Benzyl Methyl Research Articles

Pollination biology reveals challenges to restoring populations of Brighamia insignis (Campanulaceae), a critically endangered plant species from Hawai‘i

Understanding the reproductive biology of rare plant species is fundamental to managing their restoration. Brighamia insignis is a critically endangered Hawaiian lobeliad endemic to the islands of Kauaʻi and Niʻihau. The flowers appear to be adapted for moth pollination although its putative pollinator is believed to be extinct or very rare. To confirm the pollination syndrome, document the breeding system, and identify potential pollinators of B. insignis: 1) a suite of floral characters were examined, 2) pollination treatments were performed, and 3) diurnal and nocturnal floral visitor observations were conducted at an ex situ site on Kaua‘i. Brighamia insignis flowers contain sucrose-rich nectar and emit a strong floral scent containing benzyl alcohol, linalool, and methyl salicylate. Pollination treatments revealed that the species is primarily outcrossing with several of the study plants also capable of low levels of selfing. However, most of the plants had low pollen production and viability. No moths and only occasional non-native insect species visited the flowers of B. insignis. None of these insect visitors appeared to be serving as effective pollinators. In spite of this lack of flower visitation by moths, analysis of nectar and floral scent support a moth pollination syndrome in B. insignis. The potential loss of pollinators suggests that restoring populations of B. insignis may not be feasible; human assisted cross-pollination would be necessary for fruit and seed to set, as only 1% of the control and self treatment flowers formed fruit. Therefore, this species appears dependent upon intense human management to prevent its extinction.

Abstract 2749: Defining structure activity relationships for GPCR engagement and anti-cancer efficacy of imipridone small molecules

Abstract G protein-coupled receptors (GPCRs) represent the most widely exploited superfamily of drug targets for FDA-approved therapies for many diseases, however, these receptors are underexploited for oncology. ONC201 is a selective antagonist of GPCRs dopamine receptor D2 (DRD2) and DRD3 that has been shown to induce tumor regressions with a benign safety profile in high grade glioma patients. ONC201 (benzyl-2-methylbenzyl-imipridone) is the founding member of the imipridone class of small molecules that share a unique tri-heterocyclic core chemical structure. Imipridones share several chemical and biological properties that are desirable drug-like characteristics: oral administration, wide therapeutic window, chemical stability and blood brain barrier penetrance. In this study, we profiled a series of imipridones for GPCR engagement and anti-cancer efficacy. Several imipridones were screened against a large panel of human GPCRs using a β-arrestin recruitment assay. The imipridones tested resulted in GPCR agonist/antagonist activity (threshold set at >20% activity) that was heterogenous, but exclusive among Class A GPCRs that represent the largest class. Minor chemical modifications to the ONC201 chemical structure caused large shifts in agonist versus antagonist activity and selectivity for GPCRs. Specifically, switching the ONC201 imipridone core from an angular to a linear isomer resulted in loss of DRD2 antagonist activity and impaired inhibition of cancer cell viability, indicating the imipridone core structure is critical for GPCR engagement and anti-cancer effects. The addition of electron withdrawing groups (e.g. di- or tri-halogen substitution) to the methyl benzyl ring improved potency for GPCR engagement and anti-cancer effects, but not for the benzyl ring. Loss of the benzyl ring impaired anti-cancer effects. Among all of the GPCR hits identified, maximal variance in imipridone GPCR engagement was identified for DRD2/DRD3 antagonism and GPR132 agonism that were prioritized considering their known biological relevance in oncology. ONC206 (benzyl-2,4-difluoromethylbenzyl-imipridone) emerged as the most selective and potent antagonist for D2-like dopamine receptors that are overexpressed and critical for survival in several cancers. ONC212 (benzyl-4-trifluoromethylbenzyl-imipridone) was the most selective and potent agonist for tumor suppressor GPR132. Both compounds were tested in the GDSC panel of >1000 cancer cell lines and demonstrated broad spectrum nanomolar inhibition of cancer cell viability and a wide therapeutic window. GPCR target expression correlated with anti-cancer efficacy in the GDSC panel for both compounds, providing potential biomarkers of response. Thus, chemical derivatization of ONC201 has generated a class of novel GPCR-targeting agents with promising preclinical efficacy and safety profiles in oncology. Citation Format: Varun V. Prabhu, Abed Rahman Kawakibi, Neel S. Madhukar, Lakshmi Anantharaman, Sean Deacon, Neil S. Charter, Mathew J. Garnett, Ultan McDermott, Cyril H. Benes, Wolfgang Oster, Olivier Elemento, Martin Stogniew, Joshua E. Allen. Defining structure activity relationships for GPCR engagement and anti-cancer efficacy of imipridone small molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2749.

Fragrance components of Platanthera bifolia subsp. osca and Platanthera chlorantha collected in several sites in Italy

Platanthera bifolia subsp. osca sample collected at Grisolia showed as main components linalool (17.8%), benzyl benzoate (55.8%), and benzyl 2-hydroxybenzoate (6.7%). Four samples of P. bifolia subsp. osca were collected at Pignola: the main components of the aroma are lilac derivatives (49.02–79.00%), mainly lilac alcohols B (7.41–13.52%), C (10.10–18.45%), and D (7.50–34.28%). Three samples were analyzed from the site of Marsico Nuovo. The main components of the scent found in this site were linalool (1.54–10.00%), lilac aldehydes (3.98–11.15%), and mainly lilac alcohols (50.68–61.51%). The main components of the sample collected at Palena were methyl benzoate (9.04%) and benzyl benzoate (74.72%). The analysis of the composition of the aroma of a Platanthera chlorantha plant has been performed. The main components were lilac derivatives. The reported behavior could be explained admitting an adaptive modification of the scent considering the nature of possible pollinating agents due to different habitats.

Safety and efficacy of eight compounds belonging to different chemical groups when used as flavourings for cats and dogs.

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of 23 compounds belonging to different chemical groups. This opinion concerns eight out of the 23 compounds, which are currently authorised for use as flavours in food. The Panel concludes that the eight additives are safe for cats and dogs at the proposed use level: phenylmethanethiol [12.005] and benzyl methyl sulfide [12.077] at 0.05 mg/kg complete feed; 2‐pentylthiophene [15.096] at 0.1 mg/kg complete feed; tridec‐2‐enal [05.078] and 12‐methyltridecanal [05.169] at 0.5 mg/kg complete feed; 2,5‐dimethylphenol [04.019] at the 1 mg/kg complete feed; hexa‐2(trans),4(trans)‐dienal [05.057] at 1.5 mg/kg complete feed; 2‐ethyl‐4‐hydroxy‐5‐methyl‐3(2H)‐furanone [13.084] at 2.25 mg/kg complete feed. In the absence of studies to assess the safety for the user, the FEEDAP Panel cannot conclude on the safety for the users when handling the additives. Since all eight compounds are used in food as flavourings, and their function in feed is essentially the same as that in food no further demonstration of efficacy is necessary.

Convergent synthesis of phosphonopeptides via phospha-Mannich reactions: Rationale on reactivity and mechanistic insights

Phospha-Mannich reactions of benzyl carbamate, aldehydes, and methyl dichlorophosphite followed by aminolysis with amino acid esters or alcoholysis with hydroxyl acid esters produce N-Cbz(benzyloxycarbonyl)-protected phosphonopeptides or phosphonodepsipeptides. However, similar reactions do not work when Cbz-amino amides are used instead of the carbamate. Phospha-Mannich reactions of N-Cbz-amino amides/2-(Cbz-amino)alkanesulfonamides, aldehydes, and dichloroarylphosphines and subsequent aminolysis with amino acid esters or alcoholysis with hydroxyl acid esters yield phosphinopeptides or phosphinodepsipeptides and hybrid sulfonophosphinopeptides or sulfonophosphinodepsipeptides. The different reactivities and mechanistic insights are rationalized that the α-amino alcohols generated from aldehydes and amides/sulfonamides show weaker nucleophilicity than those generated from aldehydes and benzyl carbamate. They can react with stronger electrophilic dichloroarylphosphines rather than weaker electrophilic methyl dichlorophosphite. The nucleophilicity of α-amino alcohols (amine reagents, carbamates, amides, and sulfonamides) and the electrophilicity of phosphorus reagents (dichloroarylphosphines and ethyl dichlorophosphite) control the reactivity of the phospha-Mannich reactions. Phosphorus trichloride is also efficient phosphorus reagent in the phospha-Mannich reactions because it is stronger electrophile as well.

Silica Nanoparticles Decorated with Polymeric Sulfonic Acids Trigger Selective Oxidation of Benzylic Methylenes to Aldehydic and Ketonic Carbonyls

The controlled dispersion of polymeric sulfonic acids on suitable heterogeneous supports paves the way to a new catalytic method for the oxidation of a variety of benzylic methylenes to the corresp...

How the methyl group position influences the ultrafast deactivation in aromatic radicals.

Excited xylyl (methyl-benzyl) radical isomers have been studied by femtosecond time-resolved photoelectron spectroscopy and mass spectrometry. Depending on the substitution we find different deactivation channels after excitation into the D3(2A'') state (310 nm, 4 eV). While the ortho and para isomer exhibit deactivation rates similar to the benzyl radical, meta-xylyl sticks out and depletes twice as fast into the vibrationally hot ground state. We found that a ring deformation mode rather than the methyl pseudorotation enables access to a conical intersection, which is responsible for the faster deactivation. Transitions in the photoelectron spectrum can be assigned to several Rydberg series with mostly d angular momentum components. Absorption of two 4 eV photons triggers hydrogen loss reactions on a femtosecond timescale.

Cu-Catalysed oxidative amidation of cinnamic acids/arylacetic acids with 2° amines: an efficient synthesis of α-ketoamides.

A new and convenient copper-catalysed synthesis of α-ketoamides has been accomplished using readily available cinnamic acids/arylacetic acids and 2° amines in an open atmosphere. The reaction between cinnamic acid and amine involves the formation of enamine followed by its aerobic oxidation, whereas the reaction of arylacetic acid with amine involves amide formation followed by benzylic methylene oxidation.

Identyfikacja 2-acetylo-2-fenyloacetamidu (APAA) – prekursora do produkcji benzylometyloketonu (BMK, P2P)

The article presents the possibilities of using gas and liquid chromatography with MS detection (GC-MS, HPLC-Q-TOF) to identify 2-acetyl-2-phenylacetamide (APAA) – a precursor for the production of benzyl methyl ketone (BMK, P2P). In recent years, APAA has become very popular on the illegal drug market and its identification by the above-mentioned methods raises interpretation doubts. They are caused by BMK being present in small amounts and the ambiguous chromatographic image (GC and HPLC), which consists of two peaks with different retention times, but with the same mass spectrum. This is a consequence of APAA found in two tautomeric forms: ketone and enol. The phenomenon of keto-enol tautomerism occurring here is a particular case of isomerism.

Fe(ii)-Catalyzed alkenylation of benzylic C-H bonds with diazo compounds.

We report herein an alkenylation of benzylic C(sp3)-H bonds with diazo compounds via carbon cation intermediates with DDQ as the oxidant in the presence of a catalytic amount of Fe(ii). Diphenylmethane, toluene, benzyl methyl sulfide and their derivatives could be applied as substrates to afford the tetra-substituted olefin products, which may serve as useful building blocks in organic synthesis.

Recent Advances in Homogeneous Metal-Catalyzed Aerobic C–H Oxidation of Benzylic Compounds

Csp3–H oxidation of benzylic methylene compounds is an established strategy for the synthesis of aromatic ketones, esters, and amides. The need for more sustainable oxidizers has encouraged researchers to explore the use of molecular oxygen. In particular, homogeneous metal-catalyzed aerobic oxidation of benzylic methylenes has attracted much attention. This account summarizes the development of this oxidative strategy in the last two decades, examining key factors such as reaction yields, substrate:catalyst ratio, substrate scope, selectivity over other oxidation byproducts, and reaction conditions including solvents and temperature. Finally, several mechanistic proposals to explain the observed results will be discussed.

Antiglycation, antioxidant, and cytotoxic activities of Uvaria chamae root and essential oil composition

Uvaria chamae (Annonaceae), is an essential oil bearing plant; the root is acclaimed as an effective remedy for folkloric diabetic therapy. The root extracts were evaluated for composition, antiglycation, antioxidant, and cytotoxicity. Flavonoids, cardiac glycosides, and tannins were relatively high in the alcohol extract; benzyl benzoate (23.3%), dimethoxy-p-cymene (14.2%), τ-cadinol (12.1%), and methyl thymol (8.7%) predominated the constituents identified by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The ethanol extract demonstrated significant antiglycation activity (IC50, 1.12 mg/mL), and cytotoxicity to brine shrimp (LC50, 25.01 µg/mL). The extract (IC50, 8.0 µg/mL; absorbance 0.531, 100 µg/mL) also exhibited better antioxidant effects compared with the essential oil (IC50, 50.0 µg/mL; absorbance 0.292, 100 µg/mL) using 2,2-diphenyl-1-picrylhydrazyl radical and ferric reducing power assays respectively. U. chamae root possess antiglycation effect, and may also reduce oxidative stress in patients with diabetes; its antiglycation effect, oil composition, and cytotoxicity are reported for the first time.

A facile synthesis of highly fluorescent pyrido[2,3-d]pyrimidines and 1,8-naphthyridines via oxazine transformation and enaminic addition reactions

Abstract The synthesis and fluorescence properties of highly substituted bicyclic pryridine derivatives are described. 2-Substituted-4-oxo-pyrido[2,3-d]pyrimidines 2–8 resulted from the acylation reaction of α-aminonicotinonitrile 1 with aroyl chlorides, diethyl malonate, morpholine-4-carboxylate, acetic anhydride or formic acid under solvent-free conditions. [4 + 2] Cyclocondensation and cycloaddition reactions of compound type 1 with formamide and ammonium thiocyanate tolerated the fused pyrimidines 9 and 11, respectively. Finally, the Friedlander-like reaction was applied for the synthesis of 1,8-naphthyridines 12–15 via reaction of compound 1 with cyclohexanone, dimedone, acetyl acetone and benzyl methyl ketone, respectively, under AlCl3 catalysis. The fluorescence spectroscopic data of compounds 1–4, 6–8, 11, 12, 14 and 15 measured and significant results were observed.

Sulphoxide ligands inbicyclooctanium based ionic liquid: Novel solvent systems for the extraction of f-elements

ABSTRACTThe extraction of Pu4+, PuO22+, Am3+, and Eu3+ by structurally modified sulphoxides in 1-hexyl-1,4-diaza [2.2.2] bicyclooctanium Bis(trifluoromethylsulfonyl)imide was investigated at 25 ± 2 °C in an aqueous acidic medium. The extraction process followed ‘cation exchange’ mechanism. The phenyl substituted ligands showed higher extraction efficiency due to steric and electronic factors and followed the trend: Allyl phenyl sulphoxide (APSO) > Benzyl phenyl sulphoxide (BPSO) > Benzyl methyl sulphoxide (BMSO). The extraction process was thermodynamically spontaneous and only one ligand was found to coordinate in the extracted species for all the metal ions. Oxalic acid was found suitable for Pu4+ stripping. PuO22+, Am3+, and Eu3+ were efficiently back extracted by the Na2CO3 solution. APSO-IL system showed excellent radiolytic stability and all the three solvent systems were found highly selective.

Screening and analysis of acetyl-cholinesterase (AChE) inhibitors in the context of Alzheimer's disease.

Acetyl-cholinesterase enzyme (AChE) is a known target for identifying potential inhibitors against Alzheimer diseases (AD). Therefore, it is of interest to screen AChE with the CNS-BBB database. An AChE enzyme is a member of hydrolase family is activated by acetylcholine (ACh), so, targeting the AChE enzyme with the potential inhibitor may block the binding of the ACh. In this study we carried out virtual screening of drug-like molecules from Chemical Diversity Database particularly CNS-BBB compounds, to identify potential inhibitors using Glide docking program. Top ranking ten compounds, which have lower Glide Score when compared to known drugs (Tacrine and Galantamine) for AChE. For top three molecules MD simulation was carried out and calculated binding free energy. We report the best binding compounds with AChE compared to known drugs (Taine and Galantamine) for AD. We further document the salient features of their molecular interaction with the known target. Three molecules (1-benzyl-3-(2- hydroxyethyl)-N-[2-(3-pyridyl)ethyl]-3-pyrrolidinecarboxamide, N-{3[benzyl(methyl)amino]propyl}-1,5-dimethyl-4-oxo-4,5-dihydro- 1H-pyrrolo[3,2-c]quinoline-2-carboxamide, and 6-chloro-N-[2-(diethylamino)-2-phenylethyl]-4-oxo-4H-chromene-2-carboxamide) have -196.36, -204.27, -214.40 kJ/mol, binding free energy values respectively which are much lower than values calculated for the reference ligands Tacrine and Galantamine having -119.65 and -142.18 kJ/mol respectively. Thus these molecules can be very novel potential inhibitors against AChE involved in Alzheimer's disease.

Further Studies on the Pyrolytic Domino Cyclization of Stabilized Phosphonium Ylides Bearing an Ortho-Aminophenyl Group.

Four new, stabilized phosphonium ylides containing a 2-(benzyl(methyl)amino)phenyl group have been prepared and characterized and are found, upon pyrolysis under gas-phase flow conditions, to lose Ph3PO and benzyl radicals to afford new heterocyclic products resulting from domino cyclization of both C- and N-centered radicals. Most products arise from processes of the former type and have quinoline, phenanthridine, or ring-fused phenanthridine structures, while in one case, a process of the latter type leads to a benzocarbazole product. The X-ray structure of a 2-(methyl(tosyl)amino)phenyl ylide is also reported.

Combined colorimetric and gravimetric CMUT sensor for detection of benzyl methyl ketone

The detection of benzyl methyl ketone (BMK) is of interest as it is a common precursor for the synthesis of (meth)amphetamine. Resonant gravimetric sensors can be used to detect the mass and hereby the concentration of a gas while colorimetric arrays typically have exceptional selectivities to a target analyte. We present a sensor system consisting of a capacitive micromachined ultrasonic transducer (CMUT) and a colorimetric array for detection of BMK. The CMUT is used as a resonant gravimetric gas sensor where the resonance frequency shift due to mass loading of the plate. A single local oxidation of silicon (LOCOS) step was used to define the cavities which were sealed with a Si3N4 plate with a thickness of 100 nm, resulting in a resonance frequency of 38.8 MHz and a mass sensitivity of 28.3zgHz×μm2 or 8.5 × 103 cm2/g This sensitivity is, to our knowledge, the best reported as compared with the state of the art of CMUTs. The CMUTs were functionalized with the same dyes used to fabricate the colorimetric arrays. While both the CMUT and the colorimetric array showed selectivity between BMK and acetone and water, the highest selectivity was achieved with the colorimetric array. Here the analyte BMK resulted in the only signal (color change), while acetone and water did not give any signal. Furthermore, the mass of the BMK was found as a function of time. Thus, the combination of a colorimetric array and a CMUT resulted in a sensor system with a selectivity between BMK, acetone and water and in addition a quantitative value for the mass.

New Sample Preparation Method for Honey Volatiles Fingerprinting Based on Dehydration Homogeneous Liquid⁻Liquid Extraction (DHLLE).

Qualitative chemical fingerprinting of the honey volatiles by gas chromatography and mass spectrometry (GC-MS) has been an efficient authentication tool that allowed for the classification of the honey botanical origin (strongly related to its medicinal and market value). However, the usage of current sample preparation methods is limited by selectivity of the volatiles extraction from the honey matrix and requires significant solvent volume. Therefore, a new sample preparation method based on dehydrating homogeneous liquid–liquid extraction (DHLLE) involving reduced solvent usage was developed for screening volatiles and semi-volatiles from the honey. The effective extraction was achieved by implementing a miscible liquid extraction system (aqueous honey solution/isopropanol) followed by separation through dehydration with MgSO4 and purification by a solvent polarity change and washing. The method was evaluated by estimating accuracy and precision. The DHLLE method showed satisfactory recoveries (75.2 to 93.5%) for typical honey volatiles: linalool, borneol, terpinen-4-ol, α-terpineol, p-anisaldehyde, eugenol, and vanillin. It also showed superior repeatability with percent relative standard deviation (RSD%) 0.8–8.9%. For benzyl alcohol, methyl syringate, and caffeine, the recoveries were 54.3 to 63.9% and 67.3 to 77.7% at lower and higher spiking levels, respectively. Applied to unifloral apple honey, the DHLLE method allowed for the identification of 40 compounds including terpenes, hydrocarbons, phenylpropanoids, and other benzene derivatives, which makes it suitable for fingerprinting and chemical marker screening. The obtained results were comparable or better than those obtained with ultrasonic extraction with dichloromethane.

Different Selectivities in the Insertions into C(sp2 )-H Bonds: Benzofulvenes by Dual Gold Catalysis Competition Experiments.

An unprecedented, often almost quantitative access to tricyclic aromatic compounds by dual gold catalysis was developed. This synthetic route expands the scope of benzofulvene derivatives through a C(sp2 )-H bond insertion in easily available starting materials. The insertion takes place with an exclusive chemoselectivity with respect to the competing aromatic C-H positions. A bidirectional synthesis with two competing ortho-aryl C-H bonds in the selectivity-determining step also shows perfect selectivity; this result is explained by a computational investigation of the two conceivable intermediates. The intramolecular competition of two non-equivalent aryl C-H bonds with a benzylic methyl group also showed perfect selectivity.

Commercially Available Natural Benzyl Esters and Their Synthetic Analogs Exhibit Different Toxicities against Insect Pests

Benzyl methyl ester, also known as methyl benzoate (MB), is a volatile organic compound that exists naturally as a floral fragrance in many plants. Our behavioral bioassays show that MB and some of its naturally occurring and synthetic analogs kill insects at different life stages. Compared to commercial pesticides containing pyriproxyfen and acetamiprid, MB and some analogs are 1.3 to 3.4 times more toxic to gypsy moth larvae and brown marmorated stinkbug nymphs. The arthropod repellent DEET is also a benzyl ester, and shares the same chemical skeleton with MB. They differ by the diethylamide ester and a methyl group on the benzene ring in DEET. However, unlike MB, DEET does not kill insects; instead, it deters or repels them. Exactly how DEET causes the repellent effect in target organisms is still a mystery. Due to the MB’s structural similarity to DEET, exploring the structure – activity relationship (SAR) of the MB analogs will provide useful information for the discovery of the mode and mechanistic actions of DEET as an insect repellent. In addition, the SAR will allow researchers to modify the chemical structure of the MB molecule, leading to the development of more efficient, safe, and environmentally – friendly green pesticides.