Acetoxy Derivatives Research Articles

Anticancer Studies of Newly Synthesized Thiazole Derivatives: Synthesis, Characterization, Biological Activity, and Molecular Docking

Thiazole and its derivatives have received a lot of attention from researchers due to its wide biological, pharmacological, and anticancer properties. A novel series of 2-[2-[4-Hydroxy-3-substituted benzylidene hydrazinyl]-thiazole-4[5H]-ones (4a–c) and acetoxy derivative (5) were synthesized via using thiosemicarbazones (2a–c). The structure of the thiazole derivatives (4a–c) and 5 in these compounds was confirmed by spectroscopic techniques (IR and NMR), as well as elemental investigations. The synthesized derivatives biological activity was assessed based on their capacity to suppress the growth of the cancer cell lines MCF-7 and HepG2, as well as to halt the cell cycle and trigger apoptosis. Among the synthesized thiazole derivatives, compound 4c was found the most active derivative, with inhibitory concentrations IC50 = 2.57 ± 0.16 and 7.26 ± 0.44 µM in MCF-7 and HepG2, respectively, compared to Staurosporine as the standard drug with IC50 6.77 ± 0.41 and 8.4 ± 0.51 µM, respectively. Additionally, compound 4c blocked vesicular endothelial growth factor receptor-2 (VEGFR-2), according to our results (IC50 = 0.15 µM), compared to Sorafenib (IC50 = 0.059 µM) as the standard drug. Moreover, compound 4c induced cell cycle arrest at the G1/S phase, increasing the percentage and accumulation of cancer cells (DNA content) in the pre-G1 phase by 37.36% in MCF-7 cancer cells compared to untreated MCF-7 cells at 2.02%. Also, compound 4c increased the percentage of early and late apoptosis from 0.51% and 0.29%, respectively, in the case of the MCF-7 untreated control sample to 22.39% and 9.51%, respectively, in the MCF-7 treated sample. Furthermore, molecular docking studies of compounds 4a–c and 5 were conducted with four key proteins (aromatase, epidermal growth factor receptor (EGFR), cyclin-dependent kinase 2 (CDK2), and B-cell lymphoma 2 (Bcl-2)) that stimulate the growth, proliferation, and development of cancer cells. Compound 4c exhibited good docking scores with a promising and potential binding affinity toward the active site of selected docked proteins. According to these results, compound 4c showed efficient cytotoxic activity against the tested cancer cells.

Gold and Silver Chains from Tetrahydrothiophenocucurbit[6]uril as Au or Ag-Nanoparticles.

Tetrahydrothiophenocucurbit[5 and 6]uril has been synthesized from tetrathiophenoglycoluril diether, providing thioether functionality at the exterior equatorial position of the cucurbituril cage. This functionality has been investigated for chemical modification through sulfoxide formation and subsequent Pummerer rearrangement to the acetoxy derivative of the tetrahydrothiophenocucurbit[5]uril. Nanoparticles of Au and Ag were prepared in the presence of tetrahydrothiophenocucurbit[6]uril, which curiously led to the formation of nanoparticle chains, growing in length over days to weeks.

Discrimination of Olive Oil and Extra-Virgin Olive Oil from Other Vegetable Oils by Targeted and Untargeted HRMS Profiling of Phenolic and Triterpenic Compounds Combined with Chemometrics.

Extra-virgin olive oil (EVOO) and virgin olive oil (VOO) are valuable natural products of great economic interest for their producing countries, and therefore, it is necessary to establish methods capable of proving the authenticity of these oils on the market. This work presents a methodology for the discrimination of olive oil and extra-virgin olive oil from other vegetable oils based on targeted and untargeted high-resolution mass spectrometry (HRMS) profiling of phenolic and triterpenic compounds coupled with multivariate statistical analysis of the data. Some phenolic compounds (cinnamic acid, coumaric acids, apigenin, pinocembrin, hydroxytyrosol and maslinic acid), secoiridoids (elenolic acid, ligstroside and oleocanthal) and lignans (pinoresinol and hydroxy and acetoxy derivatives) could be olive oil biomarkers, whereby these compounds are quantified in higher amounts in EVOO compared to other vegetable oils. The principal component analysis (PCA) performed based on the targeted compounds from the oil samples confirmed that cinnamic acid, coumaric acids, apigenin, pinocembrin, hydroxytyrosol and maslinic acid could be considered as tracers for olive oils authentication. The heat map profiles based on the untargeted HRMS data indicate a clear discrimination of the olive oils from the other vegetable oils. The proposed methodology could be extended to the authentication and classification of EVOOs depending on the variety, geographical origin, or adulteration practices.

Genomic and Targeted Approaches Unveil the Cell Membrane as a Major Target of the Antifungal Cytotoxin Amantelide A.

Amantelide A, a polyhydroxylated macrolide isolated from a marine cyanobacterium, displays broad-spectrum activity against mammalian cells, bacterial pathogens, and marine fungi. We conducted comprehensive mechanistic studies to identify the molecular targets and pathways affected by amantelide A. Our investigations relied on chemical structure similarities with compounds of known mechanisms, yeast knockout mutants, yeast chemogenomic profiling, and direct biochemical and biophysical methods. We established that amantelide A exerts its antifungal action by binding to ergosterol-containing membranes followed by pore formation and cell death, a mechanism partially shared with polyene antifungals. Binding assays demonstrated that amantelide A also binds to membranes containing epicholesterol or mammalian cholesterol, thus suggesting that the cytotoxicity to mammalian cells might be due to its affinity to cholesterol-containing membranes. However, membrane interactions were not completely dependent on sterols. Yeast chemogenomic profiling suggested additional direct or indirect effects on actin. Accordingly, we performed actin polymerization assays, which suggested that amantelide A also promotes actin polymerization in cell-free systems. However, the C-33 acetoxy derivative amantelide B showed a similar effect on actin dynamics in vitro but no significant activity against yeast. Overall, these studies suggest that the membrane effects are the most functionally relevant for amantelide A mechanism of action.

ChemInform Abstract: Enantioselective Vicinal Diacetoxylation of Alkenes under Chiral Iodine(III) Catalysis.

AbstractIodophenylene‐linked lactate esters are applied as chiral organocatalysts in the asymmetric vicinal diacetoxylation of styrene and cinnamyl alcohol substrates affording the acetoxy derivatives in modest to good yields and good dia‐ as well as enantioselectivities.

Functionalization of soy fatty acid alkyl esters as bioplasticizers

The combination of various functional groups, such as epoxy, acetoxy, methoxy, thiirane, and aziridine, on the fatty acyl chain of soy fatty acid alkyl esters have been synthesized and evaluated as plasticizers in poly(vinyl chloride) (PVC) applications. Numerous synthetic procedures, such as epoxidation, methoxylation, acetylation, thiiration, and aziridination, were used for synthesizing multifunctional soy fatty acid alkyl esters. Epoxidized soybean oil fatty acid alkyl ester served as the key intermediate for functionalization. Partial or complete ring opening of the epoxide by reacting with methanol and the subsequent etherification or acetylation of the hydroxyl function produced epoxy, alkoxy, and acetoxy derivatives. The nucleophilic substitution of epoxide with sulfur by reacting with ammonium thiocyanate produced thiirane and epoxy thiiranes. Although the aziridine derivatives were synthesized by reacting unsaturated fatty acid alkyl esters with chloramine‐T, the compounds were fully characterized and their physical and analytical properties were determined. The high viscosity and darker color of aziridine and thiirane derivatives limit their usefulness, whereas the physical properties of the other derivatives were acceptable. The plasticizer evaluation of methoxy and acetoxy soy fatty acid esters (methyl and n‐butyl) demonstrated good compatibility with PVC, high efficiency (Shore hardness), and gelling properties were comparable to commercial plasticizer, di‐isoonyl phthalate. The abundant availability and cost‐effectiveness of starting materials and the readily adoptable chemical processes make the fatty acid ester derivatives viable bioplasticizers to replace the fossil fuel‐derived phthalates. J. VINYL ADDIT. TECHNOL., 23:93–105, 2017. © 2015 Society of Plastics Engineers

Intramolecular cationic cyclization of acetoxy derivatives of the levoglucosenone-cyclopentadiene endo-adduct

Epoxidation of diastereoisomeric benzyloxy derivatives of the levoglucosenone adduct with cyclopentadiene by treatment with m-chloroperoxybenzoic acid afforded a mixture of 1,2- and 1,4-epoxy derivatives. Intramolecular cyclization of the hydroxy derivatives of the same adduct by the action of I2-NaHCO3-MeCN gave products resulting from cleavage of the 1,6-anhydro bridge, reduction of the acetal moiety, and olefinaldehyde cyclization.

Synthesis of hydroxyethyl starch derivatives with phenylpropanoid fragments attached through ester or sulfide bonds

Approaches to the synthesis of hydroxyethyl starch derivatives containing phenylpropanoic acid fragments with various degree of substitution were suggested. Esterification of hydroxyethyl starch in heterogeneous aqueous organic medium gave rise to the corresponding esters of ferulic, p-coumaric, and sinapinic acids. A reaction of hydroxyethyl starch mercaptodeoxy derivative with acetoxy derivatives of these hydroxycinnamic acids led to the mixed polysaccharides with the oxyphenyl-3-mercaptopropanoic acid fragments.

Synthesis of new series of 3-hydroxy/acetoxy-2-phenyl-4H-chromen-4-ones and their biological importance

3-Hydroxy-2-aryl/heteroaryl-4H-chromones 4(a–n) were synthesized from appropriate chalcones 3(a–n) and acetylated to afford the corresponding acetoxy derivatives 5(a–n). All compounds were evaluated for antimicrobial activity against Staphylococus aureus, Bacillus subtillis, Escherichia coli and Pseudomonas aeruginosa as well as fungi e.g., Candida albicans and Aspergius niger. Inhibition caused by hydroxy flavones was relatively low, whereas that of their acetoxy ester analogues was substantially high. Structure of 6-chloro-2-(furan-2-yl)-4-oxo-4H-chromen-3-yl acetate (5j) was also supported by means of single crystal X-ray diffraction.

Synthesis of some nitrogen heterocycles and in vitro evaluation of their antimicrobial and antitumor activity

Treatment of ethyl β-aryl-α-cyanoacrylate (2a, b) with thiourea, guanidine hydrochloride, and thiosemicarbazide in presence of anhydrous potassium carbonate in methanol led to formation of pyrimidine derivatives 3 and 5 and thiosemicarbazone derivative 9. Thiazole derivative 10 was prepared via cyclization of thiosemicarbazone derivative 9 with 4-methoxy phenacyl bromide. Acetylation of 3a, 5, and 10 with acetic anhydride yielded the acetoxy and N-acetyl derivatives 4, 6, and 11. The mass-spectral fragmentation patterns of nitrogen heterocycles were investigated to elucidate the structure of the prepared compounds. Biological studies of nitrogen heterocycles were carried out to investigate their antimicrobial and anticancer activities; it was found that compounds 5, 10, and 11 were highly active against bacteria and fungi, and compounds 3a and 3b were also active against bacteria and fungi.

Comparative specificities of Calreticulin Transacetylase to O-acetyl, N-acetyl and S-acetyl derivative of 4-methylcoumarins and their inhibitory effect on AFB1-induced genotoxicity in vitro and in vivo

We have earlier conclusively established the Calreticulin Transacetylase (CRTAase) catalyzed modifications of functional proteins such as cytochrome-P450-linked mixed function oxidases (Cyt-P450-linked MFOs), NADPH cytochrome c reductase, and glutathione S-transferase by acetoxy derivatives of polyphenols. In this study, we have investigated the comparative specificities of CRTAase to N-acetyl derivative, 7-acetamido-4-methylcoumarin (7-N-AMC), O-acetyl derivative, 7-acetoxy-4-methylcoumarin (7-AMC), S-acetyl derivative, 7-thioacetyl-4-methycoumarin (7-S-AMC) and their parent compounds in the modulation of catalytic activities of aforesaid proteins. Special attention concentrated on the comparative inhibitory effect of aforesaid acetyl moiety on Cyt-P450-linked MFOs such as 7-ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-dealkylase (PROD) and aflatoxin B1 (AFB1)-induced genotoxicity in vitro and in vivo. The results clearly indicated that N-acetyl and O-acetyl derivatives were better substrates for CRTAase while the S-acetyl was found to be a poorer substrate. Our study involving atomic charge, charge density and molecular electrostatic potential (MEP) calculations indicated the pivotal role of electronegativity and charge distribution values of O, N and S atoms of the acetyl group at C-7 position of the 4-methylcoumarins in CRTAase activity. These facts reinforce our hypothesis that the CRTAase catalyzed modifications of the catalytic activities of aforesaid proteins by acetyl derivative of 4-methylcoumarins is probably due to acetylation of these proteins.

Photochemistry of 2-(4-hydroxystyryl)-1-naphthopyrylium

A new photochromic system based on 2-(4-hydroxystyryl)-1-naphthopyrylium encompasses the properties of the previously described naphthoflavylium and styrylflavylium systems. The photoproduct exhibits a colour deep in hue and is red shifted in comparison with the equivalent flavylium system. Reaction of 2-hydroxy-1-naphthaldehyde with p-hydroxystyrylmethylketone in acetic acid in the presence of tetrafluoroboric acid and acetic anhydride as catalysts leads to a mixture of two compounds: the photochromic 2-(4-hydroxystyryl)-1-naphthopyrylium and a second product 2-(4-acetoxystyryl)-1-naphthopyrylium resulting from the acetylation by acetic anhydride of the former. In acidic medium and at room temperature the hydrolysis of the acetoxy derivative leads to the 2-(4-hydroxystyryl)-1-naphthopyrylium, in circa 2 days, [HCl] = 0.25 M. The pH dependent chemical reactions taking place with 2-(4-hydroxystyryl)-1-naphthopyrylium were determined by UV-Vis, stooped flow, flash photolysis and (1)H NMR and follow the same general pattern of flavylium derivatives. In order to rationalize the photochromism, an energy level diagram summarizing all the equilibrium and rate constants of the network was drawn.

ChemInform Abstract: Iodonium Salts Are Key Intermediates in Pd‐Catalyzed Acetoxylation of Pyrroles.

AbstractThe reaction of pyrroles and indoles with Ph‐I(O‐Ac)2 proceeds via initial regioselective formation of iodonium acetate intermediates which are converted into acetoxy derivatives.

Substrate specificity of acetoxy derivatives of coumarins and quinolones towards Calreticulin mediated transacetylation: Investigations on antiplatelet function

Calreticulin transacetylase (CRTAase) is known to catalyze the transfer of acetyl group from polyphenolic acetates (PA) to certain receptor proteins (RP), thus modulating their activity. Herein, we studied for the first time the substrate specificity of CRTAase towards N-acetylamino derivatives of coumarins and quinolones. This study is endowed with antiplatelet action by virtue of causing CRTAase catalyzed activation of platelet Nitric Oxide Synthase (NOS) by way of acetylation leading to the inhibition of ADP/Arachidonic acid (AA)-dependent platelet aggregation. Among all the N-acetylamino/acetoxy coumarins and quinolones screened, 7-N-acetylamino-4-methylcoumarin (7-AAMC, 17) was found to be the superior substrate to platelet CRTAase and emerged as the most promising antiplatelet agent both in vitro and in vivo. Further it caused the inhibition of cyclooxygenase-1 (Cox-1) resulting in the down regulation of thromboxane A2 (TxA2), modulation of tissue factor and the inhibition of platelet aggregation. It was also found effective in the inhibition of LPS induced pro-thrombotic conditions.

Calreticulin Transacetylase mediated activation of human platelet nitric oxide synthase by acetyl group donor compounds

Polyphenols have attracted immense interest because of their diverse biological and pharmacological activities. Surprisingly, not much is documented about the biological activities of acetoxy derivatives of polyphenol called polyphenolic acetates (PA). In our previous reports, we have conclusively established the Calreticulin Transacetylase (CRTAase) catalyzed activation of neuronal nitric oxide synthase (nNOS) and tumor necrosis factor-α (TNF-α) induced nitric oxide synthase (iNOS) by PA. In the present work, specificity of CRTAase to various classes of PA was characterized in human platelet. The effect of PA, on platelet NOS and intracellular cyclic guanosine monophosphate (cGMP), and adenosine diphosphate (ADP)-induced platelet aggregation were studied in an elaborated manner. Platelet CRTAase exhibited differential specificities to polyphenolic acetates upon incubation with l-arginine leading to activation of NOS. The intraplatelet generation of NO was studied by flowcytometry using DCFH-DA. The differential specificities of CRTAase to PA were found to positively correlate with increased production of NO upon incubation of PRP with PA and l-arginine. Further, the inhibitory effect of l-NAME on PA induced NO formation in platelets substantiated the CRTAase catalyzed activation of NOS. The real-time RT-PCR profile of NOS isoforms confirmed the preponderance of eNOS over iNOS in human platelets on treatment with PA. Western blot analysis also reiterated the differential pattern of acetylation of eNOS by PA. PA were also found effective in increasing the intraplatelet cGMP levels and inhibiting ADP-induced platelet aggregation. It is worth mentioning that the effects of PA were found to be in tune with the specificities of platelet CRTAase to PA as the substrates.

Calreticulin transacetylase: A novel enzyme-mediated protein acetylation by acetoxy derivatives of 3-alkyl-4-methylcoumarins

Our earlier investigations culminated in the discovery of a unique membrane-bound enzyme Calreticulin transacetylase (CRTAase) in mammalian cells catalyzing the transfer of acetyl group from polyphenolic acetates (PAs) to certain functional proteins viz. Glutathione S-transferase (GST), NADPH Cytochrome c reductase and Nitric oxide synthase (NOS) resulting in the modulation of their biological activities. In order to develop SAR study, herein, we studied the influence of alkyl group at C-3 position of acetoxy coumarins on the CRTAase activity. The alkylated acetoxy coumarins lead to inhibition of catalytic activity of GST, and ADP induced platelet aggregation by the way of activation of platelet Nitric oxide synthase (NOS). Furthermore, the increase in size of the coumarin C-3 alkyl group was found to decrease the CRTAase activity.

Single-step incorporation of oh groups into the monosubstituted dodecahydro-closo-dodecaborate(2-) anion derivatives [B12H11SCN]2−, [B12H11I]2−, and [B12H11OC(O)CH3]2−

We have studied the reactions of the monosubstituted derivatives [B12H11X]2− (X = SCN, I, OC(O)CH3) with acetic acid in the presence of atmospheric oxygen and moisture. The results demonstrate that a hydroxyl group can be embedded in a single step, without formation of any acetoxy derivatives. The synthesized compounds were identified by elemental analysis, IR spectroscopy, and NMR. A mechanism of the process has been proposed.

ChemInform Abstract: Diplopuupehenone, a New Unsymmetrical Puupehenone‐Related Dimer from the Marine Sponge Dysidea sp.

Abstract A new unsymmetrical puupehenone-related dimer, diplopuupehenone, comprising puupehenone and puupehenol segments, was isolated from the marine sponge Dysidea sp., along with the known metabolites, puupehenone and bispuupehenone. The structure of diplopuupehenone was established from spectroscopic data and by spectroscopic analysis of an acetoxy derivative. Diplopuupehenone showed 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity with an IC50 value of 8 μM.

Selective Cytotoxicity of Oxysterols through Structural Modulation on Rings A and B. Synthesis, in Vitro Evaluation, and SAR

Chemically diverse oxysterols were prepared and evaluated for cytotoxicity, aiming to push forward potency and selectivity. They were tested against seven cancer (HT-29, HepG2, A549, PC3, LAMA-84, MCF-7, and SH-SY5Y) and two noncancerous cell lines (ARPE-19 and BJ). The influence of the oxidation pattern on rings A and B was studied. Oxygen functionalities on ring B, such as oxo, oxime, acetamide, acetate, and alkoxy, were evaluated. Most oxysterols were cytotoxic in the low micromolar range, with emphasis to the tetrols 14 and 34, the 6β methoxy and acetoxy derivatives 21 and 45, and the oxime 28. In general, the oxysterols were more toxic to cancer cells and a set of compounds (9, 14, 21, 28, 45) with very high selectivity was identified. The cytotoxicity of 3β-acetates was lower than that of the parent alcohols, although incubation for a longer period rendered them equally cytotoxic, pointing them as potential prodrugs of oxysterols.

Diplopuupehenone, a new unsymmetrical puupehenone-related dimer from the marine sponge Dysidea sp.

Abstract A new unsymmetrical puupehenone-related dimer, diplopuupehenone, comprising puupehenone and puupehenol segments, was isolated from the marine sponge Dysidea sp., along with the known metabolites, puupehenone and bispuupehenone. The structure of diplopuupehenone was established from spectroscopic data and by spectroscopic analysis of an acetoxy derivative. Diplopuupehenone showed 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity with an IC50 value of 8 μM.