Enantiomeric 4‐Acylamino‐6‐alkyloxy‐2 Alkylthiopyrimidines As Potential A3 Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy

The chiral separation of enantiomeric couples of three potential A₃ adenosine receptor antagonists: (R/S)‐N‐(6‐(1‐phenylethoxy)‐2‐(propylthio)pyrimidin‐4‐yl)acetamide ( 1 ), (R/S)‐N‐(2‐(1‐phenylethylthio)‐6‐propoxypyrimidin‐4‐yl)acetamide ( 2 ), and (R/S)‐N‐(2‐(benzylthio)‐6‐sec‐butoxypyrimidin‐4‐yl)acetamide ( 3 ) was achieved by high‐performance liquid chromatography (HPLC). Three types of chiroptical spectroscopies, namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD), were applied to enantiomeric compounds. Through comparison with Density Functional Theory (DFT) calculations, encompassing extensive conformational analysis, full assignment of the absolute configuration (AC) for the three sets of compounds was obtained. Chirality 28:434–440, 2016. © 2016 Wiley Periodicals, Inc.     

Triterpenoids from the Stem Bark of Melia toosendan and Determination of Their Absolute Configurations at C(24)

Six new triterpenoids, meliasenins S–X ( 1 – 6 , resp.), were isolated from the stem bark of Melia toosendan. Their structures were elucidated by mass spectrometry, NMR experiments, and comparison with the known compounds. Particularly, the absolute configuration at C(24) in new compounds was determined through their CD spectra of the [Pr(FOD)₃] complex (fod=1,1,1,2,2,3,3,7,7,7‐decafluoroheptane‐4,6‐dione) in CCl₄, as well as by using Mosher's method.     

Application of NMR spectroscopy for assignment of the absolute configuration of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one

In order to assign the absolute configurations of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one ( 2a , 2b ), their esters ( 5a , 5b , 5c , 5d ) with (R)‐ or (S)‐2‐methoxyphenylacetic acid ( 4a , 4b ) have been synthesized. The absolute configurations of these compounds have been determined on the basis of NOESY correlations between the protons of the tert‐butyl group and the cyclopentane fragment of the molecules. The crucial part of this analysis was assignment of the absolute configuration at C‐5. Additionally, by calculation of the chemical shift anisotropy, δ^RS, for the relevant protons, it was also possible to confirm the absolute configurations at the C‐2 centres of compounds 2a , 2b and 5a , 5b , 5c , 5d . Chirality, 25:422–426, 2013.© 2013 Wiley Periodicals, Inc.     

Chemical Constituents of Cape Aloe and Their Synergistic Growth-Inhibiting Effect on Ehrlich Ascites Tumor Cells

The constituents of cape aloe were investigated after a preliminary screening of the growth-inhibiting effect on Ehrlich ascites tumor cells (EATC) of several extracts of this plant. Ten compounds were isolated from the dichloromethane (CH₂Cl₂) extract that showed the strongest activity, and their structures were elucidated as aloe-emodin (1), p-hydroxybenzaldehyde (2), p-hydroxyacetophenone (3), pyrocatechol (4), 10-oxooctadecanoic acid (5), 10-hydroxyoctadecanoic acid (6), methyl 10-hydroxyoctadecanoate (7), 7-hydroxy-2,5-dimethylchromone (8), furoaloesone (9), and 2-acetonyl-8-(2-furoylmethyl)-7-hydroxy-5-methylchromone (10) based on MS and various NMR spectroscopic techniques. Compounds 2–7 were isolated for the first time from cape aloe. Compounds 4–7 and 10 showed a significant growth-inhibiting effect, and compound 1 exhibited a remarkable synergistic effect on compounds 8–10, which was not observed with the treatment by each compound alone on EATC. These results suggest that the strong growth-inhibiting effect of the CH₂Cl₂ extract was dependent not on one compound alone, but on the synergistic effect from the combination of compound 1 and the other compounds.     

Biotransformation of chinensiolide B and the cytotoxic activities of the transformed products

Biotransformation of chinensiolide B, 10α-hydroxy-1α,5α,15-H-3-oxoguaia-11(13)-en-6α,12-olide (1), yielded three selectively reduced products, 3β,10α-dihydroxy-1α,5α,15α-H-guaia-11(13)-en-6α,12-olide (2), 3α,10α-dihydroxy-1α,5α,15α-H-guaia-11(13)-en-6α,12-olide (3), and 3β,10α-dihydroxy-1α,5α,11β,15α-H-guaia-6α,12-olide (4) by the cell suspension cultures of Catharanthus roseus. 2 and 3 were also obtained from 1 incubated with cell cultures of a fungus Abisidia coerulea IFO 4011 and Platycodon grandiflorum, respectively. Among them, 2, 3 are two new compounds. The three products, 2–4, along with 1 were preliminarily evaluated for their in vitro cytotoxic activity against 3 cell lines (HepG2, WI-38 and VA-13) and all showed potent inhibitory effects on the cell proliferation. Of the four compounds, 3 was the most toxic to the three cell lines tested with IC₅₀ values of 22.7, 0.33 and 3.30 μM, respectively.     

Synthesis and Stereochemical Characterization of Hydroxy- and Epoxy-derivatives of Rotenone

One to four routes of synthesis are described for 8′-hydroxyrotenone, 5′-hydroxyrotenone, two epimers of 6′,7′-dihydro-6′,7′-dihydroxyrotenone, two epimers of 6′,7′-epoxyrotenone and the four rotenolones derived from each of these compounds. The stereochemical relationships are determined, in each case, by chemical interconversion, ORD and monochromatic rotation to assess the absolute configuration of the B/C ring juncture and by IR, MS and NMR for the cis- or trans-nature of this juncture. The new compounds described are useful standards for studies on the metabolites and photodecomposition products of rotenone insecticide chemical.     

Gamahonolides A,B, and Gamahorin,Novel Antifungal Compounds from Stromata of Epichloe typhina on Phleum pratense

Four novel antifungal compounds, gamahonolides A and B, gamahorin, and 5-hydroxyl-4-phenyl-2(5H)-furanone, were isolated from stromata of Epichloe typhina on Phleum pratense. Their structures were determined by spectroscopic methods. The absolute configuration of gamahonolide A was determined by its ORD spectrum and ¹H-NMR shift difference between the diastereomeric pair of its O-methylmandelates. The stereochemistry of gamahorin was determined by NOE difference spectra and its CD spectrum.     

Enantiomeric Neolignans and a Sesquiterpene from Solanum erianthum and Their Absolute Configuration Assignment

One pair of new C‐8–C‐3′/C‐7–O–C‐4′ linked neolignan enantiomers ( 1a / 1b ) and one new guaiane sesquiterpene ( 2 ) first featuring the 1(2),9(10)‐conjugated double bond were isolated from the stems of Solanum erianthum (Solanceae). Their structures were characterized on the basis of extensive spectroscopic analyses, especially from their 2D nuclear magnetic resonance (NMR) spectra. The absolute configurations of 1a / 1b were rigorously elucidated by electronic circular dichroism (ECD) experiments combined with the reversed helicity rule for the 2,3‐dihydrobenzo[b]furan chromophore, and compound 2 is the first report on the sterochemical assignment of a guaiane sesquiterpene by using the allylic axial chirality rule for the conjugated diene chromophore in combination with the calculated ECD spectrum. Chirality 28:259–263, 2016. © 2016 Wiley Periodicals, Inc.     

Simple Method to Determine the Absolute Configuration of the Glycerol Moiety in Glycosyl Glycerols Based on ORD and CD

A general method to determine the absolute configuration of the glycerol moiety in glycopyranosyl glycerols is presented, which involves per-O-benzylation and acid hydrolysis of the glycosyl glycerol to give optically active 1,2- or 2,3-di-O-benzylated sn-glycerol (III). ORD and CD measurements of III and its benzoylated derivatives gave intensive optical rotations or Cotton effects to determine the absolute configuration at C2.     

Optical rotatory dispersion and circular dichroism of benzoyl polysaccharides

Measurements of optical rotatory dispersion (ORD) and circular dichroism (CD) were made in the range of 400–205 nm for polysaccharide tribenzoates such as 2,3,6-tri-O-benzoyl amylose (I), 2,3,4-tri-O-benzoyl dextran (II), tri-O-benzoyl pullulan (III), 2,3,6-tri-O-benzoyl cellulose (IV), 2,3,6-tri-O-benzoyl mannan (V), and polyglycan dibenzoates such as 2,3,-di-O-benzoyl amylose (VI), cellulose (VII), and mannan (VIII). All compounds exhibit Cotton effects in the region of their UV absorption bands (206–285 nm). Comparison of the corresponding di- and tribenzoyl polysaccharides shows a qualitative agreement in number, position and sign of the CD bands but differences in ellipticity magnitude. The disubstituted derivatives exhibit smaller amplitudes than the trisubstituted ones. The contribution of the C(6) chromophore (linked by a CH₂-group to the asymmetric C(5) atom) was determined to be of the same sign as the combined contribution of the C(2) and C(3) substituents. The CD bonds of the individual polysaccharide derivatives, which differ in number, sign, and position, were discussed in terms of the steric position of the single chromophores and the steric arrangement and interaction caused by the configuration of the polysaccharides. The optical behavior of these polysaccharide derivatives was found to be not strongly influenced by a definite chain conformation in solution.     

New phthalimide‐appended Schiff bases: Studies of DNA binding,molecular docking and antioxidant activities

Herein, we investigated new phthalimide‐based Schiff base molecules as promising DNA‐binding and free radical scavenging agents. Physicochemical properties of these molecules were demonstrated on the basis of elemental analysis, ultraviolet–visible (UV–Vis), infra‐red (IR), ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy. All spectral data are agreed well with the proposed Schiff base framework. The DNA‐binding potential of synthesized compounds were investigated by means of UV–visible, fluorescence, iodide quenching, circular dichroism, viscosity and thermal denaturation studies. The intrinsic binding constants (K _b) were calculated from absorption studies were found to be 1.1 × 10⁴ and 1.0 × 10⁴ M^?1 for compounds 2a and 2b suggesting that compound 2a binding abilities with DNA were stronger than the compound 2b. Our studies showed that the presented compounds interact with DNA through groove binding. Molecular docking studies were carried out to predict the binding between Ct‐DNA and test compounds. Interestingly, in silico predictions were corroborated with in vitro DNA‐binding conclusions. Furthermore, the title compounds displayed remarkable antioxidant activity compared with reference standard.     

Dihydroisocoumarins and Phenylglycosides from Scorzonera longiana,Their Antimicrobial Activities and Molecular Docking Studies

Five new phenyl dihydroisocoumarin glycosides ( 1 – 5 ) and two known compounds ( 6 – 7 ) were identified from the butanol fraction of Scorzonera longiana. The structures of 1 – 7 were elucidated based on spectroscopic methods. Antimicrobial, antitubercular, and antifungal evaluation of compounds 1 – 7 were carried out using the microdilution method against nine microorganisms. Compound 1 was active only against Mycobacterium smegmatis (Ms) with a MIC value of 14.84 μg/mL. All tested compounds ( 1 – 7 ) were active against Ms but only compounds 3–7 were active against fungi (C. albicans, S. cerevisiae) with MIC values of 25.0–125 μg/mL. In addition, molecular docking studies were conducted against Ms DprE1 (PDB ID: 4F4Q), Mycobacterium tuberculosis (Mbt) DprE1 (PDB ID: 6HEZ), and arabinosyltransferase C (EmbC, PDB ID: 7BVE) enzymes. Compounds 2 , 5 , and 7 are the most effective Ms 4F4Q inhibitors. Compound 4 was the most promising inhibitory activity on Mbt DprE with the lowest binding energy of −9,9 kcal/mol.     

Solution properties of synthetic polypeptides. 18. Helix-coil transition of poly-N5-(2-hydroxyethyl)L-glutamine

The helix–coil transition of poly-N⁵-(2-hydroxyethyl)L -glutamine (PHEG) in aqueous isopropanol was examined by means of optical rotatory dispersion (ORD) and intrinsic viscosity [η] measurements. The Zimm–Bragg parameters σ and s for the transition were determined from the ORD data as a function of molecular weight. It was found that the transition was characterized by a relatively low cooperativity; the values of \documentclass{article}\pagestyle{empty}\begin{document}$ \sqrt \sigma $\end{document} were in the range from 0.039 to 0.066, depending on the solvent composition. These σ values are much larger than those reported for other polypeptide–solvent systems. The transition enthalpy was negative and its magnitude varied with the solvent composition, with a maximum of 620 cal/mol at 40 wt% isopropanol. The curve of [η] versus helical content for a high-molecular-weight sample exhibited a very broad minimum, and this behavior was attributed to the low cooperativity of the transition.     

Quinazolin‐4(3H)‐one‐Based Hydroxamic Acids: Design,Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin‐4(3H)‐ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC‐3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N‐hydroxy‐7‐(7‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5b ) and N‐hydroxy‐7‐(6‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5c ) (IC₅₀ values, 0.10–0.16 μm ) were found to be approximately 30‐fold more cytotoxic than SAHA (IC₅₀ values of 3.29–3.67 μm ). N‐Hydroxy‐7‐(4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5a ; IC₅₀ values of 0.21–0.38 μm ) was approximately 10‐ to 15‐fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC₅₀ values in sub‐micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c , strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.     

Three New Ergot Alkaloids from the Fruiting Bodies of Xylaria nigripes (Kl.) Sacc.

Three new ergot alkaloids, xylanigripones A – C ( 1  –  3 ) together with three known compounds, agroclavine ( 4 ), 8,9‐didehydro‐10‐hydroxy‐6,8‐dimethylergolin ( 5 ), and (6S)‐agroclavine N‐oxide ( 6 ) were isolated from the fungus Xylaria nigripes (Kl .) Sacc . Their structures were elucidated by comprehensive spectroscopic analyses and high‐resolution mass spectrometry as well as by comparison with the literature. The absolute configuration was determined by Density Functional Theory (DFT) calculation methods. In addition, all of the compounds were evaluated for bioactivity via a cytotoxicity assay, an acetylcholinesterase inhibition assay and a cholesterol ester transfer protein inhibition assay.     

Limonoids and Flavonoids from the Flowers of Azadirachta indica var. siamensis,and Their Melanogenesis‐Inhibitory and Cytotoxic Activities

A new limonoid, 7‐O‐acetyl‐7‐O‐debenzoyl‐22‐hydroxy‐21‐methoxylimocinin ( 2 ), and two new flavonoids, 3′‐(3‐hydroxy‐3‐methylbutyl)naringenin ( 7 ) and 4′‐O‐methyllespedezaflavanone C ( 9 ), along with nine known compounds, including two limonoids, 1 and 3 , and seven flavonoids, 4 – 6, 8 , and 10 – 12 , were isolated from a MeOH extract of the flowers of Azadirachta indica A.Juss. var. siamensis Valeton (Siamese neem tree; Meliaceae). The structures of new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. All of these compounds were evaluated for their melanogenesis‐inhibitory activities in B16 melanoma cells induced with α‐melanocyte‐stimulating hormone (α‐MSH). Compound 2 (16.9% melanin content at 30 μM ), 6‐deacetylnimbin ( 3 ; 49.6% melanin content at 100 μM ), and kaempferide ( 10 ; 41.7% melanin content at 10 μM ) exhibited inhibitory effects with no, or almost no, toxicity to the cells (81.0–111.7% cell viability). In addition, evaluation of their cytotoxic activities against HL60, A549, AZ521, and SK‐BR‐3 human cancer cell lines, isoazadironolide ( 1 ), 4′‐O‐methyl‐8‐prenylnaringenin ( 5 ), euchrestaflavanone A ( 8 ), 9 , and 3‐methoxy‐3′‐prenylnaringenin ( 12 ) revealed potent cytotoxicities against one or more cell lines with IC₅₀ values in the range of 4.5–9.9 μM .     

Diterpenoids from Wedelia prostrata and Their Derivatives and Cytotoxic Activities

One new ent‐kaurane diterpenoid, 11β,16α‐dihydroxy‐ent‐kauran‐19‐oic acid ( 1 ), together with eight known analogues 2 – 9 were isolated from the aerial parts of Wedelia prostrata. One of the acidic diterpenoids, kaurenoic acid ( 3 ), was converted to seven derivatives, 10 – 16 . All compounds were evaluated for their cytotoxic activity in vitro against human leukemia (K562), liver (HepG‐2), and stomach (SGC‐7901) cancer cell lines. Only four kaurenoic acid derivatives, 13 – 16 , with 15‐keto and substitutions at C(19) position, exhibited notable cytotoxic activities on these tumor cell lines with IC₅₀ value ranging from 0.05 to 3.71 μm . Compounds 10 – 12 , with oxime on C(15) showed moderate inhibitory effects and compounds 1 – 9 showed no cytotoxicities on them. Structure–activity relationships were also discussed based on the experimental data obtained. The known derivative, 15‐oxokaurenoic acid 4‐piperdin‐1‐ylbutyl ester ( 17 ), induced typical apoptotic cell death in colon SW480 cells upon evaluation of the apoptosis‐inducing activity by flow‐cytometric analysis.     

Conformations and optical rotatory properties of poly-O-acetylthreonine and poly-O-acetylallothreonine

Optically active poly-O-acetylthreonine and poly-O-acetyl-allothreonine exist in the β form in pyridine, in 2-chloruethanol–dichloromethane mixed solvent., and in the solid state. The optical rotatory dispersion of the β form of poly-O-acetyl-L -threonine in a 2-ehloroethanol–dichlomethane mixture showed a Cotton effect in the 230 mμ region. The ORD data in the visible spectral region fit, the Moffitt. equation. The absolute values of b₀, as measured in pyridine for polypeptides with a molecular weight above 17000, varied in the range 100–200°, the sign depending on the absolute configuration of the side chain.     

Synthesis,Conformational and Configurational Studies of Some New Acetylated Glycosides of 2-Thio-3-aryl-4(3H)-quinazolinones,Their Thiono and 3,1-Benzothiazin-2,4-dithione

Abstract

A series of some new acetylated S-glycosides of 2-thioxoquinazolin-4-ones, their thiono analogues and 3,1-benzothazin-2,4-dithione derivatives, including a D-glucose and a D-galactose derivatives and a D-xylose, and an L-arabinose derivatives have been synthesized. The conformation and configuration of these carbohydrate derivatives were determined by analysing their ¹H and ¹³C NMR chemical shifts and coupling constants. The biological activity of these compounds has been studied.     

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.