累在根和茎中,C3C6C3类主要富集在花和叶中;L-苯丙氨酸在茎、叶中相对含量较高,盐胁迫下茎中含量显著升高,且随外源NO浓度增大呈下降趋势。外源NO影响盐胁迫下植物器官中酚类化合物的积累和变化,其中根和茎响应敏感,从种类和相对含量的角度,茎和叶更适合检测酚类化合物。     

Synthesis and biological evaluation of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thioglycosides

In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a–4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a–4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a–8j and 9a–9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c–9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a–8j exhibited toxicity.     

Tin compounds interaction with membranes of egg lecithin liposomes

This work is a continuation of earlier research concerning the influence of tin compounds on the dynamic properties of liposome membranes produced with lecithin hen egg yolks (EYL). The experiments were carried out at room temperature (about 25 degrees C). Four tin compounds were chosen, including three organic ones, (CH3)4Sn, (C2H5)4Sn and (C3H7)3SnCl, and one inorganic, SnCl2. The investigated compounds were admixed to water dispersions of liposomes. The content of the admixture changed within the range 0 mol-% to 11mol-% in proportion to EYL. Two spin probes were used in the experiment: 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2-ethyl-2-(15-methoxy-15-oxopentadecyl)-4,4-dimethyl-3-oxazolidinyloxyl (16-DOXYL-stearic acid), which penetrated through different areas of the membrane. It was found that tin compounds containing chlorine were the most active in interaction with liposome membranes. In the case of (C3H7)3SnCl, after exceeding 4% admixture content, an additional line appeared in the spectrum of the TEMPO probe which can be a result of formation of domain structures in the membranes of the studied liposomes. Compounds containing chlorine are of ionized form in water solution. The obtained results can thus mean that the activity of admixtures can be seriously influenced by their ionic character. In case of an admixture of non-ionic compounds the compound with a longer hydrocarbon chain displayed a slightly stronger effect on the spectroscopic parameters of the probes.     

In search of a cytostatic agent derived from the alkaloid lycorine: synthesis and growth inhibitory properties of lycorine derivatives

As a continuation of our studies aimed at the development of a new cytostatic agent derived from an Amaryllidaceae alkaloid lycorine, we synthesized 32 analogues of this natural product. This set of synthetic analogues included compounds incorporating selective derivatization of the C1 versus C2 hydroxyl groups, aromatized ring C, lactamized N6 nitrogen, dihydroxylated C3-C3a olefin functionality, transposed olefin from C3-C3a to C2-C3 or C3a-C4, and C1 long-chain fatty esters. All synthesized compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines including those exhibiting resistance to proapoptotic stimuli and representing solid cancers associated with dismal prognoses, such as melanoma, glioblastoma, and non-small-cell lung cancer. Most active analogues were not discriminatory between cancer cells displaying resistance or sensitivity to apoptosis, indicating that these compounds are thus able to overcome the intrinsic resistance of cancer cells to pro-apoptotic stimuli. 1,2-Di-O-allyllycorine was identified as a lycorine analogue, which is 100 times more potent against a U373 human glioblastoma model than the parent natural product. Furthermore, a number of synthetic analogues were identified as promising for the forthcoming in vivo studies.     

An anthocyanin compound in buckwheat sprouts and its contribution to antioxidant capacity

The major anthocyanin compound in buckwheat sprouts was determined to be cyanidin 3-O-rutinoside (C3R), based on HPLC data and MS/MS spectra. Investigation of the content of phenolic compounds in commercial buckwheat sprouts indicated that hypocotyls are abundant in C3R and rutin, whereas all of the detected flavonoids are abundant in cotyledons. The superoxide anion radical-scavenging activities (SOD-like activities) of phenolic compounds in buckwheat sprouts and their contents indicated that rutin, isoorientin, and orientin contributed mainly to the SOD-like activity of the extract from buckwheat sprouts. In contrast, the contribution of C3R was substantially lower than that of flavonoids.     

Synthesis and SAR of sulfoxide substituted carboxyquinolines as NK3 receptor antagonists

The neurokinin-3 (NK3) receptor is regarded as a potential novel target for treating patients with schizophrenia. Herein we report the synthesis and SAR of a series of C3-alkylsulfoxide substituted quinolines as potent NK3 receptor antagonists. These compounds have excellent NK3 functional activity, good selectivity and drug-like properties. Several key compounds have good in vitro/in vivo DMPK characteristics, and are active in a gerbil locomotor activity model.     

Design,Synthesis, Antibacterial Evaluation and Molecular Docking Studies of Some Newer Baenzothiazole Containing Aryl and Alkaryl Hydrazides

The alarming rise of bacterial resistance is occurring worldwide and endangering the efficacy of antibiotics. Therefore, development of new and efficient antibacterial agents remains paramount. In the present work, we designed and synthesized a series of N′-(1,3-benzothiazol-2-yl)-substituted aryl/aralkyl hydrazides C1 – C27 and evaluated them in vitro for their antibacterial activity. Among all tested compounds, C10 , C15 , and C24 showed potent activity against Staphylococcus aureus ATCC 43300 (MRSA). Minimum bactericidal concentration studies of synthesized compounds are performed against selected bacterial strains. Time kill kinetics showed that the compounds C10 and C15 possess bactericidal activity against MRSA ATCC 43300, while compound C24 possess bactericidal activity against S. aureus NCIM 5022. In the extra-precision docking, compounds C1 – C27 exhibited interactions mainly with the N-terminal and central domains of S. aureus GyrB catalytic pocket. Binding free energy (ΔG_bind) of compounds C1 – C27 /3U2K complexes were computed by MM-GBSA approach. Free energy components indicated Coulomb energy term as favorable for binding, while van der Waals and electrostatic solvation energy terms strongly disfavored the binding. ADMET properties of synthesized compounds C1 – C27 are also computed.     

Platinum(II) compounds with chelating ligands based on pyridine and pyrimidine: Synthesis, characterizations, DFT calculations, cytotoxic assays and binding to a DNA model base

Two chelating ligands based on secondary amines have been selected to prepare four new Pt(II) compounds. The ligands bis(pyridine-2-yl)amine, abbreviated dpa, and bis(pyrimidine-2-yl)amine, abbreviated dipm, are chosen to design a rigid chelating motif to allow the study of subtle differences in electronic properties and hydrogen bonding ability. Different carrier ligands (i.e. chloride and ammine) have also been introduced to allow a study of structure–activity relationships. Two of the four compounds are cisplatin analogues, whereas the other two are cationic and coordinatively saturated compounds. The four synthesized and characterized compounds are [Pt(dpa)Cl₂], [Pt(dpa)(NH₃)₂](NO₃)₂, [Pt(dipm)Cl₂] and [Pt(dipm)(NH₃)₂](NO₃)₂ with code numbers C1–C4. The spatial structures of all these compounds have also been optimized using DFT (density functional theory) calculations. The cytotoxicity of these compounds has been investigated in seven human tumor cell lines using the SRB (sulforhodamine B) assay. The most promising antitumor active compound appears to be C3, [Pt(dipm)Cl₂]. Two water-soluble compounds, C2 and C4 exhibit selective activity in EVSA-T cell line. In addition, the reaction of the cisplatin analogues with the model base 9-ethylguanine has been followed by proton and platinum NMR spectroscopy.     

Platinum(II) compounds with chelating ligands based on pyridine and pyrimidine: DNA and protein binding studies

Four Pt(II) compounds (C1–C4) have been studied in their DNA and protein binding. The compounds contain chelating diimine ligands bis(pyridine-2-yl)amine, abbreviated dpa, and bis(pyrimidine-2-yl)amine, abbreviated dipm. The anions for the compounds C1 and C3 are chloride (coordinated) and nitrate (non-coordinated) for C2 and C4. Calf-thymus DNA and an abundant plasma protein have been taken as models for the two major targets for metallodrug interactions investigated by CD spectroscopy. The modifications in the carrier ligands (chloride or ammine) or ancillary secondary amines have been considered to reveal the mode of interactions. The simultaneous effects of coordinative binding and partial intercalation to DNA are evident from several spectroscopic studies. To evaluate the permeability of the cytoplasmic and cellular membrane and the transportation inside the cells, partition coefficients of the four platinum compounds were determined. Two compounds (C3 and C4) induce two-step single-strand DNA cleavage, initiated by partial intercalation. The combined effect of several binding modes towards different bio-molecules is elucidated, providing a rationale for their in vitro activity profile.     

Microbial Oxidation of sec-Alcohols to Ketones

The major anthocyanin compound in buckwheat sprouts was determined to be cyanidin 3-O-rutinoside (C3R), based on HPLC data and MS/MS spectra. Investigation of the content of phenolic compounds in commercial buckwheat sprouts indicated that hypocotyls are abundant in C3R and rutin, whereas all of the detected flavonoids are abundant in cotyledons. The superoxide anion radical-scavenging activities (SOD-like activities) of phenolic compounds in buckwheat sprouts and their contents indicated that rutin, isoorientin, and orientin contributed mainly to the SOD-like activity of the extract from buckwheat sprouts. In contrast, the contribution of C3R was substantially lower than that of flavonoids.     

Chemotaxis of <Emphasis Type="Italic">Burkholderia</Emphasis> sp. Strain SJ98 towards chloronitroaromatic compounds that it can metabolise

Background  

Burkholderia sp. strain SJ98 is known for its chemotaxis towards nitroaromatic compounds (NACs) that are either utilized as sole sources of carbon and energy or co-metabolized in the presence of alternative carbon sources. Here we test for the chemotaxis of this strain towards six chloro-nitroaromatic compounds (CNACs), namely 2-chloro-4-nitrophenol (2C4NP), 2-chloro-3-nitrophenol (2C3NP), 4-chloro-2-nitrophenol (4C2NP), 2-chloro-4-nitrobenzoate (2C4NB), 4-chloro-2-nitrobenzoate (4C2NB) and 5-chloro-2-nitrobenzoate (5C2NB), and examine its relationship to the degradation of such compounds.     

Deoxysugar transfer during chromomycin A3 biosynthesis in Streptomyces griseus subsp. griseus: new derivatives with antitumor activity

Chromomycin A3 is an antitumor drug produced by Streptomyces griseus subsp. griseus. It consists of a tricyclic aglycone with two aliphatic side chains and two O-glycosidically linked saccharide chains, a disaccharide of 4-O-acetyl-D-oliose (sugar A) and 4-O-methyl-D-oliose (sugar B), and a trisaccharide of D-olivose (sugar C), D-olivose (sugar D), and 4-O-acetyl-L-chromose B (sugar E). The chromomycin gene cluster contains four glycosyltransferase genes (cmmGI, cmmGII, cmmGIII, and cmmGIV), which were independently inactivated through gene replacement, generating mutants C60GI, C10GII, C10GIII, and C10GIV. Mutants C10GIV and C10GIII produced the known compounds premithramycinone and premithramycin A1, respectively, indicating the involvement of CmmGIV and CmmGIII in the sequential transfer of sugars C and D and possibly also of sugar E of the trisaccharide chain, to the 12a position of the tetracyclic intermediate premithramycinone. Mutant C10GII produced two new tetracyclic compounds lacking the disaccharide chain at the 8 position, named prechromomycin A3 and prechromomycin A2. All three compounds accumulated by mutant C60GI were tricyclic and lacked sugar B of the disaccharide chain, and they were named prechromomycin A4, 4A-O-deacetyl-3A-O-acetyl-prechromomycin A4, and 3A-O-acetyl-prechromomycin A4. CmmGII and CmmGI are therefore responsible for the formation of the disaccharide chain by incorporating, in a sequential manner, two D-oliosyl residues to the 8 position of the biosynthetic intermediate prechromomycin A3. A biosynthetic pathway is proposed for the glycosylation events in chromomycin A3 biosynthesis.     

Synthesis and evaluation of aza HUN-7293

The aza analogue of the cyclic heptadepsipeptide HUN-7293 (1), which is a potent naturally occurring inhibitor of inducible cell adhesion molecule expression, and its C2(3) (MLEU3 C2) epimer were prepared via solution-phase synthesis. Biological evaluations of these two compounds as inhibitors of cell adhesion molecules expression are detailed.     

Anti-HIV-1 protease activity of compounds from Boesenbergia pandurata

Searching for anti-HIV-1 protease (PR) inhibitors of Thai medicinal plants led to the isolation of a new cyclohexenyl chalcone named panduratin C (1) and chalcone derivatives (2-6) from the methanol extract of Boesenbergia pandurata rhizomes. The known compounds were identified to be panduratin A (2), hydroxypanduratin A (3), helichrysetin (4), 2',4',6'-trihydroxyhydrochalcone (5), and uvangoletin (6). The structures of all compounds were elucidated on the basis of chemical and spectroscopic methods. It was found that 3 possessed the most potent anti-HIV-1 PR activity with an IC50 value of 5.6 microM, followed by 2 (IC50 = 18.7 microM), whereas other compounds exhibited only mild activity. Structure-activity relationships of these compounds on anti-HIV-1 PR activity are summarized as follows: (1) hydroxyl moiety at position 4 conferred higher activity than methoxyl group; (2) prenylation of dihydrochalcone was essential for activity; (3) hydroxylation at position 4' reduced activity; and (4) introduction of double bond at C1' and C6' of chalcone gave higher activity. As regards active constituents contained in B. pandurata rhizomes, hydroxypanduratin A (3) and panduratin A (2) are active principles against HIV-1 PR.     

Hydrolysis/dehydration/aldol-condensation/hydrogenation of lignocellulosic biomass and biomass-derived carbohydrates in the presence of Pd/WO3-ZrO2 in a single reactor

Hydrolysis/dehydration/aldol-condensation/hydrogenation of lignocellulosic-biomass (corncobs) and biomass-derived carbohydrates (tapioca flour) to produce water-soluble C5-C15 compounds was developed in a single reactor system. WO3-ZrO2 efficiently catalyzed the hydrolysis/dehydration of these feedstocks to 5-hydroxymethylfurfural and furfural, while the impregnation of WO3-ZrO2 with Pd allowed sequential aldolcondensation/hydrogenation of these furans to C5-C15 compounds. The highest C5-C15 yields of 14.8-20.3% were observed at a hydrolysis/dehydration temperature of 573 K for 5 min, an aldol-condensation temperature of 353 K for 30 h, and a hydrogenation temperature of 393 K for 6 h. The C5-C15 yield from tapioca flour was higher than that from corncobs (20.3% compared to 14.8%). Tapioca flour produced more C6/C9/C15, whereas corncobs generated more C5/C8/C13 compounds due to the presence of hemicellulose in the corncobs. These water-soluble organic compounds can be further converted to liquid alkanes with high cetane numbers for replacing diesel fuel in transportation applications.