Cyclohexenone Moiety Research Articles

Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold

For mitogen-activated protein kinases (MAPKs) a shallow surface—distinct from the substrate binding pocket—called the D(ocking)-groove governs partner protein binding. Screening of broad range of Michael acceptor compounds identified a double-activated, sterically crowded cyclohexenone moiety as a promising scaffold. We show that compounds bearing this structurally complex chiral warhead are able to target the conserved MAPK D-groove cysteine via reversible covalent modification and interfere with the protein-protein interactions of MAPKs. The electronic and steric properties of the Michael acceptor can be tailored via different substitution patterns. The inversion of the chiral center of the warhead can reroute chemical bond formation with the targeted cysteine towards the neighboring, but less nucleophilic histidine. Compounds bind to the shallow MAPK D-groove with low micromolar affinity in vitro and perturb MAPK signaling networks in the cell. This class of chiral, cyclic and enhanced 3D shaped Michael acceptor scaffolds offers an alternative to conventional ATP-competitive drugs modulating MAPK signaling pathways.

Vercytochalasins A and B: Two unprecedented biosynthetically related cytochalasins from the deep-sea-sourced endozoic fungus Curvularia verruculosa

Vercytochalasins A (1) and B (2), two biosynthetically related cytochalasins featuring novel structure and substituents, were isolated from the endozoic fungus Curvularia verruculosa which was associated with the deep-sea squat lobster Shinkaia crosnieri collected from the cold seep environment in South China sea. Their structures were elucidated by detailed interpretation of NMR spectroscopic and mass spectrometric data. The absolute configurations were confirmed by NOESY experiments as well as by DP4+ and ECD calculations. Differed from common cytochalasins, compound 1 is an uncommon secocytochalasin featuring the ester group cleaved between C-9 and C-23, and incorporating an additional oxygenated C4 unit which coupled with C-20 and C-22 to form a new substituted cyclohexenone moiety, while compound 2 contains an unusual 2‑hydroxy-3-oxobutan-2-yl unit at C-22. Both compounds are distinctive from the commonly described cytochalasins. Compound 1 exhibited potent activity against angiotensin-I-converting enzyme (ACE) whereas compound 2 showed antibacterial activity. Molecular docking simulations were performed to explore the intermolecular interaction of compounds 1 and 2 with ACE.

One-pot synthesis of new alkyl 1-naphthoates bearing quinoline, pyranone and cyclohexenone moieties via metal-free sequential addition/oxidation reactions.

A mild and one-pot synthetic pathway was successfully developed for the synthesis of new naphthoate-based scaffolds containing quinoline, pyranone and cyclohexenone moieties via a multistep reaction between acenaphthoquinone and various 1,3-diketones in the presence of different primary aliphatic and benzylic alcohols. This reaction proceeds via a sequential addition/oxidation mechanistic process including a metal-free addition step of acenaphthoquinone and 1,3-diketones followed by the H5IO6-mediated C–C oxidative cleavage of the corresponding vicinal diols at room temperature. The alcohols play a dual role, as the reaction solvent as well as the nucleophile, to conduct the reaction process toward naphthoate formation. All alkyl naphthoate derivatives prepared in this work are new compounds and were definitively characterized using 1H-NMR, 13C-NMR and HRMS analysis, while X-ray crystallography was carried out for one of the products. The synthesis of a naphthalene-based nucleus attached to heterocyclic moieties is noteworthy to follow in the near future for diverse applications in biology, medicine, metal complex design, and semiconductor and optical materials.

Anticancer activities of cyclohexenone derivatives

We designed 21 ethyl 3,5-diphenyl-2-cyclohexenone-6-carboxylate derivatives to identify compounds exhibiting anticancer activity. To measure the inhibitory effects of the compounds on cancer cell growth, a long-term survival clonogenic assay was performed. Since compounds containing a cyclohexenone moiety inhibit the enzyme acetylcholinesterase, an in vitro acetylcholinesterase assay was performed for all 21 cyclohexenone derivatives. To examine the effect of the derivative that exhibited the best cancer cell growth inhibition on the induction of apoptosis by demonstrating the activation of caspases and apoptosis regulatory proteins, immunoblotting and immunofluorescence microscopic analyses were performed. The binding mode between the cyclohexenone derivatives and acetylcholinesterase was elucidated at the molecular level using in silico docking. Druggability was evaluated based on ligand efficiency.

Melophluosides A and B, new triterpene galactosides from the marine sponge Melophlus sarasinorum

Two new triterpene galactosides, melophluosides A and B, were isolated from a marine sponge Melophlus sarasinorum collected in Indonesia. Their structures were determined by the analysis of spectroscopic data and chemical reactions. The absolute configuration of cyclohexenone moiety was determined by the calculated ECD spectrum of a simplified model. Melophluosides A and B exhibited moderate cytotoxicity against HeLa cells (IC50, 11.6 and 9.7 µM, respectively).

Practical and Efficient Synthesis of Polyaryl(hetaryl)-Substituted Cyclohexenones and Salicylates

A new efficient method was developed for the synthesis of triaryl-substituted cyclohexenones and salicylates. The method is based on the Robinson annulation of readily available keto esters and chalcones, followed by the aromatization of the cyclohexenone moiety. The aromatization can be accomplished either by reaction with bromine in boiling chloroform or bromination with copper(II) bromide in ethanol followed by treatment with pyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The new synthetic method was also implemented in a one-pot protocol, which in some cases resulted in higher yields of the final product compared to those obtained in the stepwise synthesis.

Performance and Mechanism on Degradation of Estriol Using O3/PS Process

ABSTRACTIn this study, enhanced ozonation of estriol (E3) with persulfate (PS) was investigated in aqueous solution. Simultaneous generation of hydroxyl radical (•OH) and sulfate radical (•SO4−) by O3/PS process was proposed and experimentally verified. Kinetic results revealed that the degradation of E3 was affected by the solution pH, PS concentration, O3 dosage and E3 initial concentration. The optimal reaction rate was observed in alkaline solutions. The mechanism for the synergistic effect was preliminarily explored by the addition of hydroxyl and sulfate radical scavengers. The enhanced degradation of E3 by O3/PS was also observed in actual water samples, which provided impetus for practical applications. The degradation intermediates were detected using LC/MS. Results showed that the phenol structures of the estrogens were mostly oxidized to cyclohexenone moieties and quinone-like structures.

Different design of enzyme-triggered CO-releasing molecules (ET-CORMs) reveals quantitative differences in biological activities in terms of toxicity and inflammation

Acyloxydiene–Fe(CO)3 complexes can act as enzyme-triggered CO-releasing molecules (ET-CORMs). Their biological activity strongly depends on the mother compound from which they are derived, i.e. cyclohexenone or cyclohexanedione, and on the position of the ester functionality they harbour. The present study addresses if the latter characteristic affects CO release, if cytotoxicity of ET-CORMs is mediated through iron release or inhibition of cell respiration and to what extent cyclohexenone and cyclohexanedione derived ET-CORMs differ in their ability to counteract TNF-α mediated inflammation. Irrespective of the formulation (DMSO or cyclodextrin), toxicity in HUVEC was significantly higher for ET-CORMs bearing the ester functionality at the outer (rac-4), as compared to the inner (rac-1) position of the cyclohexenone moiety. This was paralleled by an increased CO release from the former ET-CORM. Toxicity was not mediated via iron as EC50 values for rac-4 were significantly lower than for FeCl2 or FeCl3 and were not influenced by iron chelation. ATP depletion preceded toxicity suggesting impaired cell respiration as putative cause for cell death. In long-term HUVEC cultures inhibition of VCAM-1 expression by rac-1 waned in time, while for the cyclohexanedione derived rac-8 inhibition seems to increase. NFκB was inhibited by both rac-1 and rac-8 independent of IκBα degradation. Both ET-CORMs activated Nrf-2 and consequently induced the expression of HO-1.This study further provides a rational framework for designing acyloxydiene–Fe(CO)3 complexes as ET-CORMs with differential CO release and biological activities. We also provide a better understanding of how these complexes affect cell-biology in mechanistic terms.

Removal of steroid estrogens from waste activated sludge using Fenton oxidation: Influencing factors and degradation intermediates

The presence of endocrine disrupting compounds (EDCs) in waste activated sludge (WAS) is raising concerns about their influence on animals and the overall food cycle. Traditional sludge stabilization processes cannot remove EDCs effectively. The main objective of this work was to study the removal of four estrogens (estrone (E1), 17β-estradiol (E2), estriol (E3), and 17α-ethinylestradiol (EE2)) in waste activated sludge treated with Fenton oxidation. The effects of H2O2 dosage, initial pH, reaction time, and Fe(II) to H2O2 molar ratio were investigated. Base on both the removal of estrogens and the solubilization of WAS, the proper reaction conditions were recommended as follows: H2O2 dosage=15.62mmolg−1, initial pH=3, reaction time=60min, Fe(II) to H2O2 molar ratio=0.167. Under these conditions, the removal efficiencies of E1, E2, EE2, and E3 were 70%, 90%, 84% and 98%, respectively; compared with non-Fenton treatment, a 24-fold increase in STOC was achieved, and the extent of solubilization of TSS and VSS was close to 13 and 20%, respectively. The degradation intermediates were detected using GC/MS. Results showed that the phenol structures of targets were mostly oxidized to cyclohexenone moieties and quinone-like structures, which indicated that estrogenic activity was weakened. Pregn-4-ene-3,20-dione and pregn-4-en-20-yn-3-one were observed for the first time. Fenton oxidation was shown to offer a promising alternative method of removing EDCs from sludge in pretreatment applications.

A Convenient Conversion of Substituted Cyclohexenones into Aryl Methyl Ketones

This work describes a straightforward multistep conversion of substrates containing a cyclohexenone moiety into mono-, bi- and tricyclic aryl methyl ketones in one single working process. Crucial steps are the addition of 1-ethoxyvinyllithium to the carbonyl group, followed by acid-catalyzed enol ether hydrolysis, dehydration, and dehydrogenation.

Triterpene Galactosides of the Pouoside Class and Corresponding Aglycones from the Sponge Lipastrotethya sp.

Nine new triterpene galactosides and aglycones, along with three known compounds from the rare pouoside class, were isolated from the tropical sponge Lipastrotethya sp. collected from Micronesia. The structures of these new compounds were determined by combined spectroscopic methods and designated as pouosides F-I (4, 8, 10, and 12) and pouogenins A-E (5-7, 9, and 11). The absolute configurations of the asymmetric centers and the cyclohexenone moiety, which had been previously undetermined, were assigned by NOESY analyses and Mosher's methods. Several of these compounds exhibited weak cytotoxicity against the K562 cell line.

Diastereodifferentiating the [2+2] Photocycloaddition of Ethylene to Arylmenthyl Cyclohexenonecarboxylates: Stacking‐Driven Enhancement of the Product Diastereoselectivity That Is Correlated with the Reactant Ellipticity

Upon diastereodifferentiating the [2+2] photocycloaddition of ethylene to a series of p-substituted (-)-8-phenylmenthyl cyclohexenonecarboxylates, the diastereoselectivity was critically controlled by the nature of the substituent introduced to the chiral auxiliary, and the p-nitro-substituted substrate afforded the cycloadducts in 90% diastereomeric excess (de) and with 97% isolated yield. Detailed experimental and theoretical conformation analyses revealed that the stacking interaction of the aromatic auxiliary with the cyclohexenone moiety plays the decisive role in determining the substrate conformation and is, therefore, responsible for the dramatic enhancement of the de. Of particular interest, the product de was directly related to the ellipticity of the substrate, enabling us to "predict" the de prior to photoirradiation.

Crystal structure of 5,5-dimethyl-3-(naphthalen-lylamino) cyclohex-2-enone, C18H19NO

the fragment indicates the significant conjugation. The other bond lengths and angles are quite typical, thus they don't call for further discussion. In the title compound, cyclohexanone ring adopts a half-chair conformation with the maximum deviation being 0.304(2) Â for CI5. The naphthyl and cyclohexenone moieties are not coplanar. The dihedral angle between the leastsquares planes is 77.72(8)°, which is slightly larger than its relative structures because of the more bulky naphthyl group, but much bigger than its acyclic /J-enaminone [4,5]. Unlike the acyclic /3-enaminones [4,5], the formation of the intramolecular hydrogen bond is forbidden [6] because of the torsional strain in the cyclic compounds. Thus, the secondary amine can only give rise

Sequential Aminodiene Diels−Alder Approach to the Ergoline Skeleton

Through a novel sequence of aminodiene Diels-Alder reactions, several substituted amidofurans were readily converted to tricyclic ketones in good yield. The formation of the tricyclic ketone system is the result of a ring opening and dehydration of a transient oxabicyclic adduct formed by an intramolecular Diels-Alder cycloaddition of an amidofuran with a cyclohexenone moiety tethered such that it participates in the cycloaddition as the 2pi component. A convenient way to construct the cyclohexenone is to make use of some aminodiene chemistry developed by Rawal. An angular carbomethoxy group is required in order to activate the olefin toward cycloaddition with Rawal's diene. The presence of this activating group not only prevents the isomerization of the advanced ergoline intermediate to a naphthalene but can also be leveraged for an oxidation to provide Uhle's ketone (13). The easily formed Kornfeld ketone analogue 25 was readily transformed into the corresponding triflate 41 by the action of triflic anhydride and a base. Oxidative addition of vinyl triflate 41 to Pd(0) and the ability of the resulting vinyl palladium species to undergo cross-coupling with terminal alkynes prompted us to devise an expeditious route to lysergic acid. Unfortunately, our inability to carry out a regioselective Heck reaction using vinyl triflate 41 and the methylene amino acrylate ester 48 thwarted the completion of the synthesis of lysergic acid.

Synthesis of 3‐Benzyl‐2‐hydroxy‐7,8‐dihydro‐6H‐quinolin‐5‐ones from Baylis—Hillman Adducts.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 3-Benzyl-2-hydroxy-7,8-dihydro-6H-quinolin-5-ones from Baylis-Hillman Adducts

2-Hydroxy-7,8-dihydro-6H-quinolin-5-one skeleton is a useful backbone for the synthesis of numerous biologically interesting compounds such as carbostyrils (2-hydroxyquinolines) or huperzine A analogues, which have shown biological activities including non-steroidal antiinflammatory activity, acetylcholinesterase (AChE) inhibitory activity and antimalarial activity. During the studies on the chemical transformation of the Baylis-Hillman adducts toward synthetically useful heterocyclic compounds we envisioned that we could synthesize 3-benzyl-5-methoxycarbostyril derivatives 5. Our synthetic rationale for 5a is depicted in Scheme 1. Reaction of the Baylis-Hillman acetate 1 and cyclic enaminone 2 would provide the tetrahydroquinoline-2,5-dione skeleton 3 via SN2' type reaction of cyclic enaminones to the BaylisHillman acetates followed by amide bond formation. We thought that the following iodine-assisted oxidative aromatization of cyclohexenone moiety and base-catalyzed isomerization of lactam moiety would afford the desired 3benzyl-5-methoxycarbostyril derivative 5. The reaction of Baylis-Hillman acetate 1a and 3-amino-2cyclohexenone (2a) in refluxing ethanol in the presence of catalytic amount of acetic acid gave 3-benzylidene-4,6,7,8tetrahydro-1H,3H-quinoline-2,5-dione (3a) as the major product (52%) together with small amounts of 4a (< 10%). The reaction could also be conducted in n-butanol without acetic acid catalyst in a similar pattern. But, when we used nbutanol as the solvent, 4a was observed as the major product on TLC presumably due to the effect of higher reaction temperature than in EtOH. But, 3a was not changed completely into 4a even after heating for a long time. Thus we examined the conditions for the effective transformation of 3a into 4a and we found a suitable condition fortunately. Conversion of 3a into 4a could be carried out easily with catalytic amounts of DBU in THF at room temperature (reflux for the conversion of 3g into 4g, entry 7 in Table 1). Thus, we prepared 4a-c according to the following procedures: reaction of 1a-c and 2a in refluxing n-BuOH, separation of 3 and 4 as a mixtures, and finally DBU treatment to form 4a-c as the final products (entries 1-3 in Table 1). It is interesting to note that the easiness for the conversion

Comparison of the gastroprotective effect of a diterpene lactone isolated from Croton cajucara with its synthetic derivatives

The effect of three new derivatives from dehydrocrotonin (DHC—compound I) on gastric damage in different animal models including gastric ulceration induced by a necrotic agent and hypothermic restrained-stress was studied: compound II (produced by reducing the cyclohexenone moiety of DHC with NaBH 4); compound III (produced by reducing the carbonyls with LiAlH 4); and compound IV (produced by transforming the lactone moiety into an amide). Their structures were confirmed on the basis of chemical and physicochemical evidence. When previously administered (p.o.) at a dose of 100 mg/kg, compound II significantly ( P<0.01) reduced gastric injury induced by HCl/ethanol (78%) and indomethacin (88%) better than did reference compound I (48 and 43%, respectively). But the anti-ulcerogenic activity of compound II was completely abolished by the stress-induced ulcer. Reduction of carbonyls with LiAlH 4 (compound III) caused decreased activity, markedly when no protective effect in any of the models was applied ( P>0.05). However, compound IV, in which the lactone moiety was changed into an amide, when administered at the same dose (100 mg/kg, p.o.), was more effective. The presence of a lactone moiety or Michael acceptor is probably essential for the anti-ulcerogenic effect of these compounds.

Derivatives of dehydrocrotonin, a diterpene lactone isolated from Croton cajucara: cytotoxicity in rat cultured hepatocytes and in V79 cells.

Derivatives of dehydrocrotonin (DHC; Compound I) with different anti-ulcerogenic properties but less toxicity were produced by reducing the cyclohexenone moiety of DHC with NaBH4 (Compound II), reducing the cyclohexenone and lactone moieties with LiAlH4 (Compound III) and transforming the lactone moiety into an amide (Compound IV) using dimethylamine. Derivatives of DHC were assayed in cultured hepatocytes and V79 fibroblasts. Three independent endpoints assays for cytotoxicity were used, namely, the DNA content, tetrazolium reduction (MTT) and neutral red uptake (NRU). Compound III was less toxic than the other DHC derivatives in both cell cultures. ICso values ranging from 250 to 600 microM were obtained for Compounds II and IV in the NRU and DNA content tests evaluated in 4-hour hepatocyte cultures. Although Compound II showed relatively low cytotoxicity in rat hepatocytes based on the NRU and DNA content assays, a very high toxicity (IC50=10 microM) was observed in the MTT test. Metabolites of Compound II in conditioned medium from 4-hour old hepatocyte cultures enhanced the MTT-reducing ability of V79 fibroblasts. The cytotoxicity of the derivatives was greater in recently isolated hepatocytes (only a 4-hour incubation for cell attachment prior to treating with the derivatives) than in hepatocytes previously cultured (24-hour incubation) before the treatment. Thus, aging reduced the cytotoxic effects of DHC derivatives in isolated hepatocytes, suggesting that P450-mediated biotransformation of such derivatives may lead to the formation of more toxic metabolites.

Cloning, sequencing, and heterologous expression of the elmGHIJ genes involved in the biosynthesis of the polyketide antibiotic elloramycin from Streptomyces olivaceus Tü2353.

Elloramycin A (1) belongs to a small family of naphthacenequinones characterized by a unique highly hydroxylated cyclohexenone moiety. A cosmid clone 16F4, harboring genes for the production of 1 from Streptomyces olivaceus Tü2353, has been previously isolated. DNA sequence analysis of a 3.2-kb fragment from 16F4 revealed four open reading frames--the elmGHIJ genes. Heterologous expressions of the elmGHI genes in either Escherichia coli or Streptomyces lividans, followed by biochemical characterizations of the ElmGHI proteins, established ElmG as tetracenomycin B2 oxygenase, ElmH as tetracenomycin F1 monooxygenase, and ElmI as tetracenomycin F2 cyclase. These results provide direct biochemical evidence for the hypothesis that the biosynthesis of 1 in S. olivaceus parallels that of tetracenomycin C (2) in Streptomyces glaucescens and support the notion that the biosynthesis of the highly hydroxylated cyclohexenone moiety in other polyketides most likely follows the same paradigm as the tetracenomycin B2 or A2 oxygenase.

Cytotoxicity of derivatives from dehydrocrotonin on V79 cells and Escherichia coli

New derivatives from dehydrocrotonin (DHC, compound I), with the same anti-ulcerogenic properties but less toxicity were synthesised by reducing the cyclohexenone moiety of DHC with NaBH 4 (compound II), by reducing the cyclohexenone and lactone moieties with LiAlH 4 (compound III) and by transforming the lactone moiety into an amide (compound IV) using dimethylamine. The cytotoxicity of these derivatives from DHC was assayed on V79 fibroblast cell line. Three independent endpoints for cytotoxicity were evaluated; namely, the nucleic acid content (NAC), tetrazolium reduction (MTT) and neutral red uptake (NRU). IC 50 values of 540 and 350 μM were obtained for compound II in the NRU and NAC tests, respectively. Compound III was less toxic than the other DHC derivatives (IC 50=1800 μM) on V79 cells based on NAC assay. Compound IV showed an IC 50 ranging from 350 to 600 μM based on the three endpoints evaluated. The three compounds were less toxic on V79 cells than DHC. DHC, compounds II, III and IV did not change the respiration rate of Escherichia coli on the acute toxicity assay.