Vanillyl Moiety Research Articles

Polymeric Antioxidant via ROMP of Bioderived Tricyclic Oxanorbornene Based on Vanillin and Furfurylamine

Herein, a bioderived antioxidant oxanorbornene lactam monomer bearing a vanillyl moiety has been successfully synthesized. The monomer was synthesized via reductive amination of two biobased molecules, vanillin and furfurylamine, followed by tandem Diels–Alder and lactamization reactions with maleic anhydride. For comparison, an inactive monomer was prepared using benzaldehyde instead of vanillin. Rapid controlled polymerization of the tricyclic strained monomers has been conducted using ring opening metathesis polymerization. The resultant polymers were fully characterized, and their antioxidant potentials had been assessed. The monomer with the vanillyl moiety and its corresponding polymer showed exceptional antioxidant activities compared to the reference analogue with a benzyl pendant group. Indeed, the developed antioxidant polymer shows promising potential in the sustainable polymer industry for a smaller ecological footprint.

Oxidative Dearomatization as a Strategy for a Facile, Metal‐Free Synthesis of Vanillyl Benzodiazepines

Abstractisovanillin was conveniently dearomatized into synthetically useful o‐quinol acetate by treatment with phenyliodine(III) diacetate (PIDA) in methylene chloride at low temperature. Subsequent treatment with o‐aryl diamines directly furnished vanillyl benzodiazepines in good yields. Vanillyl benzodiazepines, could be the prospective objects of investigation in medicinal chemistry considering the central nervous system depressant activity of benzodiazepines and potent antioxidant and anti‐inflammatory activities of vanillyl moiety by being present in a single framework. Herein we propose a simple, metal‐free, and efficient approach for the synthesis of vanillyl benzodiazepines via oxidative dearomatization. The regio‐chemistry of product isomers were established by NOE studies.

Molecular Mechanism of TRPV1 Activation by Capsaicin

Molecular Mechanism of TRPV1 Activation by Capsaicin

Dissecting the Pharmacophore of Curcumin. Which Structural Element Is Critical for Which Action?

The dietary phenolic curcumin (1a) is the archetypal network pharmacological agent, but is characterized by an ill-defined pharmacophore. Nevertheless, structure-activity studies of 1a have mainly focused on a single biological end-point and on a single structural element, the aliphatic bis-enoyl moiety. The comparative investigation of more than one end-point of curcumin and the modification of its aromatic region have been largely overlooked. To address these issues, we have investigated the effect of aromatic C-prenylation in the three archetypal structural types of curcuminoids, namely, curcumin itself (1a), its truncated analogue 2a (C5-curcumin), and (as the reduced isoamyl version) the tetrahydro derivative 3a, comparatively evaluating reactivity with thiols and activity in biochemical (inhibition of NF-κB, HIV-1-Tat transactivation, Nrf2 activation) and phenotypic (anti-HIV action) assays sensitive, to a various extent, to thia-Michael addition. Prenylation, a validated maneuver for bioactivity modulation in plant phenolics, had no effect on Michael reactivity, but was detrimental for all biological end-points investigated, dissecting thiol trapping from activity, while hydrogenation attenuated, but did not completely abrogate, the activity of 1a. The C5-curcuminoid 2a outperformed the natural product in all end-points investigated and was identified as a novel high-potency anti-HIV lead in a cellular model of HIV infection. Taken together, these observations show that Michael reactivity is a critical element of the curcumin pharmacophore, but also reveal a surprising sensitivity of bioactivity to C-prenylation of the vanillyl moiety.

Protective effect and relation structure-activity of nonivamide and iododerivatives in several models of lipid oxidation

The introduction of an iodine atom on the vanillyl moiety of nonivamide causes a switch in the vanilloid activity (TRPV1 antagonism versus TRPV1 desensitization) and nullifies the aversive properties of capsaicinoids. In the present study we investigated the effect of iodination in the vanillyl moiety on the antioxidant activity of capsaicinoids. To this aim, we have compared the protective effects of nonivamide and three iododerivatives, 2-iodononivamide (2IN), 5-iodononivamide (5IN), and 6-iodononivamide (6IN) in a series of in vitro models of lipid oxidation, namely the autoxidation and the FeCl 3-mediated oxidation of linoleic acid at 37 °C and the thermal (140 °C), solvent-free oxidation of cholesterol. All tested compounds could protect linoleic acid and cholesterol against oxidative degradation, the order of potency being: nonivamide > 5IN > 6IN ≈ 2IN. Our results show that, in general, the introduction of an iodine atom on the vanillyl moiety of nonivamide causes a decrease in the antioxidant activity, and this effect is sensitive to the position of iodine on the aromatic ring, with 5IN substantially retaining the efficacy of nonivamide to protect linoleic and cholesterol against free radical attack. Moreover, the pre-treatment with 5IN, at noncytotoxic concentrations, significantly preserved LDL from Cu 2+-induced oxidative damage at 37 °C for 2 h, inhibiting the reduction of polyunsaturated fatty acids and cholesterol and the increase of their oxidative products. The results of the present work suggest that 5IN exerts useful antioxidant properties in different in vitro systems of lipid peroxidation. This, coupled to its lacks of pungency and TRPV1 inhibiting properties, qualifies this phenolic compound as an attractive candidate for further investigations in vivo.

Structural Analogues of Homoeriodictyol as Flavor Modifiers. Part III: Short Chain Gingerdione Derivatives

In order to find new flavor modifiers, various short chain gingerdione derivatives were synthesized as structural analogues of the known bitter masker homoeriodictyol and evaluated by a sensory panel for masking and sweetness enhancing activities. 1-(4-Hydroxy-3-methoxyphenyl)hexa-3,5-dione ([2]-gingerdione) and the homologue 1-(4-hydroxy-3-methoxyphenyl)hepta-3,5-dione ([3]-gingerdione) at concentration ranges 50-500 mg kg (-1) showed the most promising masking activity of 20-30% against bitterness of a 500 mg kg (-1) aqueous caffeine solution. Additionally, both compounds were able to reduce the bitterness of a 5 mg kg (-1) quinine solution by about 20%; however, the bitter tastes of salicine, the model peptide H-Leu-Trp-OH, and KCl solutions were not reduced. Whereas for bitter masking activity a vanillyl moiety seems to be important, some of the tested isovanillyl isomers showed an interesting sweet enhancing effect without exhibiting a significant intrinsic sweetness. The isomer 1-(3-hydroxy-4-methoxyphenyl)hexa-3,5-dione ([2]-isogingerdione) at 100 mg kg (-1) caused a significant and synergistic increase of 27% of sweet taste of a 5% sucrose solution.

Probing the Molecular and Electronic Structure of Capsaicin: A Spectroscopic and Quantum Mechanical Study

The conformational preferences of capsaicin were investigated by using the hybrid meta density functional theory (DFT) method MPWB1K. Its flexible, pendant side chain allows for a multitude of conformations only slightly different in energy. The distinctive vibrational features of the most stable conformers were characterized. To elucidate the most favorable reaction sites of capsaicin for radical scavenging, various homolytic bond-dissociation energies were also calculated. Of the possible radical intermediates, the allyl and benzyl radicals are energetically preferred. The filled and empty electronic structures of capsaicin were investigated by exploiting the photoelectron and electron-transmission spectra also of reference molecules and suitable quantum-mechanical calculations. On this basis, a reliable pattern of the vertical ionization energies and electron-attachment energies of capsaicin was proposed. The frontier pi molecular orbitals are concentrated over the vanillyl moiety, with a modest influence of the amidic-aliphatic chain. The (negative) first vertical electron affinity is predicted to be similar to that of benzene. The absorption spectrum of capsaicin and its change by conversion into a phenolic deprotonated anion (modest bathochromic displacement) or a phenoxyl neutral radical (from colorless to red) were interpreted with time-dependent DFT calculations. ESR measurements following chemical or electrochemical reduction of capsaicin did not lead to detection of the corresponding radical anion. The spectra show fragmentation of the original molecule and formation of a variety of radical species which are believed to have a semiquinonic structure.

Determinants of 4α-Phorbol Sensitivity in Transmembrane Domains 3 and 4 of the Cation Channel TRPV4

TRPV4, a Ca(2+)-permeable member of the vanilloid subgroup of the transient receptor potential (TRP) channels, is activated by cell swelling and moderate heat (>27 degrees C) as well as by diverse chemical compounds including synthetic 4 alpha-phorbol esters, the plant extract bisandrographolide A, and endogenous epoxyeicosatrienoic acids (EETs; 5,6-EET and 8,9-EET). Previous work identified a tyrosine residue located in the first half of putative transmembrane segment 3 (TM3) as a crucial determinant for the activation of TRPV4 by its most specific agonist 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), suggesting that 4 alpha-PDD interacts with the channel through its transmembrane segments. To obtain insight in the 4 alpha-PDD-binding site and in the mechanism of ligand-dependent TRPV4 activation, we investigated the consequences of specific point mutations in TM4 on the sensitivity of the channel to different chemical and physical stimuli. Mutations of two hydrophobic residues in the central part of TM4 (Leu(584) and Trp(586)) caused a severe reduction of the sensitivity of the channel to 4 alpha-PDD, bisandrographolide A, and heat, whereas responses to cell swelling, arachidonic acid, and 5,6-EET remained unaffected. In contrast, mutations of two residues in the C-terminal part of TM4 (Tyr(591) and Arg(594)) affected channel activation of TRPV4 by all stimuli, suggesting an involvement in channel gating rather than in interaction with agonists. Based on a comparison of the responses of WT and mutant TRPV4 to 4 alpha-PDD and different 4 alpha-phorbol esters, we conclude that the length of the fatty acid moiety determines the ligand binding affinity and propose a model for the interaction between 4 alpha-phorbol esters and the TM3/4 region of TRPV4.

Final Report on the Safety Assessment of Capsicum Annuum Extract, Capsicum Annuum Fruit Extract, Capsicum Annuum Resin, Capsicum Annuum Fruit Powder, Capsicum Frutescens Fruit, Capsicum Frutescens Fruit Extract, Capsicum Frutescens Resin, and Capsaicin1

Final Report on the Safety Assessment of Capsicum Annuum Extract, Capsicum Annuum Fruit Extract, Capsicum Annuum Resin, Capsicum Annuum Fruit Powder, Capsicum Frutescens Fruit, Capsicum Frutescens Fruit Extract, Capsicum Frutescens Resin, and Capsaicin1

Hot Cuisine as a Source of Anti-Inflammatory Drugs

The shift in nutritional sciences from survival and safety to the promotion of well-being has led to systematic investigations on the biological activity of natural products of dietary origin, questioning the assumption that food plants contain little if any secondary metabolites apart those revealed by our senses and responsible for their colour, taste, and flavour. With 25% of the human population consuming chilli pepper every day, capsaicin is the most important pharmacological agent we get from our diet, and the study of its pungency set in motion a multidisciplinary investigation that ultimately led to the discovery of vanilloid receptors (TRPVs), a class of ion channels involved in thermo-, chemo-, and mechanosensation, and whose malfunctioning is implicated in neurogenic inflammation and a host of other pathological conditions. A series of studies centred on the modification of capsaicin will be described, focusing on a) the preparation of a library of unnatural natural capsaicinoids and the identification of leads with the lipophilic C-moiety amenable to structure-activity study, and b) the reversal of the biological activity of capsaicin from a TRPV1 agonist into an antagonist by modification of its vanillyl moiety.

Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists.

1. The C-5 halogenation of the vanillyl moiety of resiniferatoxin, an ultrapotent agonist of vanilloid TRPV1 receptors, results in a potent antagonist for these receptors. Here, we have synthesized a series of halogenated derivatives of 'synthetic capsaicin' (nonanoyl vanillamide=nordihydrocapsaicin) differing for the nature (iodine, bromine-chlorine) and the regiochemistry (C-5, C-6) of the halogenation. 2. The activity of these compounds was investigated on recombinant human TRPV1 receptors overexpressed in HEK-293 cells. None of the six compounds exerted any significant agonist activity, as assessed by measuring their effect on TRPV1-mediated calcium mobilization. Instead, all compounds antagonized, to various extents, the effect of capsaicin in this assay. 3. All 6-halo-nordihydrocapsaicins behaved as competitive antagonists against human TRPV1 according to the corresponding Schild's plots, and were more potent than the corresponding 5-halogenated analogues. The iodo-derivatives were more potent than the bromo- and chloro-derivatives. 4. Using human recombinant TRPV1, 6-iodo-nordihydrocapsaicin (IC(50)=10 nM against 100 nM capsaicin) was about four times more potent than the prototypical TRPV1 antagonist, capsazepine, and was tested against capsaicin also on native TRPV1 in: (i) rat dorsal root ganglion neurons in culture; (ii) guinea-pig urinary bladder; and (iii) guinea-pig bronchi. In all cases, except for the guinea-pig bronchi, the compound was significantly more potent than capsazepine as a TRPV1 antagonist. 5. In conclusion, 6-iodo-nordihydrocapsaicin, a stable and easily prepared compound, is a potent TRPV1 antagonist and a convenient replacement for capsazepine in most of the in vitro preparations currently used to assess the activity of putative vanilloid receptor agonists.

Mechanisms of vanilloid-induced apoptosis.

Chemical compounds that contain the vanillyl moiety (4-hydroxy-3-methoxybenzyl) are collectively classified as vanilloids. Vanilloid phytochemicals can be found in a variety of sources, some of which are routinely consumed by humans throughout the world. The dietary and/or medicinal use of vanilloids may be effective in inhibiting or reversing carcinogenesis, which has sparked a considerable interest in these compounds as potential chemopreventive or chemotherapeutic agents. Certain vanilloids are also valuable as pharmacological tools for investigating neurobiology, and have been proven effective in alleviating neurogenic pain and inflammation. Recently several vanilloids have demonstrated the ability to induce apoptosis in various cell types. Vanilloids can interact with proteins and membranes to initiate pleiotropic effects, some of which are potentially cytotoxic. Certain vanilloids bind to cation channels on nociceptive sensory neurons to regulate Ca(2+) uptake, which can promote neurotoxicity resulting in apoptosis and necrosis. Furthermore, some vanilloids appear to interfere with enzymatic processes in the plasma membrane and the mitochondria by functioning as coenzyme Q antagonist. This can promote reactive oxygen species production and/or the disruption of redox homeostasis resulting in apoptosis. This review will examine the cellular targets, cytotoxic effects, and the downstream effector mechanisms associated with vanilloid-induced apoptosis.

Examining the role of mitochondrial respiration in vanilloid-induced apoptosis.

The vanilloids capsaicin and resiniferatoxin are natural products that contain a vanillyl moiety (4-hydroxy-3-methoxybenzyl). Both vanilloids can induce apoptosis in certain cell types by a mechanism that has not been fully elucidated but may involve plasma membrane or mitochondrial targets. We investigated the role of mitochondrial respiration in vanilloid-induced apoptosis. Cytofluorometric analysis was used to evaluate the effects of vanilloids on apoptosis, Ca(2+) mobilization, hydroperoxide generation, and DNA content in cells from two human cutaneous squamous cell carcinoma (SCC) cell lines (parental cells) and in their respiration-deficient clones. Oxygen consumption by the cells was determined polarographically. The majority of the parental SCC cells underwent apoptosis after a 12-hour exposure to 100 micro M capsaicin or 10 micro M resiniferatoxin. The induction of apoptosis was associated with the mitochondrial permeability transition (i.e., an increase in the permeability of the inner mitochondrial membrane associated with the opening of a nonspecific pore). Exposure of parental cells to either vanilloid was not associated with an increase in intracellular free Ca(2+) levels but was associated with a rapid increase in hydroperoxide generation and a decrease in oxygen consumption. After vanilloid treatment, the respiration-deficient clones generated less hydroperoxide and were resistant to the mitochondrial permeability transition and the induction of apoptosis. Moreover, vanilloid treatment inhibited cell proliferation in the respiration-deficient clones by promoting G(1) arrest. Vanilloid-induced apoptosis in the parental SCC cells appears to involve the inhibition of mitochondrial respiration. The apoptogenic effects promoted by vanilloid treatment in parental SCC cells, as well as the antiproliferative effects observed in their respiration-deficient clones, suggest that vanilloids may be useful for preventing or treating skin cancers or other hyperproliferative skin disorders.

Conformational studies on resiniferatoxin (RTX), an ultrapotent vanilloid agonist

In polar solution, NOE studies show a pronounced clustering of the aromatic moieties (9,13,14-phenylacetate orthoester and 20-homovanillate) of the ultrapotent vanilloid agonist resiniferatoxin (RTX). This clustering is absent in nonpolar solution. Low energy clustered structures from molecular dynamics simulations account for the observed NOEs. These results suggest that the phenylorthoacetate moiety can assist the attainment of specific alignments between the terpenoid core and the vanillyl moiety, possibly preorganizing them for ideal receptor binding.

The synthesis of (2R)‐ and (2S)‐[2‐3H]‐propionic acid

AbstractA practical synthesis of (2R)‐ and (2S)‐[2‐3H]‐propionic acid is described. The key steps in the synthesis are the reduction of [formyl‐3H]‐3‐methoxy‐4‐mesyloxybenzaldehyde with R‐ or S‐Alpine Borane to (7S)‐ and (7R)‐[7‐3H]‐3‐methoxy‐4‐mesyloxybenzyl alcohol and the use of the vanillyl moiety as a masked carboxyl group.