Cyclohexenyl Ring Research Articles

CYP2C9, CYP3A and CYP2C19 metabolize Δ9-tetrahydrocannabinol to multiple metabolites but metabolism is affected by human liver fatty acid binding protein (FABP1)

Δ9-tetrahydrocannabinol (THC) is the psychoactive constituent of cannabis. It is cleared predominantly via metabolism. Metabolism to 11-OH-THC by cytochrome P450 (CYP) 2C9 has been proposed as the main clearance pathway of THC, with the estimated fraction metabolized (fm) about 70%. The remaining clearance pathways are not well established, and it is unknown how THC is eliminated in individuals with reduced CYP2C9 activity. The goal of this study was to systematically identify the CYP enzymes contributing to THC clearance and characterize the metabolites formed. Further, this study aimed to characterize the impact of liver fatty acid binding protein (FABP1) on THC metabolism by human CYPs. THC was metabolized to at least four different metabolites including 11-OH-THC in human liver microsomes (HLMs) and with recombinant CYPs. 11-OH-THC was formed by recombinant CYP2C9 (Km,u = 0.77 nM, kcat = 12 min−1) and by recombinant CYP2C19 (Km,u = 2.2 nM, kcat = 14 min−1). The other three major metabolites were likely hydroxylations in the cyclohexenyl ring and were formed mainly by recombinant CYP3A4/5 (Km,u > 10 nM). HLM experiments confirmed the contributions of CYP2C9, CYP2C19 and CYP3A to THC metabolism. The presence of FABP1 and THC binding to FABP1 altered THC metabolism by recombinant CYPs and HLMs in an enzyme and metabolite specific manner. This suggests that FABP1 may interact with CYP enzymes and alter the fm by CYPs towards THC metabolism. In conclusion, this study is the first to systematically establish the metabolic profile of THC by human CYPs and characterize how FABP1 binding alters CYP mediated THC metabolism.

Phosphine-Catalyzed Domino Regio- and Stereo-Selective Hexamerization of 2-(Bromomethyl)acrylates to 1,2-Bis(cyclohexenyl)ethenyl Derivatives.

A phosphine-catalyzed domino assembly of six units of 2-bromomethyl acrylates afforded polyalkenyl adducts containing two cyclohexenyl rings. This reaction occurs under mild conditions providing the final product by formation of seven carbon-carbon bonds and four stereocenters. Experimental and computational studies support an initial dimerization of the substrate, which in turn trimerizes involving two totally regio- and stereocontrolled Diels-Alder cycloadditions. The yield of the hexamerization of the 2-bromomethyl acrylates depends on the size of the ester function. The protocol has also proved to be practicable on a gram scale.

Sustainable Syntheses of Paracetamol and Ibuprofen from Biorenewable β-pinene.

Scalable processes have been developed to convert β-pinene into 4-isopropenylcyclohexanone which is then used as a feedstock for the divergent synthesis of sustainable versions of the common painkillers, paracetamol and ibuprofen. Both synthetic routes use Pd(0) catalysed reactions to aromatise the cyclohexenyl rings of key intermediates to produce the benzenoid ring systems of both drugs. The potential of using bioderived 4-hydroxyacetophenone as a drop-in feedstock replacement to produce sustainable aromatic products is also discussed within a terpene biorefinery context.

Carotenoid metabolites, their tissue and blood concentrations in humans and further bioactivity via retinoid receptor-mediated signalling.

Many epidemiological studies have emphasised the relation between carotenoid dietary intake and their circulating concentrations and beneficial health effects, such as lower risk of cardiometabolic diseases and cancer. However, there is dispute as to whether the attributed health benefits are due to native carotenoids or whether they are instead induced by their metabolites. Several categories of metabolites have been reported, most notably involving (a) modifications at the cyclohexenyl ring or the polyene chain, such as epoxides and geometric isomers, (b) excentric cleavage metabolites with alcohol-, aldehyde- or carboxylic acid-functional groups or (c) centric cleaved metabolites with additional hydroxyl, aldehyde or carboxyl functionalities, not counting their potential phase-II glucuronidated / sulphated derivatives. Of special interest are the apo-carotenoids, which originate in the intestine and other tissues from carotenoid cleavage by β-carotene oxygenases 1/2 in a symmetrical / non-symmetrical fashion. These are more water soluble and more electrophilic and, therefore, putative candidates for interactions with transcription factors such as NF-kB and Nrf2, as well as ligands for RAR-RXR nuclear receptor interactions. In this review, we discuss in vivo detected apo-carotenoids, their reported tissue concentrations, and potential associated health effects, focusing exclusively on the human situation and based on quantified / semi-quantified carotenoid metabolites proven to be present in humans.

Poly(2-ethyl-2-oxazoline)-IR780 conjugate nanoparticles for breast cancer phototherapy.

Aims: To address the limitations of IR780 by preparing hydrophilic polymer-IR780 conjugates and to employ these conjugates in the assembly of nanoparticles (NPs) intended for cancer photothermal therapy. Materials & methods: The cyclohexenyl ring of IR780 was conjugated for the first time with thiol-terminated poly(2-ethyl-2-oxazoline) (PEtOx). This novel poly(2-ethyl-2-oxazoline)-IR780 (PEtOx-IR) conjugate was combined with D-α-tocopheryl succinate (TOS), leading to the assembly of mixed NPs(PEtOx-IR/TOSNPs). Results: PEtOx-IR/TOS NPs displayed optimal colloidal stability as well as cytocompatibility in healthy cells at doses within the therapeutic range. In turn, the combination of PEtOx-IR/TOS NPs and near-infrared light reduced heterotypic breast cancer spheroid viability to just 15%. Conclusion: PEtOx-IR/TOS NPs are promising agents for breast cancer photothermal therapy.

Is Vitamin A an Antioxidant or a Pro-oxidant?

Antioxidant efficiency of all-trans-retinol has been studied on the basis of characteristic thermochemical properties using density functional theory. The influence of the solvent polarity has also been evaluated. It is found that retinol may act in parallel as an effective antioxidant via H atom donating as well as a pro-oxidant in yielding reactive hydroxyl radical. In fact, the lowest values of bond dissociation enthalpy were found at the C18-H and C18-OH positions. Retinol was also determined to be a good electron donor but bad acceptor in the single electron transfer (ET) reaction with hydroperoxyl (HOO•) radical. In addition, potential energy surfaces of H atom transfer (HAT) and radical adduct formation (RAF) reactions between retinol and HOO• radical were also investigated in the gas phase and in the solvent. The results demonstrated that the RAF mechanism was generally more predominant than ET and HAT ones. The most favored radical addition position was found at the C2═C3 double bond in the cyclohexenyl ring. Moreover, the radical scavenging reactivity via RAF reactions was strongly exergonic and thermodynamically feasible while the ET one was endergonic. Natural bond orbital analysis showed that the lone pairs of electrons on the oxygen atom of the HOO• radical were donated to the unoccupied antibonding orbital of transferred H atom in HAT reactions. In contrast, in the case of RAF reactions, strong interactions between 2p orbitals on oxygen atoms of the radical and the π orbital of the double bond on the retinol molecule were recognized. The results obtained in this work were in agreement with previous experimental observations.

1-(Cyclohex-1-en-1-yl)-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1H-benzimidazol-2(3H)-one

In the title compound, C22H21N5O, the triazole ring is inclined at 16.88 (12)° to its phenyl substituent and is almost normal to the benzimidazole ring system, making a dihedral angle of 88.40 (8)°. The cyclohexenyl ring adopts a half-chair conformation and its mean plane is inclined to the benzimidazole ring system by 78.75 (12)°. In the crystal, molecules are linked by C—H...O and C—H...N hydrogen bonds, forming a three-dimensional network.

N-[1,4,4-Trimethyltricyclo[6.3.1.03,9]dodec-8(12)-en-2-yl]acetamide

The title compound, C17H27NO, crystallizes with three independent molecules in the asymmetric unit with almost identical conformations. Each molecule is built up from a seven-membered ring to which a bridged six-membered ring is fused. In each of the three molecules, the seven-membered rings have a twist-chair conformation, while the cyclohexenyl rings display perfect boat conformations. In the crystal, N—H...O hydrogen bonds link the molecules into zigzag chains running along theb-axis direction.

Structural studies of (E)-2-(benzylidene)-1-tetralone derivatives: crystal structures and Hirshfeld surface analysis

Abstract Crystal structures are reported from data collected at 100 K of (E)-2-(X-benzylidene)-1-tetralone (2: X=3-O2N; 3: X=4-O2N; 5: X=4-HO; 6: X=4-Me2N; 7: 4-NC), (E)-2-(X-benzylidene)-6-MeO-1-tetralone, 8, and (E)-2-(X-benzylidene)-5-MeO-1-tetralone 9. Also reported herein are the Hirshfeld surface calculations for these compounds as well as those of (E)-2-(X-benzylidene)-1-tetralone (1: X=H; 4: X=4-MeO), whose structures were previously reported. The molecules are not planar as shown by the dihedral angles of 45.66(5)–69.78(5)° between the phenyl groups and by the puckered cyclohexenyl rings. A common feature of the molecular conformations is the C–H···O1(carbonyl) intramolecular hydrogen bond. The carbonyl oxygen atom plays significant roles in the interactions in all compounds baring compound 8. However, there is no consistent set of intermolecular interaction in this group of compounds. Intermolecular interactions present in each compound are some of the O–H···O, C–H···A (A=O, N or π), A–O···π (A=C or N) and π···π interactions. The only compound exhibiting a classical O–H···O hydrogen bond is compound 5. C–H···π interactions are found in all compounds, and while π···π interactions are present in compounds 2, 3, 7 and 9, no consistent type of stacking arrangement is shown. The Hirshfeld surface calculations, while generally concurring with the intermolecular interactions indicated by PLATON analyses, also reveal short interactions, which fall below the PLATON cut-off parameters.

Total Synthesis of Notoamides F, I, and R and Sclerotiamide

AbstractThe total synthesis of the natural indole alkaloids (+)‐notoamide F, I, and R and (−)‐sclerotiamide is described. The four heptacyclic compounds were synthesized in 10–12 steps in a convergent and highly stereoselective manner from the readily available Seebach acetal. Key steps of the synthesis include a stereoselective oxidative aza‐Prins cyclization to construct the bicyclo[2.2.2]diazaoctane, and a cobalt‐catalyzed radical cycloisomerization to create the cyclohexenyl ring.

Total Synthesis of Notoamides F, I, and R and Sclerotiamide.

The total synthesis of the natural indole alkaloids (+)-notoamide F, I, and R and (-)-sclerotiamide is described. The four heptacyclic compounds were synthesized in 10-12 steps in a convergent and highly stereoselective manner from the readily available Seebach acetal. Key steps of the synthesis include a stereoselective oxidative aza-Prins cyclization to construct the bicyclo[2.2.2]diazaoctane, and a cobalt-catalyzed radical cycloisomerization to create the cyclohexenyl ring.

Novel synthetic approach to near-infrared heptamethine cyanine dyes and spectroscopic characterization in presence of biological molecules

Abstract Two near-infrared symmetric heptamethine cyanine dyes, containing integrated chlorosubstituted cyclohexenyl ring were obtained via a novel synthetic approach, using mild conditions at room temperature. UV–vis and fluorescence properties of the dyes were evaluated in organic solutions varying solvent polarity. Further spectral studies illustrating their application as potential labels for biological molecules, were reported in the presence of deoxyribonucleic acid (DNA), bovine serum albumin (BSA), and phospholipids (PC). The dyes undergo H-type intramolecular complexation between the two cyanine subunits when free in buffer. Absorption studies show that binding of cyanines to DNA, BSA and lipid membranes leads to the red shift in the H-aggregates peak with appearance of monomeric and dimeric dye species pointing to the disaggregation of the dyes under study in the presence of biological molecules. The fact that the decrease of liposome-induced cyanine aggregation was more pronounced in the zwitterionic phosphatidylcholine bilayer, suggests that the disruption of highly organized molecular arrangements are most likely electrostatically-controlled.

Insights into the structure–activity relationship of the anticancer compound ZJ-101: A critical role played by the cyclohexene ring

Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure–activity relationship study, a new analog ZJ-102 was designed and synthesized to probe the importance of the cyclohexenyl group through its replacement to a phenyl group using a concise and convergent synthetic approach. The biological evaluation showed that this new analog ZJ-102 is significantly less active against cancer cells in vitro than ZJ-101, suggesting that the cyclohexenyl ring (along with its two stereogenic centers) present in ZJ-101 is important for its anticancer activity.

Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers.

(2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure-activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a disubstituted cyclohexenyl ring. Among the 12 class I and class II rexinoids evaluated, the class I rexinoid 11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid 11 also reduces the size of established tumors and exhibits a therapeutic effect. However, 11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid 10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.

Photoswitching Behavior of a Cyclohexene-Bridged versus a Cyclopentene-Bridged Dithienylethene System.

Photoswitching is an intriguing way of incorporating functionality into molecules or their subunits. Dithienylethene switches are particularly promising, but have so far mostly been studied with five-membered ring (cyclopentenyl) backbones. We aim at comparing the switching properties of backbones with five and six carbon atoms in the ring. A major advantage is that cyclohexenyl rings offer new options for chiral functionalization. A slight change in the reaction conditions of a McMurry ring closure reaction leads to the formation of dithienyl derivatives with a cyclohexene backbone in reasonable yield. Density functional theory calculations were carried out, demonstrating the similarity of both compounds. Experimental results confirm the theoretical outcomes.

Pinnatoxin H: a new pinnatoxin analogue from a South China Sea Vulcanodinium rugosum isolate

Pinnatoxin H was isolated from a culture of the dinoflagellate Vulcanodinium rugosum isolated from the South China Sea. The structure of pinnatoxin H was elucidated by LC–MS/MS and NMR spectroscopy. It was found to have the same macrocyclic structure and substituents as pinnatoxins D, E and F, but the side chain on the cyclohexenyl ring was an ethenyl group, as found in pinnatoxin G and portimine. The observation that this strain of V. rugosum produced only pinnatoxin H and portimine is consistent with previous findings that the profile of pinnatoxins can vary significantly among strains. The acute toxicity of pinnatoxin H to mice was 67μg/kg (intraperitoneal) and 163μg/kg (gavage).

Bromolactamization: key step in the stereoselective synthesis of enantiomerically pure, cis-configured perhydropyrroloquinoxalines.

Compounds based on the pyrroloquinoxaline system can interact with serotonin 5-HT3 , cannabinoid CB1 , and μ-opioid receptors. Herein, a chiral pool synthesis of diastereomerically and enantiomerically pure bromolactam (S,R,R,R)-14A is presented. Introduction of the cyclohexenyl ring at the N-atom of (S)-proline derivatives 8 or methyl (S)-pyroglutamate (12) led to the N-cyclohexenyl substituted pyrrolidine derivatives 4 and 13, respectively. All attempts to cyclize the (S)-proline derivatives 4 with a basic pyrrolidine N-atom via [3 + 2] cycloaddition, aziridination, or bromolactamization failed. Fast aromatization occurred during treatment of cyclohexenamines under halolactamization conditions. In contrast, reaction of a 1:1 mixture of diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB with LiO(t) Bu and NBS provided the tricyclic bromolactam (S,R,R,R)-14A with high diastereoselectivity from (S,R)-13bA, but did not transform the diastereomer (S,S)-13bB. The different behavior of the diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB is explained by different energetically favored conformations.

A silicon-position dependent 6-endo-trig cyclization during Tsuji–Trost alkylation

Two silylated cyclohexenes products have been prepared by using a Tsuji–Trost palladium-catalyzed cyclization. It involves the generation of a cationic π-allylic palladium complex bearing a triethylsilyl group on C-3, which cyclizes via a 6-endo-trig process to afford the cyclohexene derivatives. It is also demonstrated that the position of the silyl group on the starting allylic substrate strongly influenced the reaction. It could favor either the production of the expected cyclohexenyl ring or a diene by an elimination that occurs on the silyl-substituted C-2 π-allylic palladium complex.

Stereoselective Synthesis of Deuterium-Labeled (2S)-Cyclohexenyl Alanines, Biosynthetic Intermediates of Cinnabaramide

Dideuterated β-cyclohexenylalanines, proposed biosynthetic intermediates of the cinnabaramides, can be obtained from chiral alkynols via a sequence of Irland-Claisen rearrangement, ring closing metathesis, and radical decarboxylation. Feeding experiments indicate that both (2S)-β-cyclohexenylalanines can be incorporated into cinnabaramide, while the configuration at the cyclohexenyl ring does not restrict biosynthetic processing.

Irradiation Induced Fluorescence Enhancement in PEGylated Cyanine-Based NIR Nano- and Mesoscale GUMBOS

We report on the synthesis and characterization of a PEGylated IR786 GUMBOS (Group of Uniform Materials Based on Organic Salts). The synthesis of this material was accomplished using a three step protocol: (1) substitution of chloride on the cyclohexenyl ring in the heptamethine chain of IR786 by 6-aminohexanoic acid, (2) grafting of methoxy polyethylene glycol (MeOPEG) onto the 6-aminohexanoic acid via an esterification reaction, and (3) anion exchange between [PEG786][I] and lithium bis(trifluoromethylsulfonyl)imide (LiNTf(2)) or sodium bis(2-ethylhexyl)sulfosuccinate (AOT) in order to obtain PEG786 GUMBOS. Examination of spectroscopic data for this PEG786 GUMBOS indicates a large stokes shift (122 nm). It was observed that this PEG786 GUMBOS associates in aqueous solution to form nano- and mesoscale self-assemblies with sizes ranging from 100 to 220 nm. These nano- and mesoscale GUMBOS are also able to resist nonspecific binding to proteins. PEGylation of the original IR786 leads to reduced cytotoxicity. In addition, it was noted that anions, such as NTf(2) and AOT, play a significant role in improving the photostability of PEG786 GUMBOS. Irradiation-induced J-aggregation in [PEG786][NTf(2)] and to some extent in [PEG786][AOT] produced enhanced photostability. This observation was supported by use of both steady state and time-resolved fluorescence measurements.