Cyclic Depsipeptide BE‐43547A2: Synthesis and Activity against Pancreatic Cancer Stem Cells

Asymmetric total synthesis of the cyclic depsipeptide BE‐43547A₂ was achieved in 15 linear steps on a 350 mg scale in one batch. The synthesis features the highly diastereoselective construction of an α‐hydroxy‐β‐ketoamide through α‐hydroxylation with a d.r. of up to 86:1. BE‐43547A₂ significantly reduces the percentage of pancreatic cancer stem cells (PCSCs) in Panc‐1 cell cultures, and dramatically reduces the tumorsphere‐forming capability of Panc‐1 cells. An in vivo tumor‐initiation assay, a gold standard for cancer stem cell assays, confirmed that BE‐43547A₂ can abolish the tumorigenesis of Panc‐1 cells. The anti‐PCSC activity of BE‐43547A₂ could make this depsipeptide scaffold a promising starting point for discovering new PCSC‐targeting drugs.     

New aqua rhenium oxocomplex; synthesis,characterization, thermal studies,DFT calculations and catalytic oxidations

The aqua rhenium oxocomplex [ReO(OH)(H₂O)₄]^2? (1) has been prepared and characterized by spectroscopy, thermogravimetry, and elemental analysis and its reactivity towards triphenylphosphine has been evaluated. Complex (1) acts as a catalyst precursor in the presence of molecular oxygen for the oxidation of PPh₃ to OPPh₃. This proceeds through complex intermediates like [Re(PPh₃)_n]³⁺ (2), and [ReO(PPh₃)_n]³⁺ (3). The newly prepared complex (1) was also employed as catalyst for catalytic oxidation of cyclohexane. The geometry of [ReO(OH)(H₂O)₄]^2? has also been optimized in the singlet state by the DFT method with B3LYP level of theory.     

An investigation of Prussian Blue analogues by Mössbauer spectroscopy and magnetic susceptibility

The Mössbauer spectra and magnetic susceptibilities have been obtained for a series of Prussian Blue analogues of general formula M_j^A[M^B(CN)₆]_k·mH₂O where M^A and M^B are transition metal ions, j and k vary with the oxidation states of M^A and M^B and m typically has values from 8 to 14. The compounds were prepared from the hexacyano acids or with large quaternary ammonium counterions and are therefore not contaminated with alkali cations. In each analogue, A or B is iron and the second metal is Mn, Cu, Co, Cr or Ru. In each case it was possible to assign the site (A or B), oxidation state and spin state to each transition metal ion. This group of compounds are all class II mixed valence species from their colours, but do not show evidence of linkage isomerism or redox changes compared to the starting materials. The Mössbauer linewidths are consistent with the Ludi model of Prussian Blue.     

Conformational study of α-arylethylamides of (−)-camphanic acid

The absolute conformation and configuration of diastereomeric amides (4A,B–6A,B) of (1S,3R)-camphanic acid (lactone of 1-hydroxy-2,2,3-trimethylcyclopentan-1,3-dicarboxylic acid, (−)-camphanic acid 9) with α-arylethylamines 1–3 are deduced from ¹H NMR data and MM2 calculations. The α-arylethyl group in diastereomers A and B adopt nearly opposite absolute conformations, stabilized by hydrogen bonding in the syn-oriented O–C(1)–C(6)–N–H unit, and repulsive interaction between the 1′C–Me group and the amide CO group. The absolute configuration (1′S) is assigned to the 4A–6A diastereomers, and the (1′R)-configuration to the 4B–6B diastereomers; this assignment is confirmed by the preparation of 4A and 5A from enantiomerically pure (1′S)-α-arylethylamines 1 and 2, respectively. These results also enabled the assignment of pro-R (H_R) and pro-S (H_S) protons in the benzyl derivative 7.     

Synthesis of bengamide E analogues and their cytotoxic activity

A series of bengamide E analogues were prepared from the corresponding polyketide chain and amino acids via amide coupling reactions. Opening of the polyketide chain lactone ring with α-aminolactams was successfully achieved under microwave irradiation in the presence of sodium 2-ethyl hexanoate. A cytotoxic activity evaluation against a panel of cancer cell lines (KB, HepG-2, Lu-1, MCF-7, HL-60 and Hela) indicated that the 2′R analogues were generally more cytotoxic than the 2′S analogues. Additionally, several analogues exhibited selective inhibition against various cancer cell lines: compounds 32a and 32b selectively inhibited MCF-7 cells, while 33b and 35b were more sensitive toward Lu-1 and HepG-2, respectively. Notably, some of the synthetic analogues possess cytotoxic activities with IC₅₀ values less than 1 µM.     

Organoselenium chemistry : A study of intermediates in the fragmentation of aliphatic ketoselenoxides. Characterization of selenoxides,selenenamides and selenolseleninates by 1H-,13C-and 77Se-NMR

A series of β-ketoselenenic acids was generated at low temperature ( - 20° to - 50°) by selenoxide syn elimination of appropriate selenoxides (13-ox, 16-ox, 35-ox, 38-ox, and 39-ox). No evidence for the buildup of significant concentrations of selenenic acid was obtained. A selenolseleninate (15, 2,2' - diseleno - bis(1 - phenyl - 2 - methyl -1 - propanone) - Se - oxide) was detected as an intermediate in the decomposition of 13-ox and 16-ox. This compound, which is stable in solution below - 50° was charaeterized by NMR spectroscopy (¹H, ¹³C,⁷⁷Se) and by its thermal decomposition and reactions with phosphite (reduction to diselenide 6) and dialkylamines (formation of selenenamide 11). Decomposition of 15 in the presence of dibenzylamine resulted in trapping of a selenenic acid-like species (RSeSeOH) to give RSeSeN(CH₂Ph)₂ (R = PhC(O)C(CH₃)₂). Although 15 could not be prepared by oxidation of diselenide 6, it was possible to prepare a cyclic selenolseleninate (4,4-dimethyl-1,2-diselenolane monoxide, 20) by oxidation of the related diselenide (19). Attempts to prepare more stable aliphatic selenenic acids by blocking the principal decomposition pathway of 15 were not successful. Thus 1 - benzoyl -1 - cyclopropaneselenenic acid was generated from 35-ox and 38-ox and 1 - benzoyl - 2,2 - dimethylcyclopropaneselenenic from 39-ox. The former underwent normal disproportionation (to 36 and 37) even when prepared at -49°. The latter gave what appeared to be a selenolseleninate (40) which again disproportionated at -17°.     

Reactions of 2,2-bis(trifluoromethyl)oxirane with alcohols under phase transfer catalysis

It was demonstrated that the reaction of 2,2-bis(trifluoromethyl)oxirane (1) with variety of alcohols could be successfully carried out under phase transfer catalysis conditions using sodium or potassium hydroxide as a base. For example, reaction of CH₃OH, C₂H₅OCH₂CH₂OH, HOCH₂CH₂OH with one or two moles of 1 in the presence of the catalyst [(C₄H₉)₄N⁺HSO₄⁻] gives the corresponding tertiary alcohols R[OCH₂C(CF₃)₂OH]_n (n=1 or 2) in 43-53% yield, along with some O[CH₂C(CF₃)₂OH]₂. Benzyl alcohol and phenol under similar conditions are less active, producing in the reaction with 1 the corresponding adducts ArOCH₂C(CF₃)₂OH in 31-35% yield. Fluorinated alcohols, such as CF₃CH₂OH, ClCF₂CH₂OH, HCF₂CF₂CH₂OH have much higher reactivity towards 1 giving ring opening products in 82-97% yield. Even in the reaction of hindered hexafluoro-iso-propanol the corresponding adduct was isolated in 43% yield. Surprisingly, the reaction of iso-propanol and epoxide 1, results in the formation of O[CH₂C(CF₃)₂OH]₂ as a major product, isolated in 56% yield. Possible mechanism for the formation of the last product was proposed.     

The preparation of novel histrionicotoxin analogues and their activity towards the α4β2 and α7 nicotinic acetylcholine receptors

Four histrionicotoxin analogues were prepared in an efficient manner utilizing a nitrone dipolar cycloaddition reaction as the key step in forming tricyclic intermediate 13. The nitrile in intermediate 13 was reduced with DIBAL to an aldehyde which then underwent Z-selective Wittig reactions to produce intermediates containing the Z-alkene side-chain. Hydrogenation of the Z-alkenes produced saturated histrionicotoxin analogues whereas reduction with SmI₂ afforded the unsaturated histrionicotoxin analogues. The histrionicotoxin analogues were shown to be potent non-competitive antagonists of the α4β2 and α7 nAChR's with the most potent analogue 3 displaying IC₅₀'s of 0.10 μM and 0.45 μM against the α4β2 and α7 nAChR's, respectively. The unsaturated analogues 15 and 18 displayed Hill slope (n_H) of approximately 1 whilst the saturated analogues 16 and 3 had a n_H of approximately 0.5, which may indicate that the saturated analogues are binding to more than one binding site.     

Crystal structure and optical properties of new 0D-hybrid hydroxyfluorotitanates

New 0D hybrid organic–inorganic hydroxyfluorotitanates result from the microwave assisted reactions in autoclaves of TiF₄ with organic amines (3-5 diamino-1,2,4,triazol (guaz), ethylenediamine (en) and diethylenetriamine (dien)) and concentrated aqueous HF in ethanol at 190 °C for 1 h. Four compounds, [Hguaz]₂·(TiF_4.9(OH)_1.1) (I), [H₂guaz]·(TiF_4.8(OH)_1.2) (II), [H₂en]·(TiF_4.3(OH)_1.7) (III) and [H₂dien]·(Ti(F,OH)₆)·2H₂O (IV) are prepared and characterized. All structures are built up from isolated (Ti(F,OH)₆)²⁻ anions interacting with mono- or di-protonated amines which local symmetry dictates the long range stacking of the Ti(F,OH)₆ octahedra. Insertion of crystallized water molecules is only observed for IV. The experimental optical gaps of I, II and III have been measured at about 3.4 eV and compare well with the theoretical values estimated from the examination of density of state diagrams. The optical thresholds are mainly due to O(2p) → Ti(3d) electronic transitions, the F(2p) → Ti(3d) charge transfers occurring at higher energy.     

pH-Metrische Studien an den binären Komplexen von Oxovanadium(IV) mit Hippur- und Anthranilsäure und Pyridin-2-aldoxim

pH-metric studies on the interaction of oxovanadium(IV) with hippuric and anthranilic acids and pyridine-2-aldoxime indicate the formation of monohydroxo derivatives of 1:1 chelates. The equilibrium constants for the reaction, VO²⁺+HA+H₂O?VO(OH)A+2H⁺ have been calculated as 4.47±0.07 and 6.32±0.05 in the 1:1 VO²⁺-hippuric or anthranilic acid systems resp. and for the reaction, VO²⁺+H₂ A ⁺+H₂O?VO(OH)A+3H⁺ as 8.40±0.09 in the 1:1 VO²⁺-pyridine-2-aldoxime hydrochloride system at 30±0.5°C (μ=0.1-KNO₃).     

Synthetic and Structural Studies on Some New Butterfly Fe/S Cluster Complexes Containing 2,6-(CH2)2C5H3N or (CH2)2 Groups

Four new butterfly Fe/S cluster complexes bearing 2,6-(CH₂)₂C₅H₃N or (CH₂)₂ groups, as the active site models of [FeFe]-hydrogenase, have been prepared by condensation reaction and structurally characterized. Treatments of the parent complex Fe₂(CO)₆[(μ-SCH₂)₂CHCO₂H] (A) with 2,6-(HOCH₂)₂C₅H₃N or HOCH₂CH₂OH in the presence of 4-dimethylaminopyridine and dicyclohexylcarbodiimide afforded the single-butterfly Fe/S complexes Fe₂(CO)₆[(μ-SCH₂)₂CHC(O)OCH₂(2,6-C₅H₃N)CH₂OH] (1) and Fe₂(CO)₆[(μ-SCH₂)₂CHC(O)OCH₂CH₂OH] (3) and the double-butterfly Fe/S complexes [Fe₂(CO)₆(μ-SCH₂)₂CHC(O)OCH₂]₂(2,6-C₅H₃N) (2) and [Fe₂(CO)₆(μ-SCH₂)₂CHC(O)OCH₂]₂ (4). The new complexes 1–4 were fully characterized by elemental analysis, ESI-MS, IR, and ¹H (¹³C) NMR spectroscopy.     

Acid-catalysed acylations of bicyclo[3.3.1]nonan-2,6-diones: A novel preparation of the adamantane skeleton

The acid-catalysed acylations of bicyclo[3.3.1]nonan-2,6-dione 1 and its 9-thia-2 and 9-oxa-3 analogues with Ac₂O are described. At high acidity, C-acylation is favoured over O-acylation and for 1 and 2 intramolecular aldol condensation occurs with the formation of adamantanes 18 and 19 and 2-thiaadamantanes 15 and 16. These results are compared with alternative acylations of 2 using 2-acetoxypropene, (PhCO)₂O and acid halides.     

Versatile building blocks from disaccharides: glycosylated 5-hydroxymethylfurfurals

A practical protocol for the elaboration of O-glycosyl-HMF’s from glycosyl-(1→6)-glucoses is reported, the two steps involving aluminate-promoted isomerization to the respective 6-O-glycosyl-fructoses and subsequent selective dehydration of the fructose portion. Accordingly, melibiose, gentiobiose, and primeverose are converted into the corresponding 2-uloses and, then, into α-GalMF 11, β-GMF 12, and β-XylMF 13. Pt/C-catalyzed oxidation with oxygen in NaOH at 25 °C efficiently generated the respective furoic acids from α-GalMF and α-GMF, whilst Pt/O₂ in water at 50 °C also oxidizes the primary OH to give the dicarboxylic acids 15 and 17–key building blocks for the generation of novel types of polyesters and polyamides.     

Subtle role of counteranions in molecular construction: Structures and properties of novel Cu(II) coordination complexes with bis-(1-benzoimidazolymethylene)-(2,5-thiadiazoly)-disulfide

The direct self-assembly of bis-(1-benzoimidazolymethylene)-(2,5-thiadiazoly)-disulfide (L) with CuSO₄, Cu(NO₃)₂ and CuCl₂ affords three novel supramolecular complexes: 1-D ladder-like chain complex {[Cu(SO₄)(L)] · (CH₃OH)}_n (1), dimer complexes {[Cu(L)(CH₃O)]₂(NO₃)₂} · 2H₂O (2) and [Cu(L)(Cl)(N₃)]₂ · 2CH₃OH (3). The nature of the anions is the underlying reason behind the differences in the structures of this series of complexes. Furthermore, utilizing the coordinatively unsaturated complexes 2 and 3 as precursor complexes, two new derivative complexes [Cu(L)(NCS)(CH₃O)]₂ · 2CH₃OH (2A) and [Cu(L)(ClO₄)(N₃)]₂ · 2CH₃OH (3A) are obtained by the addition and exchange reactions of complexes 2 and 3 with anions. X-ray crystallographic analysis shows that the two derivatives retain the skeletons of their precursor complexes, and the anions with the stronger coordination capacity only bind to the active position of precursor complexes. In addition, different from the obvious effects on the structures in the direct self-assembly of the metal and ligand, the change of counteranions has no great impact on the structures in the anion exchange reactions. We also study the catalytic activities of the complexes 2, 2A, 3, and 3A, which have similar skeletons, for the oxidative coupling polymerization of 2,6-dimethylphenol (DMP). And we find that the introductions of different coordination counterions produce significant impacts on the catalytic properties of these complexes.     

DEPMPO and lipophilic analogues: synthesis and EPR studies

DEPMPO (5-diethylphosphono-5-methyl-1-pyrroline N-oxide) is now recognised as a major trap for the applications of spin-trapping techniques in biological milieu. We report herein a new synthetic route for DEPMPO ending with the reductive cyclisation of the phosphorylated γ-nitroaldehyde 8. In comparison with the usual synthesis of DEPMPO, involving the oxidation of the parent pyrrolidine 3, the new approach avoids the formation of over oxidation by-products thus making easier the purification of DEPMPO. Lipophilic analogues of DEPMPO have been prepared through addition of various Y₂P(O)H on 2-methyl-1-pyrroline, followed by oxidation of the ensuing pyrrolidines. These new nitrones were used to trap different radicals in water and organic solvents.     

The use of Pearlman's catalyst for the oxidation of Si–H bonds. Synthesis, structures and acid-catalysed condensation of novel α, ω-oligosiloxanediols HOSiMe2O(SiPh2O)nSiMe2OH (n = 1−4)

The preparation of α , ω-oligosiloxanediolsHOSiMe₂O(SiPh₂O)_nSiMe₂OH(5–8; n=1–4) by the mild oxidation of thecorresponding organo-H-siloxaneHSiMe₂O(SiPh₂O)_nSiMe₂H(1–4; n = 1–4) using Pearlman's catalyst,Pd(OH₂)/C, is reported. Compounds 5–7 possessnew hydrogen bonding modes, whose influences on the Si–O chainconformation are discussed and compared with the published analoguesHOSiPh₂OSiPh₂OSiPh₂OH (9),HOSit-Bu₂OSiMe₂OSit-Bu₂OH (10) andHOSiPh₂OSiPh₂OSiPh₂OSiPh₂OH(11), whereas compound 8 appears to be polycrystalline.Preliminary results of the HCl-catalysed condensation of5–8 are also reported, which provided complex mixtures ofoligomeric products in the case of 5 and 8, and (almost)exclusivelycyclo-(Me₂SiO)₂(Ph₂SiO)₂(12) andcyclo-(Me₂SiO)₂(Ph₂SiO)₃(13) in the case of 6 and 7, respectively. Compounds5–7 and 13 were investigated by X-raycrystallography.     

Zum verhalten von Pb(OAc)4-n(N3)n gegenüber androsta-4,9(11)-dien-3,17-dion : Pb(OAc)4-n(N3)n Als oxigenierungsmittel

An entirely new property of Pb(OAc)_4-n(N₃)_n consists in direct transfer of an O atom to the 9-,11-doublebond of the title compound with formation of the oxirane 2 and the introduction of an OH function in the allylic position at C 12 with formation of 1. In addition to the new concept,² 12α-azide 3 and the triketon 4 were also formed.     

Synthesis and structural characterisation of alkylaluminium and alkylgallium pinacolates

The influence of the steric repulsion of ligands on the structure of alkylaluminium and alkylgallium 2,3-dimethylbutane-2,3-diolates (pinacolates) has been studied. Reaction of Me₃Al and pinacol afforded the compound Me₅Al₃[OC(CH₃)₂C(CH₃)₂O]₂ (1) possessing two diolate ligands. The treatment of pinacol with the more sterically hindered ^tBu₃Al resulted in the formation of aluminium tripinacolate ^tBu₃Al₃[OC(CH₃)₂C(CH₃)₂O]₃ (2) as the only product. In contrast, the reaction of the less reactive ^tBu₃Ga with pinacol stopped at the stage of the compound ^tBu₃Ga₂[OC(CH₃)₃C(CH₃)₂O] [OC(CH₃)₃C(CH₃)₂OH] (3), which is an intermediate product of the reaction of 1,2-diols with group 13 trialkyls. Compounds 1, 2 and 3 were crystallographically characterised.     

Isolation and characterisation of both the first fluoroxyfluorofullerene C60F17OF and oxahomofluorofullerenol C60F17O.OH

The first fluoroxyfluorofullerene C₆₀F₁₇OF (A) has been isolated from the fluorination of [60]fullerene with a mixture of MnF₃ and K₂NiF₆ at 480 °C. This compound has a shorter HPLC retention time than the isomeric fluorofullerene ethers (oxahomofullerenes) and is less stable towards EI mass spectrometry. It fragments by losing OF as a single entity and shows no formation of C₆₀O as a fragment ion. By contrast, the ethers fragment by first losing a number of F atoms and then CO, and ultimately show also the presence of C₆₀O, whilst epoxides lose CO as a main fragmentation step and do not give C₆₀O. The first oxahomofluorofullerenol C₆₀F₁₇O.OH (B) has been isolated from the UV-irradiation of a toluene solution of C₆₀F₁₈ in air during 65 h and readily eliminates HF due to adjacent F and OH groups during EI mass spectrometry. The structures of both the compounds have been deduced from 1D and 2D NMR spectroscopy. Just as oxygen inserts into FCCF bonds of C₆₀F₁₈ to give ethers, so insertion into a CF bond gives A. The oxahomofluorofullerenol B is produced by S_N2′ substitution of F by OH, followed by oxygen insertion into a 6:5-bond (αβ to the OH group) giving a motif not seen previously in fluorofullerenes.     

Cycloaddition reactions of N-heterocyclic stable silylenes with ethylene and formaldehyde

The cycloaddition reactions of N-heterocyclic silylenes 1-4 with ethylene (C₂H₄) and formaldehyde (CH₂O) molecules were performed at the MP2/6-31G** level of theory, respectively. Full optimizations and frequency analyses were done for the stationary points on the potential energy surface. The intrinsic reaction coordinate (IRC) was also calculated for all the transition states at the same level of theory. The possible cycloaddition mechanisms were investigated and results from various reactions were compared in detail. The theoretical results indicated that the cycloaddition reactions of N-heterocyclic silylenes with C₂H₄ and CH₂O proceeded through a concerted mechanism to form a three-membered ring containing C1, C2 (O), and Si atoms in the products, which was similar to those of simple silylene H₂Si. Silylenes 1-4 exhibit some electrophilicity toward C₂H₄ whereas nucleophilicity toward CH₂O leading to the reaction process. Based on the reaction energy barrier and the exothermic energy, the reaction activities of saturated silylene (2) were stronger than those of unsaturated silylenes (1, 3, and 4).