Site Covalent Modification of Methionyl Peptides for the Production of FRET Complexes

Flax cyclic peptides (orbitides, linusorbs (LOs)) [1–8‐NαC],[1‐MetO₂]‐linusorb B1 ([MetO₂]‐LO1) and [1–9‐NαC],[1‐MetO₂]‐linusorb B2 ([MetO₂]‐LO2) are biologically active. These LOs lack active nuclei commonly used in peptide modification. We have developed reactions to activate methionine methyl sulphide to produce stable derivatives. In these reactions, LOs are converted to sulfonium intermediates and subsequently to derivatives containing active nuclei while preserving their fundamental structures. The reaction conditions preserved cyclic peptide fundamental structure and organic solvent solubility. [Met]‐LO1 and [Met]‐LO2 analogues containing activated groups (?CN, ?COOEt, and ?NH₂) in the form of methionine, methionine (S)‐oxide, and methionine (S,S)‐dioxide amino acids were synthesized and characterized by LCMS and 1D and 2D NMR spectroscopy. Coumarin orbitide complexes produced in this manner bind Eu³⁺ yielding FRET compounds that absorb energy through coumarin antennae and emit photons at lanthanide wavelengths.     

The Control of the Stereochemistry in the Palladium‐Catalyzed Alternating Styrene/Carbon Monoxide Copolymerization: Effect of the Chirality of the Ligand and of the Ligand‐to‐Palladium Ratio,Preliminary Communication

Diaquapalladium(2+) trifluoromethanesulfonates modified with (4R,4′S)‐ or (4S,4′S)‐2,2′‐bis(4‐benzyl‐4,5‐dihydrooxazole) (C_s‐ and C₂‐ligands) produce isotactic poly(1‐oxo‐2‐phenylpropane‐1,3‐diyl) through copolymerization of styrene with carbon monoxide. However, the same meso‐catalyst in the presence of the free ligand leads to prevailingly syndiotactic growth of the copolymer, whereas the optically active catalyst, when used in the presence of the free enantiomeric ligand, gives an atactic copolymer.     

S‐Adamantyl Group Directed Site‐Selective Acylation: Applications in Streamlined Assembly of Oligosaccharides

The site‐selective functionalization of carbohydrates is an active area of research. Reported here is the surprising observation that the sterically encumbered adamantyl group directed site‐selective acylation at the C2 position of S‐glycosides through dispersion interactions between the adamantyl C?H bonds and the π system of the cationic acylated catalyst, which may have broad implications in many other chemical reactions. Because of their stability, chemical orthogonality, and ease of activation for glycosylation, the site‐selective acylation of S‐glycosides streamlines oligosaccharide synthesis and will have wide applications in complex carbohydrate synthesis.     

Total Synthesis of Bistramide A and Its 36(Z) Isomers: Differential Effect on Cell Division,Differentiation, and Apoptosis

The total synthesis of bistramide A and its 36(Z),39(S) and 36(Z),39(R) isomers shows that these compounds have different effects on cell division and apoptosis. The synthesis relies on a novel enol ether‐forming reaction for the spiroketal fragment, a kinetic oxa‐Michael cyclization reaction for the tetrahydropyran fragment, and an asymmetric crotonylation reaction for the amino acid fragment. Preliminary biological studies show a distinct pattern of influence of each of the three compounds on cell division, differentiation, and apoptosis in HL‐60 cells, thus suggesting that these effects are independent activities of the natural product.     

Non‐iterative Asymmetric Synthesis of C15 Polyketide Spiroketals

The 2,2′‐methylenebis[furan] ( 1 ) was converted to 1‐{(4R,6S))‐6‐[(2R)‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2R,4R)‐tetrahydro‐4,6‐dihydroxy‐2H‐pyran‐2‐yl)propan‐2‐one ((+)‐ 18 ) and its (4S)‐epimer (?)‐ 19 with high stereo‐ and enantioselectivity (Schemes 1–3). Under acidic methanolysis, (+)‐ 18 yielded a single spiroketal, (3R)‐4‐{(1R,3S,4′R,5R,6′S,7R)‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐6′‐yl}butane‐1,3‐diol ((?)‐ 20 ), in which both O‐atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (?)‐ 20 (methyl pyranoside formation). Compound (?)‐ 19 was converted similarly into the (4′S)‐epimeric tricyclic spiroketal (?)‐ 21 that also adopts a similar (3S)‐configuration and conformation. Spiroketals (?)‐ 20 , (?)‐ 21 and analog (?)‐ 23 , i.e., (1R,3S,4′R,5R,6′R)‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2S)‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐4′‐ol, derived from (?)‐ 20 , were assayed for their cytotoxicity toward murine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic (±)‐ 21 showed evidence of cancer‐cell‐growth inhibition (P388, ED₅₀: 6.9 μg/ml).     

Synthesis of chloro,fluoro, and nitro derivatives of 7‐amino‐5‐aryl‐6‐cyano‐5H‐pyrano pyrimidin‐2,4‐diones using organic catalysts and their antimicrobial and anticancer activities

Chloro, fluoro, and nitro derivatives of 7‐amino‐5‐aryl‐6‐cyano‐5H‐pyrano pyrimidin‐2,4‐diones were produced by reacting malononitrile, barbituric acid, and aromatic aldehydes together with a DABCO catalyst in an aqueous one‐pot reaction. This is the first report of these compounds being synthesized with DABCO as a catalyst, which produced the compounds in yields in excess of 90%. The 2,4‐difluoro derivative ( 11 ) was novel. The structures of the synthesized compounds were elucidated by means of ¹H, ¹³C, and 2D NMR spectroscopy. Compound 2 (2‐Cl derivative) had MBC values of <200μM against both Staphylococcus aureus and MRSA, and the 2‐nitro derivative 5 had an MBC of 191μM against the Gram–ve Escherichia coli. The synthesized compounds were also tested for their anticancer activity against a HeLa cell line, where all the compounds showed better activity (IC₅₀ values between 129μM and 340μM) than 5‐fluorouracil, a commonly known anticancer drug.     

A practical approach to the synthesis of insect antifeedant tonghaosu analogs

Tonghaosu and its analogs are a class of structurally interesting spiroketal enol‐ether compounds. A practical route to furandiol, a key intermediate for their syntheses, was developed. Using Friedel‐Crafts benzoylation of 3‐(2‐fury I) propyl acetate, a diarylketone was obtained in high yield, which was further transformed into corresponding furandiol by reduction with NaBH₄ in basic medium with simultaneous ester hydrolysis. The furandiol was then cyclized into the desired spiroketal enol‐ether compound in the presence of CuSO₄ 5H₂O.     

Discovery of New S‐Glycosides and N‐Glycosides of Pyridine‐biphenyl System with Antiviral Activity and Induction of Apoptosis in MCF7 Cells

Glycosylation of small molecule‐based drugs can dramatically improve the biological activities of the parent scaffold. In the current study, S‐glycosides and N‐glycosides of polyfunctionalized pyridine‐biphenyl system tethered with benzotriazole moiety were designed and synthesized. S‐Glycosides of pyridine‐2‐thione derivatives 5a – h and N‐glycosides of pyridine‐2‐one derivatives 9a , b were synthesized by a facile, convenient, and high‐yielding procedure. The epimers glucose and galactose, acetylated or deacetylated, were used to form the glycone part. The structures of these compounds were confirmed by microanalysis and spectroscopic data (IR, ¹ H–NMR, and ¹³C‐NMR). The anticancer activities of the target compounds, in comparison with standard cisplatin, were assessed by MTT assay against MCF7 cell line. Compounds 4f , 4g , 5f , and 5h exhibited the highest cytotoxic effect on MCF7. The anticancer effect of these four compounds induced the apoptosis as evident by the up‐regulated expression of the apoptotic genes Bax and p53 and down‐regulated expression of the anti‐apoptotic gene BCl₂. S‐Glycoside derivatives are more active than N‐glycosides. Moreover, the nontoxic doses of the tested compounds were evaluated in MA104, FRHK4, BGM, Hep2, and Vero cells. Compounds 4a – d and 5a – d were also evaluated for their antiviral effect against HSV‐1, HAV, and rotavirus Wa strain. The compounds' results showed less, moderated, and high antiviral activities. The docking study for these compounds with MDM2 revealed that deacetylated galactose is important for binding with the receptor as it facilitates the formation of hydrogen bond in the receptor. Rapid overlay of chemical structures analysis was employed to understand the compounds' similarity on the basis of their shape structure using the Tanimoto scores.     

Terpenoids from Eupatorium fortunei Turcz

Four new terpenoids, namely, rel‐(1R,2S,3R,4R,6S)‐p‐menthane‐1,2,3,6‐tetrol ( 1 ), rel‐(1R,2R,3R,4S,6S)‐p‐menthane‐1,2,3,6‐tetrol ( 2 ), 9‐hydroxythymol 3‐O‐angelate ( 3 ), and (3β,20R)‐20‐hydroxylanost‐25‐en‐3‐yl palmitate ( 4 ), together with fourteen known compounds, were isolated from the AcOEt part of the MeOH extracts of Eupatorium fortunei. In addition, two other monoterpenoids, ‘acetone thymol‐8,9‐diyl ketal’ ( 19 ) and 8‐methoxy‐9‐hydroxythymol 3‐O‐angelate ( 20 ) were also obtained which were probably artifacts but have never been reported in the literature. The structures of the new compounds, including their relative configurations, were established by an extensive study of their spectral data, especially 1D‐ and 2D‐NMR. The cytotoxic activity of the new compounds against human hepatoma (SMMC‐7721), human leukemia (HL‐60), and human hepatocyte (LO₂) cells was investigated.     

Structural studies of the chemical constituents of Tithonia tagetiflora Desv. (Asteraceae)

Tithonia tagetiflora Desv. (Asteraceae) is a widespread plant in Vietnam, and the species of Tithonia are known as plants containing many biologically active compounds. However, T. tagetiflora's chemical composition remains mostly unknown. Therefore, we now report the structural elucidation of two new sesquiterpene lactones, 8‐angeloyloxy‐2,14‐epoxygermacra‐4,10(1),11(13)‐trien‐6,12‐olide (1) and 6‐angeloyloxy‐1‐hydroxy‐3,4‐epoxygermacra‐9,11(13)‐dien‐8,12‐olide (2), together with three known compounds, including two norisoprenoids, (6S,9S)‐vomifoliol or (6R,9R)‐vomifoliol (3) and (6S,9S)‐roseoside (4), and one glutinane type triterpene, epi‐glutinol (5), from the leaves of T. tagetiflora. Their structures are established by 1D and 2D NMR spectroscopy, as well as ESI‐MS analysis and comparison with literature data. Copyright © 2013 John Wiley & Sons, Ltd.     

The absolute configuration of (2S,4S)‐ and (2R,4R)‐2‐tert‐butyl‐4‐methyl‐3‐(4‐tolyl­sulfon­yl)‐1,3‐oxazolidine‐4‐carbaldehyde

The title enanti­omorphic compounds, C₁₆H₂₃NO₄S, have been obtained in an enanti­omerically pure form by crystallization from a diastereomeric mixture either of (2S,4S)‐ and (2R,4S)‐ or of (2R,4R)‐ and (2S,4R)‐2‐tert‐butyl‐4‐methyl‐3‐(4‐tolyl­sulfon­yl)‐1,3‐oxazolidine‐4‐carbaldehyde. These mixtures were prepared by an aziridination rearrangement process starting with (S)‐ or (R)‐2‐tert‐butyl‐5‐methyl‐4H‐1,3‐dioxine. The crystal structures indicate an envelope conformation of the oxazolidine moiety for both compounds.     

Conformational studies of dammarane‐type triterpenoids using computational and NMR spectroscopic methods

Natural triterpenoids are of great interest to researchers of various fields as they possess diverse physicochemical and biological properties. In medicinal chemistry, detailed information about the chemical structures of bioactive triterpenoids often helps find new lead compounds. Herein, the low‐energy structures of (20S)‐protopanaxadiol and (20S)‐protopanaxatriol, the aglycones of various triterpenoid saponins found in Panax ginseng, and their (20R)‐epimers have been predicted by the geometry optimization of the conformers extracted from molecular dynamics simulations with the self‐consistent‐charge density functional tight‐binding method. By performing quantum mechanical calculations on the low‐energy conformers, we have estimated the NMR chemical shifts of the compounds, which display good agreement with the most recently reported experimental values within an expected range of errors. Our results indicate that theoretical estimation of the NMR parameters of a relatively large molecule with a molecular mass of 500 is feasible. Copyright © 2015 John Wiley & Sons, Ltd.     

Asymmetric reaction of diethylzinc with aldehydes catalyzed by l‐menthopyrazole derivatives

N‐Hydroxyalkyl‐1‐menthopyrazoles acted as a chiral catalyst for the diethylzinc ( 1 ) addition to aromatic aldehydes, and 1‐aryl‐1‐propanols were afforded enantioselectively. These reactions were carried out optimally in toluene at 40 °C in the presence of 30 mol% of (2′S)‐2‐(2‐phenyl‐2‐hydroxyethyl)‐3‐phenyl‐1‐men‐thopyrazole ((S)‐ 16d ) to afford optically active 1‐aryl‐1‐propanols up to 70% ee (S).     

Enantioselective Sulfoxidation Catalyzed by a Bisguanidinium Diphosphatobisperoxotungstate Ion Pair

The first enantioselective tungstate‐catalyzed oxidation reaction is presented. High enantioselectivities were achieved for a variety of drug‐like phenyl and heterocyclic sulfides under mild conditions with H₂O₂, a cheap and environmentally friendly oxidant. Synthetic utility was demonstrated through the preparation of (S)‐Lansoprazole, a commercial proton‐pump inhibitor. The active ion‐pair catalyst was identified to be bisguanidinium diphosphatobisperoxotungstate using Raman spectroscopy and computational studies.     

Three New Diterpenoids from Rabdosia lophanthoides var. gerardiana

Three new diterpenoids, together with three known ones, were isolated from the air‐dried whole herbs of Rabdosia lophanthoides var. gerardiana. The structures of the new diterpenoids were established as 3,4‐dihydro‐11‐hydroxy‐10‐(1‐hydroxy‐1‐methylethyl)‐2,2,6‐trimethylnaphtho[1,8‐bc]oxocin‐5(2H)‐one ( 1 ), 11,12,15‐trihydroxyabieta‐5,8,11,13‐tetraen‐7‐one ( 2 ), (2R,3S,4S,4aR,8S,9aS,13aS,16aS)‐3,4,4a,8,9,9a,10,11,12,13,14,16a‐dodecahydro‐2‐(hydroxymethyl)‐6,6,10,10‐tetramethyl‐2H‐benzo[4,5]cyclohepta[1,2‐h]pyrano[2,3‐b][1,4]benzodioxepine‐3,4,8,13a,15(6H)‐pentol ( 3 ) by spectroscopic methods, including extensive 1D‐ and 2D‐NMR analyses. The structures of the known compounds were identified by comparison of their physical and spectroscopic data with those reported in the literature.     

Planarity of benzoylthiocarbazate tuberculostatics. III. Diesters of 3‐(2‐hydroxybenzoyl)dithiocarbazic acid

Searches for new tuberculostatic agents are important considering the occurrence of drug‐resistant strains of Mycobacterium tuberculosis . The structures of three new potentially tuberculostatic compounds, namely isopropyl methyl (2‐hydroxybenzoyl)carbonohydrazonodithioate, C₁₂H₁₆N₂O₂S₂, (Z )‐benzyl methyl (2‐hydroxybenzoyl)carbonohydrazonodithioate, C₁₆H₁₆N₂O₂S₂, and dibenzyl (2‐hydroxybenzoyl)carbonohydrazonodithioate propan‐2‐ol monosolvate, C₂₂H₂₀N₂O₂S₂·C₃H₈O, were determined by X‐ray diffraction. The mutual orientation of the three main fragments of the compounds, namely an aromatic ring, a dithioester group and a hydrazide group, can influence the biological activity of the compounds. In all three of the structures studied, the C(=O)NH group is in the anti conformation. In addition, the presence of the hydroxy group in the ortho position of the aromatic ring in all three structures leads to the formation of an intramolecular hydrogen bond stabilizing the planarity of the molecules.     

Understanding Trends in 27Al Chemical Shifts and Quadrupolar Coupling Constants in Chloroalkyl Aluminum [AlClx(Me)3 − x]n = 1 or 2 Compounds

The usage of alkyl aluminum compounds and related structures as co‐catalyst finds a broad range of application in homogeneous and heterogeneous catalysis. While understanding the nature of the aluminum species in solution or in solids can be a challenge, ²⁷Al solid state NMR is a powerful tool to understand the structures of Al species, but their assignment remains mostly empirical, typically by comparing chemical shifts with known compounds. In this work, the observed trends in ²⁷Al‐NMR parameters – chemical shift and quadrupolar coupling constant – of chloroalkyl aluminum compounds, a prototypical class of important Lewis activators, are traced back to their frontier orbitals and electron polarization through a natural localized molecular orbital analysis. This study thus provides guidelines to understand the nature of chemical shift and thereby assignment of possible structure.     

Solvent‐ and Temperature‐Controlled In Situ Ligand Reactions Mediated by CuII and 3′‐[(E)‐{[(1S,2S)‐2‐Aminocyclohexyl]imino}methyl]‐4′‐hydroxy‐4‐biphenylcarboxlic Acid

Three new compounds, CuL, CuL′, and Cu₂O₂L′′₂ (H₂L=3′‐[(E)‐{[(1S,2S)‐2‐aminocyclohexyl]imino}methyl]‐4′‐hydroxy‐4‐biphenylcarboxlic acid, H₂L′=3′‐[(E)‐{[(1S,2S)‐2‐aminocyclohexyl]imino}methyl]‐4′‐hydroxy‐5′‐nitro‐4‐biphenylcarboxlic acid, H₂L′′=3′‐(N,N‐dimethylamino methyl)‐4′‐hydroxy‐4‐biphenylcarboxlic acid), were selectively synthesized through a controlled in situ ligand reaction system mediated by copper(II) nitrate and H₂L. Selective nitration was achieved by using different solvent mixtures under relatively mild conditions, and an interesting and economical reductive amination system in DMF/EtOH/H₂O was also found. All crystal structures were determined by single‐crystal X‐ray diffraction analysis. Both CuL and CuL′ display chiral 1D chain structures, whereas Cu₂O₂L′′₂ possesses a structure with 13×16 Å channels and a free volume of 41.4 %. The possible mechanisms involved in this in situ ligand‐controlled reaction system are discussed in detail.     

Stereoselective total synthesis of (-)-spirofungin A by utilising hydrogen-bond controlled spiroketalisation

The stereoselective total synthesis of the spiroketal containing Streptomyces metabolite (?)‐spirofungin A ( 1 ) is described. A key step involved a spiroketalisation controlled by an intramolecular H‐bond which favoured the desired spiroketal 4 (13:1 ratio). The presence of the intramolecular H‐bond in 4 is possibly due to a 1,5‐alkyne–oxygen interaction. Other key steps include an efficient cross‐metathesis to form the spiroketal precursor, a tin mediated syn‐aldol reaction and a Stille cross‐coupling reaction to create the C22? C23 bond. A final Wittig extension followed by deprotection gave (?)‐spirofungin A ( 1 ).     

Novel Antileukemic Sterol Glycosides from Ajuga salicifolia

Two novel and three new sterol glycosides were isolated from the MeOH extract of the aerial parts of Ajuga salicifolia (L.) Schreber . The structures of the compounds were elucidated as (3R,16S,17S,20R,22S,23S, 24S,25S)‐16,23 : 16,27 : 22,25‐triepoxy‐3‐(β‐D ‐glucopyranosyloxy)coprostigmast‐7‐en‐17‐ol ( 1 ), (3R,16S,17S, 20R,22S,23S,24S,25S)‐16,23 : 16,27 : 22,25‐triepoxy‐3‐{[β‐D ‐glucopyranosyl‐(1→2)‐β‐D ‐glucopyranosyl]oxy}coprostigmast‐7‐en‐17‐ol ( 2 ), (3R,16S,17R,20S,22R,24S,25S)‐22,25‐epoxy‐3,27‐bis(β‐D ‐glucopyranosyloxy)coprostigmast‐7‐en‐16‐ol ( 3 ), (3R,16S,17R,20S,22R,24S,25S)‐22,25‐epoxy‐3‐{[β‐D ‐glucopyranosyl‐(1→2)‐β‐D ‐glucopyranosyl]oxy}‐27‐(β‐D ‐glucopyranosyloxy)coprostigmast‐7‐en‐16‐ol ( 4 ), and (3R,16R,17S,20R,22S,23S, 24S,25S)‐22,25‐epoxy‐3‐(β‐D ‐glucopyranosyloxy)coprostigmast‐7‐ene‐16,17,23,27‐tetrol 27‐acetate ( 5 ) by means of 1D and 2D NMR spectroscopy and HR‐MALDI mass spectrometry. The novel compounds, which consist of three additional ring systems at the coprostigmastane skeleton, were named ajugasalicioside A ( 1 ) and B ( 2 ), and the new compounds C ( 3 ), D ( 4 ) and E ( 5 ). In our cytotoxicity assays (HeLa cells, Jurkat T cells, and peripheral mononuclear blood cells), ajugasaliciosides A–D specifically inhibited the viability and growth of Jurkat T‐leukemia cells at concentrations below 10 μM . Ajugasalicioside A ( 1 ; (IC₅₀=6 μM ) and C ( 3 ; IC₅₀=3 μM ) were the most active compounds. Ajugasalicioside A ( 1 ) induced cell‐cell contact, inhibited Jurkat T cell proliferation, and up‐regulated mRNA levels of the cell‐cycle regulator cyclin D1, which might be an indication for cell differentiation. Furthermore, 1 down‐regulated the mRNA levels of the NF‐κB subunit p65 in a concentration‐dependent manner. These effects were not found for ajugasalicioside B ( 2 ), which has an additional glucose unit, and the onset of cytotoxicity of 2 (IC₅₀=10 μM ) was delayed by 24 h.