Acetyloxy Groups Research Articles

Synthesis of Rhodamine-Conjugated Lupane Type Triterpenes of Enhanced Cytotoxicity.

Various conjugates with rhodamines were prepared by starting with betulinic acid (BA) and platanic acid (PA). The molecules homopiperazine and piperazine, which were identified in earlier research, served as linkers between the rhodamine and the triterpene. The pentacyclic triterpene's ring A was modified with two acetyloxy groups in order to possibly boost its cytotoxic activity. The SRB assays' cytotoxicity data showed that conjugates 13-22, derived from betulinic acid, had a significantly higher cytotoxicity. Of these hybrids, derivatives 19 (containing rhodamine B) and 22 (containing rhodamine 101) showed the best values with EC50 = 0.016 and 0.019 μM for A2780 ovarian carcinoma cells. Additionally, based on the ratio of EC50 values, these two compounds demonstrated the strongest selectivity between malignant A2780 cells and non-malignant NIH 3T3 fibroblasts. A375 melanoma cells were used in cell cycle investigations, which showed that the cells were halted in the G1/G0 phase. Annexin V/FITC/PI staining demonstrated that the tumor cells were affected by both necrosis and apoptosis.

Ethyl 3,4-bis-(acet-yloxy)-2-(4-meth-oxy-phen-yl)pyrrol-idine-1-carboxyl-ate.

The title pyrrolidine compound, C18H23NO7, is a tetra-substituted species in which the five-membered ring has a twisted conformation with the twist occurring in the C-C bond bearing the adjacent acet-yloxy substituents; the Cm-Ca-Ca-Cp torsion angle is -40.76 (18)° [m = methyl-ene, a = acet-yloxy and p = phen-yl]. The N atom, which is sp 2-hybridized [sum of bond angles = 359.4°], bears an ethyl-carboxyl-ate substitutent and is connected to a methyl-ene-C atom on one side and a carbon atom bearing a 4-meth-oxy-phenyl group on the other side. Minor disorder is noted in the ethyl-carboxyl-ate substituent as well as in one of the acet-yloxy groups; the major components of the disorder have site occupancies of 0.729 (9) and 0.62 (3), respectively. The most notable feature of the mol-ecular packing is the formation of helical, supra-molecular chains aligned along the b-axis direction whereby the carbonyl-O atom not involved in a disordered residue accepts C-H⋯O inter-actions from methyl-ene-H and two-C atom separated methine-H atoms to form a six-membered {⋯HCCCH⋯O} synthon.

Chiral/Achiral Copolymers of Biphenylylacetylenes Bearing Various Substituents: Chiral Amplification through Copolymerization, Followed by Enhancement/Inversion and Memory of the Macromolecular Helicity

A series of dynamic helical homo- and copolymers of chiral and/or achiral biphenylylacetylenes (PBPAs) bearing achiral methoxymethoxy or acetyloxy groups at the 2,2′-positions along with a chiral o...

Selective Diacetoxylation of Disubstituted 1,2,3-Triazoles through Palladium-Catalyzed C–H Activation

A simple and efficient selective diacetoxylation of 1,4-disubstituted 1,2,3-triazoles by Pd-catalyzed C–H bond activation is described. PhI(OAc)2 was used as an acetyloxy source to convert aromatic sp2 C–H bonds into C–O bonds with high selectivity by employing a 1,2,3-triazole ring as an elegant directing group. A range of 1,2,3-triazoles bearing two acetyloxy groups can be readily synthesized by the reaction.

Chromatographic enantioseparation by poly(biphenylylacetylene) derivatives with memory of both axial chirality and macromolecular helicity

Novel poly(biphenylylacetylene) derivatives bearing two acetyloxy groups at the 2- and 2'-positions and an alkoxycarbonyl group at the 4'-position of the biphenyl pendants (poly-Ac's) were synthesized by the polymerization of the corresponding biphenylylacetylenes using a rhodium catalyst. The obtained stereoregular (cis-transoidal) poly-Ac's folded into a predominantly one-handed helical conformation accompanied by a preferred-handed axially twisted conformation of the biphenyl pendants through noncovalent interactions with a chiral alcohol and both the induced main-chain helicity and the pendant axial chirality were maintained, that is, memorized, after complete removal of the chiral alcohol. The stability of the helicity memory of the poly-Ac's in a solution was lower than that of the analogous poly(biphenylylacetylene)s bearing two methoxymethoxy groups at the 2- and 2'-positions of the biphenyl pendants (poly-MOM's). In the solid state, however, the helicity memory of the poly-Ac's was much more stable and showed a better chiral recognition ability toward several racemates than that of the previously reported poly-MOM when used as a chiral stationary phase for high-performance liquid chromatography. In particular, the poly-Ac-based CSP with a helicity memory efficiently separated racemic benzoin derivatives into enantiomers.

Synthesis of t-Butyl (2R)-Hydroxyisovalerate, A Precursor of Aureobasidin B

Aureobasidins are a family of cyclodepsipeptides have antifungal properties. They were isolated from the black yeast Aureobasidium pullulans R106 and over 30 derivatives have been successfully characterized. There are few publications reporting the total synthesis of aureobasidins. The limited reports of the synthesis of the aureobasidin derivatives are due to the difficult access to the preparations of precursors. The aim of this research is to synthesise a precursor of aureobasidin B, t-butyl (2R)-hydroxyisovalerate (t-Bu-Hiv), that is prepared for the total synthesis of aureobasidin B. The synthesis of AbB is planned to be undertaken by using a solid phase method, so the ester formation between t-Bu-Hiv and the Fmoc-β-hydroxymethylvaline will be carried out in solution phase to form depsidipeptide. The t-butyl group was used as protecting agent that is due to the straightforward elimination of the protecting group from the Fmoc-depsidipeptide. The t-Bu-Hiv acid was prepared from D-valine through diazotisation to form (2R)-acetyloxyisovaleric acid in 62.7% yield. Product of the first step was then protected by t-butyl group by using Boc-anhydride in t-butanol to give t-butil (2R)-acetyloxyisovalerate in 44% yield. In the last step, the acetyloxy group was eliminated by using potassium carbonate in methanol/water to give the desired product, t-Bu-Hiv in 33.5% yield. The t-Bu-Hiv is ready to be combined with Fmoc-β-hydroxymethylvaline to result in depsidipeptide that will be attached to the resin in the total synthesis of AbB. Each stage of this synthesis was controlled by thin layer chromatography and all products were purified by open column chromatography. All the synthesized products were characterized by various spectroscopic techniques, including infrared spectrophotometer, mass spectroscopy (ESI-MS), 1H-NMR and 13C-NMR.

Total synthesis of (-)-bucidarasin a starting from an original chiral building block.

The highly stereoselective total synthesis of (-)-bucidarasin A, which also elucidated the absolute structure of its natural form, is described. The total synthesis features effective use of the original chiral building block prepared by us and a series of highly stereoselective reactions, i.e., hydroxy-directed hydrogenation, [4 + 2] cycloaddition of a sterically hindered dienophile, reduction of ketones, formation of the C9 side-chain diene, and formation of the THF moiety bearing two acetyloxy groups.

Hydrogen bonding in crystal forms of primary amide functionalised glucose and cellobiose

A glucoside and cellobioside of glycolamide were synthesised and the crystal chemistry of these compounds investigated. The amidoglucoside crystallised in the P21 space group. The primary amide group participates in C(7) and C(17) chains also involving the pyranose oxygen and hydroxyl groups. The amidocellobioside crystallised as a methanol solvate in the P21 space group. The amide N–H groups donate hydrogen bonds to oxygen atoms on the cellobiose units, while intramolecular hydrogen bonds give rise to S(7) and S(9) motifs in addition to a R33 (9) motif. A tetra-O-acetylglucoside derivative of thioglycolamide and its sulfoxide derivative were synthesised to examine the effect of protecting the glucopyranose hydroxyl groups. The thioglycolamido derivative, which crystallised in the P212121 space group, featured amide N–H groups donating to the glucopyranose oxygen and an acetyloxy group. The sulfoxy derivative crystallised in the P21 space group and featured the primary amide groups forming R23(8) motifs generating a 21 ladder.

Synthesis, reactions and antineoplastic activity of 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromene derivatives

Abstract The key 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromen-5-yl acetates 3 were synthesized in high yields by cyclocondensation of 4-oxo-4H-chromen-3-carbaldehydes 1 with coumarin-3-acetic acids 2 under mild conditions. The reaction pathway involves aldol condensation and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton 3. Further treatment of acetates 3 with alcohols, water or nitrogen containing compounds led to 5-alkoxy-, 5-hydroxy- or 5-acylamino-2H,5H-pyrano[3,2-c]chromen-2-ones 4-6 via nucleophilic substitution of acetyloxy group at C-5. Acetates and hydroxyl derivatives 3 and 5 undergo facile rearrangement in an acid medium yielding 5-hydroxypyrano[2,3-b]chromen-2(10aH)-ones 7. Twelve prepared compounds were evaluated on their antineoplastic activities on 60 human tumour cell line panels in NCI USA. The obtained biological results confirmed that 3-(2-oxo-2H-chromen-3-yl)-2H,5H-pyrano[3,2-c]chromen-2-one represents a new leading skeleton suitable for further antitumour activity study.

Reaction Kinetics and Mechanism of Sulfuric Acid‐Catalyzed Acetolysis of Acylated Methyl L‐Ribofuranosides

AbstractThe mechanism of the sulfuric acid‐catalyzed acetolysis of methyl 2,3,5‐tri‐O‐acetyl‐ and methyl 2,3,5‐tri‐O‐benzoyl‐L‐ribofuranosides and the accompanying anomerization of both the starting material and the 1,2,3,5‐tetra‐O‐acetyl‐ and 1‐O‐acetyl‐2,3,5‐tri‐O‐benzoyl‐L‐ribofuranoses formed was investigated. The progress of the reactions was followed by 1H NMR spectroscopy and the rate constants for the reactions were determined for a proposed kinetic model. The role of H+ and Ac+ as the catalytically active species was clarified, proving that the anomerization of the acylated methyl furanosides is activated by protonation, while, on the contrary, the anomerization of the 1‐O‐acetyl ribofuranoses is activated by the acetyl cation. The anomerization of the acylated methyl furanosides was verified to be activated on the ring oxygen leading to endocyclic CO‐bond rupture while the 1‐O‐acetyl ribofuranoses are activated on the acetyloxy group on C(1) leading to exocyclic cleavage.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Abstract A64: Ester-protected hydroxybenzyl phosphates (EHBP) inhibit the growth of various cultured human cancer cells: Evidence of a tissue type-independent effect

Abstract A64 Introduction Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consisting of a conventional NSAID to which an NO releasing moiety -ONO2 is covalently attached through a spacer have emerged as a new class of pharmaceutical agents. For several years we have been exploring the mechanism of action of NO-NSAIDs and in particular NO-aspirin (NO-ASA), with emphasis on their application to cancer. Our structure-activity studies with NO-ASA indicated that NO was pivotal for biological activity. However, careful re-examination regarding the contribution to the overall biological effect of each of the three structural components of NO-ASA, led to the surprising conclusion that the NO-releasing moiety was not required for the observed biological effects. Rather, it was the spacer that was responsible for the biological actions of NO-ASA. The NO-releasing moiety was acting as a leaving group leading to the generation of a reactive quinone methide (QM) intermediate which behaved as a powerful electrophile. The ASA component made no biological contribution (BBRC 2007:358, 1096-1101). We therefore synthesized a series of ortho, para, and meta EHBPs, in which the -ONO2 leaving group was replaced by a substituted phosphate as the leaving group and the ASA was replaced by an acetate. We also incorporated electron donating/withdrawing groups about the aromatic spacer in order to evaluate the effect of substitution on QM formation/stability and biological activity. Methods EHBPs as potential drugs: para-, ortho-, and meta-acetyloxybenzyl diethyl phosphate (Agents 1-3 respectively), p-acetyloxy-3-methylbenzyl diethyl phosphate (Agent 4), and p-acetyloxy-2-chlorobenzyl diethyl phosphate (Agent 5) were synthesized and purified at our lab with 1H-NMR verifying the structures. In some experiments we also used NO-ASA for comparison. Cell lines: Human colon, breast, leukemia, and pancreatic cancers. Growth inhibition: colorimetric MTT assay kit. Cell cycle phase distribution: flow cytometry. Apoptosis: subdiploid (sub-G0/G1) peak in DNA content histograms. Results Agent 1 was very effective in inhibiting the growth of all cell lines with IC50s of 0.6-0.8 µM, in contrast, p-NO-ASA had significantly higher IC50s, 10-20 µM. Agent 2 was less potent than agent 1 in all cell lines with IC50s of 63-155 µM, presumably because of steric interference between the diethyl phosphate and the acetyloxy groups making it difficult for the QM to form. Agent 3 was the least effective, with IC50s of 162-451 µM, this agent is comparable in potency to m-NO-ASA, both of which do not form QMs. Agent 4 containing an electron donating group, was extremely potent, IC50s being 0.3-0.5 µM. Agent 5 containing an electron withdrawing group had slightly higher IC50s, 0.5-1.0 µM. Agent 1 induced dose-dependent apoptosis, which was significantly higher compared to p-NO-ASA. Agent 1 dose-dependently altered the distribution of the cells in the cell cycle, causing an arrest in G0/G1. Conclusions EHBPs inhibited the growth of various human cancer cells, indicating a tissue type independent effect. They exercise pleiotropic effects involving cell death as well as cell cycle phase transitions. These results raise the possibility that EHBPs possess chemotherapeutic activity against a wide variety of human cancers. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A64.

Understanding the Polymorphism of Aspirin with Electronic Calculations

This report presents electronic calculations of two aspirin polymorphs in order to understand the origin of polymorphism in aspirin crystals. Analysis of the calculated electronic structures, particularly the nuclear Fukui functions, reveals a structural tension between the carboxylic and acetyloxy groups, which may play a key role in the formation of aspirin polymorphs. Calculations of the lattice energies of the two polymorphs indicate that aspirin crystals may be enantiotropic.

Competitive inhibitory effect of external nucleophile concentration on intramolecular O- to N-acylation in O-acetylsalicylamide.

A model esterolytic mechanisminvolving the cooperative effect of an amide functionalityand the cleavage of a neighboring acetyloxy group waspreviously reported [1,2]. The O- to N- transacylationreaction of O-acetylsalicylamide (compound 1) to givecompound 2 is rapid, pH-dependent, and independent ofbuffer concentration (see Scheme 1). In addition, the rateof such reactions can be greatly enhanced through anintramolecular general acid catalysis mechanism. Forexample, in compounds containing a terminal carboxylicacid functionality as part of the O-acyl group (i.e.,compounds of general structure 3), the involvement of thefree carboxylate group in the rate enhancement of O- toN-acylation was postulated to proceed via the transitionstate 4 [3]. Thus, the O-glutaryl hemiester derivative 3awas found to exhibit a transacylation rate that was 400times faster than that observed for compound 1 (3a, K

New NO-donors with antithrombotic and vasodilating activities, Part 21. Pseudonitrosites and other azodioxides with vicinal electron acceptors.

Twelve vicinally substituted nitro-nitroso compounds (pseudonitrosites) were synthesized, nine of them for the first time. In the solid state the dimeric azodioxides are present. In the class of the pseudonitrosites 2a-h, all compounds exhibited comparatively strong antiplatelet activity in vitro (Born test, collagen). Four of them showed an IC50 below 10 microM, 2a being the most active substance with an IC50 = 2.1 microM. When administered orally to rats (60 mg/kg) small antithrombotic effects were observed. The pseudonitrosite 6d was the most active compound (18% inhibition in arterioles). The in vitro decomposition of 2a at 37 degrees C gave NO and N2O, indicating that the above pharmacological effects were mediated by an NO-dependent mechanism. The replacement of the nitro group in the pseudonitrosite partial structure by other electron acceptors i.e. acetyl, carboxyl, or acetyloxy groups leads to inactive (10a) or less active compounds (10b, e).

Novel features of acceptor recognition by β-(1→4)-galactosyltransferase

In order to understand how β-(1→4)-galactosyltransferase recognizes its glycosyl acceptor, substrate specificities were investigated using synthetic 2-acetamido-2-deoxy- d-glucopyranose ( N-acetylglucosamine) derivatives in which the 1-, 2-, 3-, 4-, and 6-positions were systematically substituted. The hydroxyl groups at the 3-, 4-, and 6-positions were substituted by fluoride, thiol or hydrogen. For modification of the 2- position, the acetamido group was converted to ethylamino-, N-methylacetamido- and acetyloxy groups. For the anomeric position, several sugar residues were introduced as the aglycon of N-acetylglucosaminide. Galactose transfer assay using synthetic N-acetylglucosamine derivatives indicated that both the acetamido group and the 4-hydroxyl group were essential for binding of N-acetylglucosamine toward the β-(1→4)-galactosyltransferase. The assay also showed that the N-acetylglucosamine having a large substitution at the 6-position can be recognized as an acceptor. It is suggested that in this case the bulky substitutent is positioned away from the catalytic site or out of enzyme. Since the 2-acetamido and the 4-hydroxyl group are essential for recognition, the side composed of the 2, 3, and 4-positions may face the acceptor-binding site.

Substituted methyl 5β‐cholan‐24‐oates II. 13C NMR spectral assignment

AbstractThe 13C NMR spectra were recorded and assigned for nine derivatives of methyl 5β‐cholan‐24‐oates (esters of bile acids) including hydroxy, oxo and/or acetyloxy groups. Assignments were based on the empirical substituent‐induced chemical shifts (SCS), spectral comparison with compounds of similar structure, distortionless enhancement by polarization transfer (DEPT) and proton coupled 13C NMR measurements.

The complexing ability of crown ethers incorporating glucose

The complexing (in CHCl3) and extracting abilities of 18-crown-6 type compounds (1–15) were measured with Li, Na, K and NH4 cations. The substituents on the sugar part affected these properties significantly (Ka=103–107). Some substituents, like acetyloxy groups (3) decreased whereas others, like tosyloxy groups (10, 11) significantly increased the complexing ability and thus changed the selectivity. The compound with four tosyloxy groups (11) shows an excellent picrate salt extracting ability in a CH2Cl2-water system.