Propyl Side Chain Research Articles

Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.

Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.

Brachytherapy with Intratumoral Injections of Radiometal-Labeled Polymers That Thermoresponsively Self-Aggregate in Tumor Tissues.

Brachytherapy is a type of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radioirradiation to tumor tissues around the seeds. Although marked therapeutic effects have been demonstrated, brachytherapy needs a complicated implantation technique under general anesthesia and the seeds could migrate to other organs. The aim of this study was to establish a novel brachytherapy using biocompatible, injectable thermoresponsive polymers (polyoxazoline [POZ]) labeled with 90Y, which can self-aggregate above a specific transition temperature (Tt), resulting in long-term intratumoral retention of radioactivity and therapeutic effect. Therefore, we evaluated the tumor retention of radiolabeled POZ derivatives and their therapeutic effects. Methods: Using oxazoline derivatives with ethyl (Et), isopropyl (Isp), and propyl (Pr) side chains, we synthesized EtPOZ, IspPOZ, Isp-PrPOZ (heteropolymer), and PrPOZ and measured their characteristic Tts. The intratumoral retention of 111In-labeled POZ was evaluated until 7 d after injection in nude mice bearing PC-3 human prostate cancer. The intratumoral localization of 111In-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using 90Y-labeled Isp-PrPOZ was performed, and tumor growth and survival rate were evaluated. Results: The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ (∼20 kDa) were greater than 70°C, 34°C, 25°C, and 19°C, respectively. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2,000 μM) with Tts lower than tumor temperature (33.5°C under anesthesia) showed a significantly higher retention of radioactivity at 1 d after injection (73.6% and 73.9%, respectively) than EtPOZ (5.6%) and IspPOZ (15.8%). Even at low injected dose (100 μM), Isp-PrPOZ exhibited high retention (68.3% at 1 d). The high level of radioactivity of Isp-PrPOZ was retained in the tumor 7 d after injection (69.5%). The autoradiographic study demonstrated that the radioactivity of 111In-labeled Isp-PrPOZ and PrPOZ was localized in a small area. In the therapeutic study using 90Y-labeled Isp-PrPOZ, significant suppression of tumor growth and prolonged survival rate were achieved in an injection dose-dependent manner compared with that observed for the vehicle-injected group and nonradioactive Isp-PrPOZ-injected group. Conclusion: The injectable 90Y-labeled Isp-PrPOZ was retained for a prolonged period within tumor tissues via self-aggregation and exhibited marked therapeutic effect, suggesting its usefulness for brachytherapy.

Sources and dynamics of sedimentary organic matter in Sundarban mangrove estuary from Indo-Gangetic delta

IntroductionMangrove forests are highly productive ecosystems distributed along the tropical coast line. Nutrient biogeochemistry of mangroves are primarly driven by both allochthonous and autochthonous sources. Characterization of organic matter in coastal ecosystems enables to understand the biogeochemical transformation of organic matter and its influence on ecosystem productivity in response to various changing environmental conditions. Therefore, the elemental and stable carbon and nitrogen levels were employed to understand the organic matter (OM) dynamics in the Sundarban mangrove ecosystem (India-Bangladesh).ResultsDifferences in stable isotope values indicate that variable sources influence the OM dynamics in Sundarban sediments. The progressive enrichment in δ 13C levels along the land-coastal continuum indicates that the terrestrial and marine inputs are dominant at the landward and seaward ends, respectively. The CuO oxidation-derived lignin phenol monomers describe significant levels of total lignin are preserved in Sundarban mangrove sediments during diagenesis. The phenol monomer ratios are lower than the plant litter explaining that aromatic ring cleavage is the dominant mechanism for the lignin degradation. Furthermore, the Ad/Al ratios were higher than the plant litter explaining the oxidation of propyl side chain of vascular OM influencing the carbon cycling in Sundarban sediments. Largely, the Ad/Al ratios describe the vascular OM degradation is through the oxidation of propyl side chain.ConclusionsThe regional variability in land-use regulates the spatial variability in C, N, OC/TN ratio, δ 13C and δ 15N between the Indian and the Bangladesh Sundarban mangroves and indicates that in the upstream terrestrial organic matter and/or mangrove plant litter contribute significant amount of organic matter, whereas the marine POC influences the organic matter dynamics in downstream. The three end-member mixing model applying terrestrial plant litter, seston, and marine POC as end-members explains the relative contribution of OM from various sources, and marine inputs were dominant in Sundarban sediments.

Design, synthesis, biological evaluation, molecular docking and QSAR studies of 2,4-dimethylacridones as anticancer agents

Drug resistance in cancer is an unmet medical challenge and a major drawback for the failure of many chemotherapeutic drugs. Search for targeted, effective drug with minimum toxicity is an urgent need. Acridone which is an alkaloid derivative has been attributed as molecule in reversing drug resistance in cancer cells for a long time now. In the present investigation, an attempt has been made to explore the chemosensitizing ability of 2,4-dimethylacridones with alkyl side chain containing terminally substituted tertiary amino groups. Considering the structural features required for the MDR reversal activity, acridone derivatives have been synthesized with propyl and butyl side chain containing morpholinyl, piperidinyl, N-methylpiperazinyl, N,N-diethylamino, N-diethanolamino, N-[(β-hydroxylethyl)]piperazino at the terminus of the alkyl side chain. cLogP values for the synthesized compounds ranged from 2.96 to 4.72 for the propyl derivatives and 3.41 to 5.15 for the butyl derivatives. All the compounds were screened against breast cancer sensitive MCF7 and resistant MCF7/ADR cell lines. Compounds 12e and 12f have shown better cytotoxicity profiles with IC50 of 4 ± 0.05 and 2 ± 0.03 μM against MCF7 cells, 5.21 ± 0.13 and 2.56 ± 0.05 μM against MCF7/ADR cells. Photolabelling studies with [3H]-azidopine and molecular docking studies have identified that 2,4-dimethylacridones have potential to modulate the P-gp mediated multidrug resistance. Docking studies identified that compounds have shown favorable interactions with P-gp. QSAR equation was derived for cytotoxicity vs molecular descriptors of acridone derivatives. Best models with good predictive ability have been generated with very high square correlation coefficient (R2) values of 0.889, 0.964 and 0.983.

Effect of methanol in controlling defunctionalization of the propyl side chain of phenolics from catalytic upstream biorefining.

In recent years, lignin valorization has gained upward momentum owing to advances in both plant bioengineering and catalytic processing of lignin. In this new horizon, catalysis is now applied to the 'pulping process' itself, creating efficient methods for lignocellulose fractionation or deconstruction (here referred to as Catalytic Upstream Biorefining or 'CUB'). These processes render, together with delignified pulps, lignin streams of low molecular weight (Mw) and low molecular diversity. Recently, we introduced a CUB process based on Early-stage Catalytic Conversion of Lignin (ECCL) through H-transfer reactions catalyzed by RANEY® Ni. This approach renders a lignin stream obtained as a viscous oil, comprising up to 60 wt% monophenolic compounds (Mw < 250 Da). The remaining oil fraction (40 wt%) is mainly composed of lignin oligomers, and as minor products, holocellulose-derived polyols and lignin-derived species of high Mw (0.25-2 kDa). Simultaneously, the process yields a holocellulose pulp with a low content of residual lignin (<5 wt%). Despite the efficiency of aqueous solutions of 2-propanol as a solvent for lignin fragments and an H-donor, there is scant information regarding the CUB process carried out in the presence of primary alcohols, which often inhibit the catalytic activity of RANEY® Ni, as revealed in model compound studies performed at low temperature. Considering the composition of the lignin oils obtained from CUB based on ECCL, the processes commonly render ortho-(di)methoxy-4-propylphenol derivatives with a varied degree of defunctionalization of the propyl side chain. In this contribution, we present the role of the alcohol solvent (methanol or 2-propanol) and Ni catalyst (Ni/C or RANEY® Ni) in control over selectivity of phenolic products. The current results indicate that solvent effects on the catalytic processes could hold the key for improving control over the degree of functionalization of the propyl side-chain in the lignin oil obtained from CUB, offering new avenues for lignin valorization at the extraction step.

Surface tension and density for members of four ionic liquid homologous series containing a pyridinium based-cation and the bis(trifluoromethylsulfonyl)imide anion

Pyridinium-based cations are the second most frequently occurring cations in the commonly studied ionic liquid mixtures - a new prospective field just opened for the property tuning of substances of practical use. To this purpose, a sufficiently accurate knowledge of the properties of pure components is necessary. Presented here are results of a study of the surface tension and 0.1 MPa densities for members of four homologous series consisting of a 1-alkyl-pyridinium or 1-alkyl-m-methylpyridinium cation with m = 2, 3, or 4 and of the bis(trifluoromethylsulfonyl)imide anion. Empirical models are presented, based on the parachor and group contribution approach, which generate recommended surface tension and 0.1 MPa density values for ionic liquids from the studied homologous series including those for which no experimental data are available. The models have been developed both on the basis of data from the literature and on our own data for four ionic liquids with a pyridinium-based cation bearing a propyl side-chain, yet studied poorly in those two respects or even not at all. The presented density data were measured using the buoyancy method with an estimated combined expanded uncertainty at the 0.95 level of confidence Uc = 0.8 kg m−3 (6⋅10−4ϱ) at the most. The du Noüy ring method and the Wilhelmy plate method were used to obtain the data on the surface tension with Uc near (0.2 and 0.05) mN m−1, respectively. The surface tension and buoyancy forces were measured at temperatures from (263 to 365) K using the Krűss K100 Mk2 tensiometer. The deviation of the recommended surface tension and density values from their true values is estimated not to exceed 0.3 mN m−1 and 0.15%, respectively.

Role of a thermostable laccase produced by Streptomyces ipomoeae in the degradation of wheat straw lignin in solid state fermentation

Streptomycetes are actually considered one of the main groups of ligninolytic microoganisms producing a lignin-carbohydate complex named APPL (acid precipitable polymeric lignin) when growing on lignocellulosic materials. Although in these conditions the production of hemicellulolytic and oxidative extracellular enzymes were reported the specific role of laccases in lignin degradation is poorly understood. SilA, a thermostable salt-resistant and pH-versatile laccase produced by Streptomyces ipomoeae CECT 3341 was recently discovered and their particular characteristics make attractive to deep in its knowledge for biotechnological and environmental purposes. Pyrolysis/GC–MS was used to analyse the behaviour of the laccase-producing strain (SilA strain) and a laccase-negative mutant (SilA− strain) when growing on wheat straw in solid-state fermentation (SSF). Quantitative yields of APPL and the relative abundance of lignin-derived compounds were much higher for SilA strain than for SilA− showing a higher solubilizing activity of S. ipomoeae wild-type on lignocellulosic residues. Nonetheless the patterns of lignin derived compounds found in the APPL pyrograms were similar for both strains and distinct from the control showing a shortening of lignin propyl side-chains. Our results demonstrate that SilA laccase is a key enzyme in the lignin solubilization by S. ipomoeae and also points to the involvement of other oxidative enzymatic activities distinct to laccase in this process.

Microwave Assisted Prospective Synthesis of New 5-Arylidene Rhodanine Derivatives Bearing a 3-[4-(3-Aminopropyl)piperazin-1-yl]propyl Side Chain

A series of (5Z) 5-arylidene 2-thioxo-1,3-thiazolidin-4-one derivatives 7(a-l) bearing a [4-(3-aminopropyl)piperazin-1-yl]propyl side chain in N-3 position was prepared using a solution phase protocol assisted by microwave dielectric heating. These new compounds were synthesized in four steps with overall yields ranging from 12 to 33% via a "one-pot two-steps" protocol based on Holmberg reaction followed by a stereocontrolled Knoevenagel condensation. The rhodanine intermediate 4' issued from Holmberg reaction under microwave was also isolated and identified by spectroscopic methods of analysis. The twelve deprotected products 7(a-l) have been obtained with a Z-geometry about their exocyclic double bond. All N-Boc intermediates 6(a-l) and deprotected rhodanine derivatives 7(a-l) issued from trifluoroacetic acid treatment have been characterized by 1H, 13C and HRMS. Keywords: 5-arylidene rhodanine, holmberg reaction, koenevenagel condensation, microwave, N-boc carbamate, one-pot twosteps, solution phase, trifuoroacetate salt.

Comparing the structure of different ionic liquid series: Bistriflamide v. hexafluorophosphate; pure v. equimolar mixtures

The structure at a molecular level of two ionic liquid homologous series —1-alkyl-3-methylimdazolium hexafluorophosphate and 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide— are probed using Molecular Dynamics simulations. The studied systems include pure ionic liquids with propyl, hexyl, nonyl and dodecyl side chains and also four selected equimolar binary mixtures within each series. The results show that nano-segregation between the polar network of the ionic liquid and its non-polar domains occurs more effectively for longer alkyl side chains and the hexafluophosphate anion. The non-homogeneous character of the alkyl length found in the mixtures is also detrimental for the formation of well-defined and segregated non-polar domains.

Revisiting the crystallization of poly(2-alkyl-2-oxazoline)s

Poly(2-alkyl-2-oxazoline)s (PAOx) exhibit different crystallization behavior depending on the length of the alkyl side chain. PAOx having methyl, ethyl, or propyl side chains do not show any bulk crystallization. Crystallization in the heating cycle, that is, cold crystallization, is observed for PAOx with butyl and pentyl side chains. For PAOx with longer alkyl side chains crystallization occurs in the cooling cycle. The different crystallization behavior is attributed to the different polymer chain mobility in line with the glass transition temperature (Tg) dependency on alkyl side chain length. The decrease in chain mobility with decreasing alkyl side chain length hinders the relaxation of the polymer backbone to the thermodynamic equilibrium crystalline structure. Double melting behavior is observed for PButOx and PiPropOx which is explained by the melt-recrystallization mechanism. Isothermal crystallization experiments of PButOx between 60 and 90 °C and PiPropOx between 90 and 150 °C show that PAOx can crystallize in bulk when enough time is given. The decrease of Tg and the corresponding increase in chain mobility at T > Tg with increasing alkyl side chain length can be attributed to an increasing distance between the polymer backbones and thus decreasing average strength of amide dipole interactions. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016, 54, 721–729

Lignin decomposition is sustained under fluctuating redox conditions in humid tropical forest soils.

Lignin mineralization represents a critical flux in the terrestrial carbon (C) cycle, yet little is known about mechanisms and environmental factors controlling lignin breakdown in mineral soils. Hypoxia is thought to suppress lignin decomposition, yet potential effects of oxygen (O2 ) variability in surface soils have not been explored. Here, we tested the impact of redox fluctuations on lignin breakdown in humid tropical forest soils during ten-week laboratory incubations. We used synthetic lignins labeled with 13 C in either of two positions (aromatic methoxyl or propyl side chain Cβ ) to provide highly sensitive and specific measures of lignin mineralization seldom employed in soils. Four-day redox fluctuations increased the percent contribution of methoxyl C to soil respiration relative to static aerobic conditions, and cumulative methoxyl-C mineralization was statistically equivalent under static aerobic and fluctuating redox conditions despite lower soil respiration in the latter treatment. Contributions of the less labile lignin Cβ to soil respiration were equivalent in the static aerobic and fluctuating redox treatments during periods of O2 exposure, and tended to decline during periods of O2 limitation, resulting in lower cumulative Cβ mineralization in the fluctuating treatment relative to the static aerobic treatment. However, cumulative mineralization of both the Cβ - and methoxyl-labeled lignins nearly doubled in the fluctuating treatment relative to the static aerobic treatment when total lignin mineralization was normalized to total O2 exposure. Oxygen fluctuations are thought to be suboptimal for canonical lignin-degrading microorganisms. However, O2 fluctuations drove substantial Fe reduction and oxidation, and reactive oxygen species generated during abiotic Fe oxidation might explain the elevated contribution of lignin to C mineralization. Iron redox cycling provides a potential mechanism for lignin depletion in soil organic matter. Couplings between soil moisture, redox fluctuations, and lignin breakdown provide a potential link between climate variability and the biochemical composition of soil organic matter.

Reactions of HO2 with n-propylbenzene and its phenylpropyl radicals

Abstraction of an H atom from the propyl side chain by hydroperoxyl radicals (HO2) constitutes a central reaction in the low-temperature oxidation of n-propylbenzene (nPB). Herein, we calculate reaction rate constants for H abstraction from primary, secondary and benzylic sites in nPB. Rate of abstraction of a benzylic H atom dominates that of a secondary H atom with negligible abstraction of the primary H atom at T⩾600K. We present the reaction enthalpies for 1-phenyl-1-propyl (R1), 1-phenyl-2-propyl (R2) and 1-phenyl-3-propyl (R3) radicals, and compare the computed reaction rate constants and bond dissociation enthalpies with analogous scarce literature values. Addition of HO2 radicals to radical sites in R1, R2 and R3 proceeds in a highly exothermic process and results in the formation of HO2–phenylpropyl adducts. Mapped potential energy surfaces illustrate all plausible exit channels of the three HO2–phenylpropyl adducts. Master equation calculations for the three phenylpropyl+HO2 reactions indicate that direct O–OH bond fission and water elimination control the fate of the adducts leading to the formation of ketonic-type structures. Results from this study should be useful to update kinetic models for the low-temperature oxidation of alkylbenzenes in general.

A highly diastereoselective oxidant contributes to Ligninolysis by the white rot basidiomycete Ceriporiopsis subvermispora.

The white rot basidiomycete Ceriporiopsis subvermispora delignifies wood selectively and has potential biotechnological applications. Its ability to remove lignin before the substrate porosity has increased enough to admit enzymes suggests that small diffusible oxidants contribute to delignification. A key question is whether these unidentified oxidants attack lignin via single-electron transfer (SET), in which case they are expected to cleave its propyl side chains between Cα and Cβ and to oxidize the threo-diastereomer of its predominating β-O-4-linked structures more extensively than the corresponding erythro-diastereomer. We used two-dimensional solution-state nuclear magnetic resonance (NMR) techniques to look for changes in partially biodegraded lignin extracted from spruce wood after white rot caused by C. subvermispora. The results showed that (i) benzoic acid residues indicative of Cα-Cβ cleavage were the major identifiable truncated structures in lignin after decay and (ii) depletion of β-O-4-linked units was markedly diastereoselective with a threo preference. The less selective delignifier Phanerochaete chrysosporium also exhibited this diastereoselectivity on spruce, and a P. chrysosporium lignin peroxidase operating in conjunction with the P. chrysosporium metabolite veratryl alcohol did likewise when cleaving synthetic lignin in vitro. However, C. subvermispora was significantly more diastereoselective than P. chrysosporium or lignin peroxidase-veratryl alcohol. Our results show that the ligninolytic oxidants of C. subvermispora are collectively more diastereoselective than currently known fungal ligninolytic oxidants and suggest that SET oxidation is one of the chemical mechanisms involved.

A new 9-alkyladenine-cyclic methylglyoxal diadduct activates wt- and F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in vitro and in vivo

Cystic fibrosis transmembrane conductance regulator (CFTR) is the main chloride channel present in the apical membrane of epithelial cells and the F508 deletion (F508del-CFTR) in the CF gene is the most common cystic fibrosis-causing mutation. In the search for a pharmacotherapy of cystic fibrosis caused by the F508del-CFTR, a bi-therapy could be developed associating a corrector of F508del-CFTR trafficking and an activator of the channel activity of CFTR. Here, we report on the synthesis of 9-alkyladenine derivatives analogues of our previously discovered activator of wt-CFTR and F508del-CFTR, GPact-11a, and the identification of a new activator of these channels, GPact-26a, through various flux assays on human airway epithelial CF and non-CF cell lines and in vivo measurement of rat salivary secretion. This study reveals that the possible modifications of the side chain introduced at the N9 position of the main pharmacophore are highly limited since only an allyl group can replace the propyl side chain present in GPact-11a to lead to a strong activation of wt-CFTR in CHO cells. Docking simulations of the synthesised compounds and of four described modulators performed using a 3D model of the wt-type CFTR protein suggest five possible binding sites located at the interface of the nucleotide binding domains NBD1/NBD2. However, the docking study did not allow the differentiation between active and non-active compounds.

Novel amino propyl substituted organo tin compounds

In this work, a new synthetic pathway yielding unprotected amino propyl tin compounds is described. For this purpose, mono stannanes with different substitution patterns are used. In a first step, tin hydrides are deprotonated using lithium diisopropyl amide and mixed with an electrophile containing a protected amine in the ω-position. After deprotection via acidic hydrolysis, the desired amino propyl tin compounds are obtained in high yield and purity. The thermal reaction behavior of the amino propyl tin hydrohalide intermediates containing one aromatic residue at the central tin atom is also investigated. For this purpose, amino propyl tin hydrohalides are heated under vacuum until the aromatic hydrocarbon is liberated. This thermal treatment leads to so far unknown tin halides containing an amino propyl side chain. For all of these substances detailed liquid 1H, 13C, and 119Sn-nuclear magnetic resonance (NMR) data were obtained, and in one case solid state NMR is also conducted. Regarding solids, single crystal X-ray analysis is performed. Some derivatization reactions with these new substances are demonstrated, especially the synthesis of an amino propyl tin carboxylate, which might be very interesting for biological, pharmaceutical, or technical processes.

The Origin and Biosynthesis of the Benzenoid Moiety of Ubiquinone (Coenzyme Q) in Arabidopsis.

It is not known how plants make the benzenoid ring of ubiquinone, a vital respiratory cofactor. Here, we demonstrate that Arabidopsis thaliana uses for that purpose two separate biosynthetic branches stemming from phenylalanine and tyrosine. Gene network modeling and characterization of T-DNA mutants indicated that acyl-activating enzyme encoded by At4g19010 contributes to the biosynthesis of ubiquinone specifically from phenylalanine. CoA ligase assays verified that At4g19010 prefers para-coumarate, ferulate, and caffeate as substrates. Feeding experiments demonstrated that the at4g19010 knockout cannot use para-coumarate for ubiquinone biosynthesis and that the supply of 4-hydroxybenzoate, the side-chain shortened version of para-coumarate, can bypass this blockage. Furthermore, a trans-cinnamate 4-hydroxylase mutant, which is impaired in the conversion of trans-cinnamate into para-coumarate, displayed similar defects in ubiquinone biosynthesis to that of the at4g19010 knockout. Green fluorescent protein fusion experiments demonstrated that At4g19010 occurs in peroxisomes, resulting in an elaborate biosynthetic architecture where phenylpropanoid intermediates have to be transported from the cytosol to peroxisomes and then to mitochondria where ubiquinone is assembled. Collectively, these results demonstrate that At4g19010 activates the propyl side chain of para-coumarate for its subsequent β-oxidative shortening. Evidence is shown that the peroxisomal ABCD transporter (PXA1) plays a critical role in this branch.

Characterization of the structural determinants required for potent mechanism-based inhibition of human cytochrome P450 1A1 by cannabidiol

We previously demonstrated that cannabidiol (CBD) was a potent mechanism-based inhibitor of human cytochrome P450 1A1 (CYP1A1). However, the moiety of CBD that contributes to the potent mechanism-based inhibition of human CYP1A1 remains unknown. Thus, the effects of compounds structurally related to CBD on CYP1A1 activity were examined with recombinant human CYP1A1 in order to characterize the structural requirements for potent inactivation by CBD. When preincubated in the presence of NADPH for 20min, olivetol, which corresponds to the pentylresorcinol moiety of CBD, enhanced the inhibition of the 7-ethoxyresorufin O-deethylase activity of CYP1A1. In contrast, d-limonene, which corresponds to the terpene moiety of CBD, failed to inhibit CYP1A1 activity in a metabolism-dependent manner. Pentylbenzene, which lacks two free phenolic hydroxyl groups, also did not enhance CYP1A1 inhibition. On the other hand, preincubation of the CBD-2′-monomethyl ether (CBDM) and CBD-2′,6′-dimethyl ether (CBDD) enhanced the inhibition of CYP1A1 activity. Inhibition by cannabidivarin (CBDV), which possessed a propyl side chain, was strongly potentiated by its preincubation. Orcinol, which has a methyl group, augmented CYP1A1 inhibition, whereas its derivative without an alkyl side chain, resorcinol, did not exhibit any metabolism-dependent inhibition. The preincubation of CBD-hydroxyquinone did not markedly enhance CYP1A1 inhibition. We further confirmed that olivetol, CBDM, CBDD, CBDV, and orcinol, as well as CBD (kinact=0.215min−1), inactivated CYP1A1 activity; their kinact values were 0.154, 0.0638, 0.0643, 0.226, and 0.0353min−1, respectively. These results suggest that the methylresorcinol structure in CBD may have structurally important roles in the inactivation of CYP1A1.

Antimicrobial Polycarbonates: Investigating the Impact of Nitrogen-Containing Heterocycles as Quaternizing Agents

Synthetic polymeric antimicrobials have received enormous attention recently on the back of increasing multidrug-resistance microbes. While conventional small molecular antibiotics act on specific targets to inhibit microbe activities, macromolecular antimicrobials physically destroy cell membranes of the organism rendering them ineffective; the mechanism of the latter aids in the prevention of developing drug-resistance microbes. In this investigation, we report on the synthesis of biodegradable cationic polycarbonates containing propyl and hexyl side chains quaternized with various nitrogen-containing heterocycles, such as imidazoles and pyridines, and their in vitro antimicrobial application. These polymers demonstrate a wide spectrum of activity (using minimum inhibitory concentrations analysis) against Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative), Pseudomonas aeruginosa (Gram-negative), and Candida albicans (fungus). Hemolysis experiments also show high selectivity toward the tested microbes over mammalian (rat) red blood cells (rRBCs). In particular, some of the polymers can achieve >250 times selectivity of S. aureus over rRBCs. In addition, the polymers function via a membrane-lytic mechanism; hence, they are less likely to develop drug resistance. All these properties make them ideal candidates as antimicrobial agents.

The phenylpropene synthase pathway and its applications in the engineering of volatile phenylpropanoids in plants

Phenylpropenes such as eugenol, isoeugenol, chavicol, and anethole are C6–C3 volatile compounds derived from phenylalanine by modification of its benzene ring and reduction of its propyl side chain, with the final reduction step catalyzed by a product-specific phenylpropene synthase. Recent advances in the biochemical and molecular analysis of phenylpropene synthases have improved our understanding of their evolution, structural properties, and reaction mechanism, providing insights into how plants produce and regulate the many types of phenylpropene volatiles. Since phenylpropenes are important in determining the flavor of foods and the quality of essential oils in cosmetics, the identification of the genes and enzymes responsible for the biosynthesis of phenylpropene volatiles has also provided us with tools to meet the challenge of improving plant aromas through genetic engineering.

Influence of alkyl length on properties of piezofluorochromic aggregation induced emission compounds derived from 9,10-bis[(N-alkylphenothiazin-3-yl)vinyl]anthracene

Three 9,10-bis[(N-alkylphenothiazin-3-yl)vinyl]anthracene derivatives with different propyl, hexyl, and dodecyl side chains (AnPh3, AnPh6, and AnPh12) were synthesized and confirmed by standard spectroscopic methods. All of the compounds exhibited obvious aggregation induced emission (AIE) and piezofluorochromic (PFC) properties. The PFC behaviors were investigated and showed that proportional alkyl-length dependent relationship existed not only in the ground states of the compounds, but also in the melted states compared with the fumed states of the compounds. The PFC mechanism was explored and ascribed to the crystalline–amorphous phase transformation. More importantly, these derivatives showed reversible significant PFC properties and reproducibility in various states including fumed, ground, annealed, and melted states, making them promising stimuli-responsive and smart luminescent materials for pressure-sensors, information-recording, and light-emitting device applications.