Design, Synthesis, and Biological Evaluation of Linear Aliphatic Amine-Linked Triaryl Derivatives as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction with Promising Antitumor Effects In Vivo.

A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound 58 could bind with hPD-L1 on the cellular surface and competitively block the interaction of hPD-1 with hPD-L1. In a T cell function assay, 58 restored the T cell function, leading to increased IFN-γ secretion. Moreover, in a humanized mouse model, compound 58 significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that 58 is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.

Microwave-Assisted, Base-Catalyzed Synthesis of Fatty Acid Methyl Esters from Seeds and Fish Oil Supplements.

Growing health awareness has resulted in the increased use of dietary supplements derived from plants and marine sources, leaving consumers unsure of their best options. There were three objectives of the present study. The first was to design and evaluate an efficient derivatization procedure. The second was to perform a comparative analysis of liquid oils and their corresponding capsules of hemp, chia, and flax seeds. The final objective was to determine the fatty acid (FA) composition of six fish oil products and compare it to the one provided on the label. For the FA profiling, we implemented two efficient, one-step, sustainable methods with high percentage recovery for the synthesis of FA methyl esters (FAME), which use base catalysis and microwave-assisted heating. Our results found no difference in nutritional value between liquid oils and capsules of the seed supplements, with flaxseed and chia offering a higher, beneficial n-3:n-6 ratio compared to hemp oil. Four of the fish oils analyzed contained significantly less eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than their reported label, and the other two not only agreed with the manufacturers' declaration but were able to fulfill the daily adequate intake (AI) with fewer capsules.

Facile lipase-catalyzed synthesis of a chocolate fat mimetic.

A cocoa butter equivalent (CBE) was synthesized enzymatically from readily available edible fats with fatty acid and triacylglycerol compositions that closely resemble the fat present in chocolate, cocoa butter. A commercially available immobilized fungal lipase, Lipozyme RM IM, was used as the reaction catalyst. Reaction parameters were a temperature of 65 °C, water activity of 0.11, a 4 h reaction time, and a substrate mass ratio of a commercial enzymatically synthesized shea stearin (SS) to palm mid-fraction (PMF) of 6:4 (w/w). Fractionation was also used after reaction completion to further approach the triacylglycerol composition of cocoa butter by removing trisaturated and unsaturated triacylglycerols. The yield of the triglyceride 1-palmitoyl-2-oleoyl, 3-stearoyl-glycerol (POS) produced was 57.7% (w/w). The amounts of 1,3-dipalmitoyl-2-oleoyl-glycerol (POP), (POS) and 1,3-stearoyl-2-oleoyl-glycerol (SOS) in the final CBE were 11.2%, 36.3%, and 34.8%, respectively. In comparison, the amounts of POP, POS and SOS in the cocoa butter used in this study were 15.2%, 38.2%, and 27.8%, respectively. No significant differences (P > 0.05) in melting point and enthalpy of fusion between CB and the CBE were observed. In comparison, a non-interesterified blend of SS and PMF (60:40 w/w) showed significantly (P < 0.05) higher melting point and lower enthalpy of fusion compared to CB. The crystal polymorphic form V of CB (ß2-3L) was similar to that of CBE and SS/PMF (60:40 w/w). The solid fat content (SFC) vs. temperature profile of the CBE generally resembled that of CB, except that the CBE had significantly (P < 0.05) higher SFCs at 5, 10, 15, 20 and 25 °C compared to both CB and SS/PMF (60:40 w/w). Addition of 15% (w/w) CBE to CB did not cause any changes in physical properties (melting point, SFC and crystal polymorphic forms) of the CB. This study demonstrates the potential for synthesizing a CB-like CBE using a green, rapid, straightforward one step enzymatic conversion followed by fractionation from widely available edible fats.

Lipase immobilized on ionic liquid-functionalized magnetic silica composites as a magnetic biocatalyst for production of trans-free plastic fats.

The main objective of this study is to develop an efficient and environmentally gentle process for production of trans-free plastic fats. To acheive this, the core-shell structured magnetic composites were prepared, and then imidazole-based ionic liquids (ILs) were covalently grafted on the magnetic composites. Thereafter, Candida rugosa lipase was immobilized on the magnetic IL-functionalized composites. The immobilized lipase could be facilely separated using an external magnetic filed. With the magnetic biocatalyst, enzymatic interesterifications of solid palm stearin and liquid rice bran oil blends were performed at 45 °C. It was shown that the total fatty acid (FA) compositions of the binary blends were almost unchanged after the interesterifications, whereas the FA positional distribution and triacylglycerol species were significantly varied. As compared with the physical blends, the interesterified products had a lower slip melting point, and the interesterification could result in an obvious change in the microstructure of the final products.

Cyclopentenyl Fatty Acids: History, Biological Activity and Synthesis.

This review discusses the substantial cyclopentenyl fatty acid class of naturally occurring lipids. These compounds are historically important and have recently been shown to exhibit remarkable biological activity relevant to producing new antibiotic agents. Information about the history of cyclopentenyl fatty acids, their use in traditional and modern medicine, as well as biological activity, and methods for their synthesis are given.

Synthesis of fatty acid methyl ester from the transesterification of high- and low-acid-content crude palm oil (Elaeis guineensis) and karanj oil (Pongamia pinnata) over a calcium-lanthanum-aluminum mixed-oxides catalyst.

The synthesis of fatty acid methyl ester (FAME) from the high- and low-acid-content feedstock of crude palm oil (CPO) and karanj oil (KO) was conducted over CaO-La2O3-Al2O3 mixed-oxide catalyst. Various reaction parameters were investigated using a batch reactor to identify the best reaction condition that results in the highest FAME yield for each type of oil. The transesterification of CPO resulted in a 97.81% FAME yield with the process conditions of 170°C reaction temperature, 15:1 DMC-to-CPO molar ratio, 180min reaction time, and 10wt.% catalyst loading. The transesterification of KO resulted in a 96.77% FAME yield with the conditions of 150°C reaction temperature, 9:1 DMC-to-KO molar ratio, 180min reaction time, and 5wt.% catalyst loading. The properties of both products met the ASTM D6751 and EN 14214 standard requirements. The above results showed that the CaO-La2O3-Al2O3 mixed-oxide catalyst was suitable for high- and low-acid-content vegetable oil.

Effective heterogeneous transition metal glycerolates catalysts for one-step biodiesel production from low grade non-refined Jatropha oil and crude aqueous bioethanol.

The utilization of bioethanol as the alcohol source for biodiesel production is more environmentally advantageous over methanol owing to its lower toxicity, lower flammability and its sustainable supply from renewable agricultural resources. However, as the presence of water in crude bioethanol is the critical factor limiting the biodiesel production process, the energy-intensive and costly purification of bioethanol is necessary for biodiesel application. Manganese glycerolate (MnGly) is reported the first time here as a robust heterogeneous catalyst that exhibited over 90% conversion by using aqueous ethanol containing 80 wt.% of water in the production of fatty acid ethyl ester (FAEE). The employment of 95 wt.% ethanol with respect to water could achieve 99.7% feedstock conversion in 6 hours under the optimal reaction conditions: reaction temperature (150 °C), feedstock-to-ethanol molar ratio (1:20) and catalyst loading (6 wt.%). Commercially available low grade crude bioethanol with the presence of impurities like sugars were applied which demonstrated remarkable catalytic activity in 24 hours. The high water tolerance of MnGly towards biodiesel production could eventually simplify the purification of bioethanol that consumes less energy and production cost.

Pterandric acid--its isolation, synthesis and stereochemistry.

Some plant families have a specialized type of pollination system, with floral lipid rewards for pollinators, which is common. In neotropical Malpighiaceae species like Pterandra pyroidea, this specialized type of pollination system is apparently shifting from floral oils/lipids to pollen reward. Mass spectrometric analysis (GC/MS-EI) indicated that P. pyroidea floral oil has a unique chemical composition, i.e., few fatty acid constituents possessing acetoxy groups at positions 5 and 7, which is distinct from the other floral oils of sympatric Malpighiaceae species. The structure of the major floral oil constituent, a novel fatty acid, anti-5,7-diacetoxydocosanoic acid, was confirmed based on synthesis, mass fragmentation, and 1H and 13C NMR analyses; the compound is herein named pterandric acid.

Ultrasound-assisted biodiesel production from Camelina sativa oil.

The main drawbacks of biodiesel production are high reaction temperatures, stirring and time. These could be alleviated by aiding transesterification with alternative energy sources, i.e. ultrasound (US). In this study, biodiesel was obtained from Camelina sativa oil, aided with an ultrasonic probe (20kHz, 70% duty cycle, 50% amplitude). Design of experiments included the combination of sonication and agitation cycles, w/wo heating (50°C). To gain knowledge about the implications of the proposed methodology, conventional transesterification was optimized, resulting in higher needs on catalyst concentration and reaction time, compared to the proposed reaction. Although FAME content met EN 14103 standard, FAME yields were lower than those provided by US-assisted transesterification. Energy consumption measurements showed that ultrasound assisted transesterification required lower energy, temperature, catalyst and reaction time.

Reaction parameters for the synthesis of N,N-dimethyl fatty hydrazides from oil.

Hydrazide derivatives have been synthesized from methyl esters, hydrazones and vegetable oils. They are important due to their diverse applications in pharmaceutical products, detergents as well as in oil and gas industries. The chemical synthesis of fatty hydrazides is well-established; however, only a few publications described the synthesis of fatty hydrazide derivatives, particularly, when produced from refined, bleached and deodorized palm olein. Here, the synthesis and characterization of N,N-dimethyl fatty hydrazides are reported. The N,N-dimethyl fatty hydrazides was successfully synthesized from fatty hydrazides and dimethyl sulfate in the presence of potassium hydroxide with the molar ratio of 1:1:1, 6 hours reaction time and 80℃ reaction temperature in ethanol. The product yield and purity were 22% and 89%, respectively. The fatty hydrazides used were synthesized from refined, bleached and deodorized palm olein with hydrazine monohydrate at pH 12 by enzymatic route. Fourier transform infrared, gas chromatography and nuclear magnetic resonance (NMR) spectroscopy techniques were used to determine the chemical composition of N,N-dimethyl fatty hydrazides. Proton NMR confirmed the product obtained were N,N-dimethyl fatty hydrazides.

[Comparative assessment of Cladophora, Spirogyra and Oedogonium biomass for the production of fatty acid methyl esters].

The use of alternative fuels for the mitigation of ecological impacts by use of diesel has been focus of intensive research. In the present work, algal oils extracted from cultivated biomass of Cladophora sp., Spirogyra sp. and Oedogonium sp. were evaluated for the lipase-mediated synthesis of fatty acid monoalkyl esters (FAME, biodiesel). To optimize the transesterification of these oils, different parameters such as the alkyl group donor, reaction temperature, stirring time and oil to alcohol ratio were investigated. Four different alcohols i.e. methanol, ethanol, n-propanol and n-butanol were tested as alkyl group donor for the biosynthesis FAME and methanol was found to be the best. Similarly, temperature 50 C and stirring time of 6 h were optimized for the transesterification of oils with methanol. The maximum biodiesel conversions from Cladophora (75.0%), Spirogyra (87.5%) and Oedogonium (92.0%) were obtained when oil to alcohol ratio was 1 : 8.

Development and evaluation of glyceryl behenate based solid lipid nanoparticles (SLNs) using hot self-nanoemulsification (SNE) technique.

The purpose of this research was to improve oral bioavailability of poorly aqueous soluble drug lopinavir using solid lipid nanoparticles (SLNs). Glyceryl behenate based SLNs of lopinavir were prepared using hot self-nanoemulsification (SNE) technique. The hot isotropic mixture of glyceryl behenate, Poloxamer 407 and polyethylene glycol 4000 was spontaneously self-nanoemulsify in hot water (80 °C) and SLNs were subsequently formed with rapid cooling. Hot SNE ability of isotropic mixture was visually assessed by ternary phase diagram study. Optimized SLNs were having particle size of 214.5 ± 4.07 nm, entrapment efficiency of 81.6 ± 2.3 % and zeta potential of -12.7 ± 0.87 mV. SLNs were evaluated by transmission electron microscopy and atomic force microscopy for morphological details. Further, differential scanning calorimetry and x-ray diffraction were also performed for solid state characterization of SLNs. Higher oral bioavailability (3.56-fold) was found for lopinavir loaded SLNs in comparison to bulk lopinavir due to higher lymphatic drug transport (p < 0.05). Results indicate that SLNs of glyceryl behenate can be successfully prepared by hot SNE technique.

Synthesis and effect of fatty acid amides as friction modifiers in petroleum base stock.

Fatty acid amides were prepared by using Lewis acid as a catalyst. The products from reaction was subjected to solvent extraction with chloroform and then followed by purification with n-hexane, ethanol and acetonitrile. Fatty acid amide, characterized by various physicochemical and tribological properties like wear scar, weld load and coefficient of friction. These compounds found good antiwear (AW) and extreme pressure (EP) additive. The addition of various EP and AW additives in lubricating oil is an important and effective way to reduce friction and wear. Fatty acid amides were used as antiwear and friction modifier additive and a comparative study was carried out for 1%, 3%, 5% additive blend with commercial petroleum base stocks 150N and 500N.

Synthesis of 9-oxononanoic acid, a precursor for biopolymers.

Polymers based on renewable resources have become increasingly important. The natural functionalization of fats and oils enables an easy access to interesting monomeric building blocks, which in turn transform the derivative biopolymers into high-performance materials. Unfortunately, interesting building blocks of medium-chain length are difficult to obtain by traditional chemical means. Herein, a biotechnological pathway is established that could provide an environmentally suitable and sustainable alternative. A multiple enzyme two-step one-pot process efficiently catalyzed by a coupled 9S-lipoxygenase (St-LOX1, Solanum tuberosum) and 9/13-hydroperoxide lyase (Cm-9/13HPL, Cucumis melo) cascade reaction is proposed as a potential route for the conversion of linoleic acid into 9-oxononanoic acid, which is a precursor for biopolymers. Lipoxygenase catalyzes the insertion of oxygen into linoleic acid through a radical mechanism to give 9S-hydroperoxy-octadecadienoic acid (9S-HPODE) as a cascade intermediate, which is subsequently cleaved by the action of Cm-9/13HPL. This one-pot process afforded a yield of 73 % combined with high selectivity. The best reaction performance was achieved when lipoxygenase and hydroperoxide lyase were applied in a successive rather than a simultaneous manner. Green leaf volatiles, which are desired flavor and fragrance products, are formed as by-products in this reaction cascade. Furthermore, we have investigated the enantioselectivity of 9/13-HPLs, which exhibited a strong preference for 9S-HPODE over 9R-HPODE.

Novel pyrazoline amidoxime and their 1,2,4-oxadiazole analogues: synthesis and pharmacological screening.

A novel series of pyrazoline amidoxime (2a-d) and pyrazoly-1,2,4-oxadiazole (3a-p) and (4) of pharmacological significance have been synthesised. Structures of newly synthesised compounds were characterized by spectral studies. New compounds were screened for their in vitro antioxidant, antimicrobial and antiinflammatory activities. Among the synthesized compounds, compound 2a, 3l and 3o were found to be active antimicrobial agents in addition to having potent antioxidant activity, while the compound 3f showed promising antiinflammatory activity in comparison with standard drug.

Enzymatic production of zero-trans plastic fat rich in α-linolenic acid and medium-chain fatty acids from highly hydrogenated soybean oil, Cinnamomum camphora seed oil, and perilla oil by lipozyme TL IM.

In the present study, zero-trans α-linolenic acid (ALA) and medium-chain fatty acids (MCFA)-enriched plastic fats were synthesized through enzymatic interesterification reactions from highly hydrogenated soybean oil (HSO), Cinnamomum camphora seed oil (CCSO), and perilla oil (PO). The reactions were performed by incubating the blending mixtures of HSO, CCSO, and PO at different weight ratios (60:40:100, 70:30:100, 80:20:100) using 10% (total weight of substrate) of Lipozyme TL IM at 65 °C for 8 h. After reaction, the physical properties (fatty acids profile, TAG composition, solid fat content, slip melting point, contents of tocopherol, polymorphic forms, and microstructures) of the interesterified products and their physical blends were determined, respectively. Results showed that the fatty acid compositions of the interesterified products and physical blends had no significant changes, while the content of MCFA in both interesterified products and physical blends increased to 8.58-18.72%. Several new types of TAG species were observed in interesterified products (SSL/SLS, PLO/LLS, and OLLn/LnLO/LOLn). It should be mentioned that no trans fatty acids (TFA) were detected in all products. As the temperature increased, the solid fat content (SFC) of interesterified products was obviously lower than that of physical blends. The SFCs of interesterified products (60:40:100, 70:30:100, and 80:20:100, HSO:CCSO:PO) at 25 °C were 6.5%, 14.6%, and 16.5%, respectively, whereas the counterparts of physical blends were 32.5%, 38.5%, and 43.5%, respectively. Meanwhile, interesterified products showed more ß' polymorphs than physical blends, in which ß' polymorph is a favorite form for production of margarine and shortening. Such zero-trans ALA and MCFA-enriched fats may have desirable physical and nutritional properties for shortenings and margarines.

Production of ethoxylated fatty acids derived from Jatropha non-edible oil as a nonionic fat-liquoring agent.

Natural fatty derivatives (oleochemicals) have been used as intermediate materials in several industries replacing the harmful and expensive petrochemicals. Fatty ethoxylates are one of these natural fatty derivatives. In the present work Jatropha fatty acids were derived from the non edible Jatropha oil and used as the fat source precursor. The ethoxylation process was carried out on the derived fatty acids using a conventional cheap catalyst (K2CO3) in order to obtain economically and naturally valuable non-ionic surfactants. Ethoxylation reaction was proceeded using ethylene oxide gas in the presence of 1 or 2% K2CO3 catalyst at 120 and 145°C for 5, 8 and 12 hours. The prepared products were evaluated for their chemical and physical properties as well as its application as non- ionic fat-liquoring agents in leather industry. The obtained results showed that the number of ethylene oxide groups introduced in the fatty acids as well as their EO% increased as the temperature and time of the reaction increased. The highest ethoxylation number was obtained at 145°C for 8 hr. Also, the prepared ethoxylated products were found to be effective fat-liquors with high HLB values giving stable oil in water emulsions. The fat-liquored leather led to an improvement in its mechanical properties such as tensile strength and elongation at break. In addition, a significant enhancement in the texture of the treated leather by the prepared fat-liquors as indicated from the scanning electron microscope (SEM) images was observed.

Copper extraction by fatty hydroxamic acids derivatives synthesized based on palm kernel oil.

Fatty hydroxamic acids derivatives based on palm kernel oil which are phenyl fatty hydroxamic acids (PFHAs), methyl fatty hydroxamic acids (MFHAs), isopropyl fatty hydroxamic acids (IPFHAs) and benzyl fatty hydroxamic acids (BFHAs) were applied as chelating agent for copper liquid-liquid extraction. The extraction of copper from aqueous solution by MFHAs, PFHAs, BFHAs or IPFHAs were carried out in hexane as an organic phase through the formation of copper methyl fatty hydroxamate (Cu-MFHs), copper phenyl fatty hydroxamate (Cu-PFHs), copper benzyl fatty hydroxamate (Cu-BFHs) and copper isopropyl fatty hydroxamate (Cu-IPFHs). The results showed that the fatty hydroxamic acid derivatives could extract copper at pH 6.2 effectively with high percentage of extraction (the percentages of copper extraction by MFHAs, PFHAs, IPFHs and BFHAs were found to be 99.3, 87.5, 82.3 and 90.2%, respectively). The extracted copper could be quantitatively stripped back into sulphuric acid (3M) aqueous solution. The obtained results showed that the copper recovery percentages from Cu-MFHs, Cu-PFHs, Cu-BFHs and Cu-IPFHs are 99.1, 99.4, 99.6 and 99.9 respectively. The copper extraction was not affected by the presence of a large amount of Mg (II), Ni (II), Al (III), Mn (II) and Co (II) ions in the aqueous solution.

Synthesis of fatty acid methyl ester from palm oil (Elaeis guineensis) with Ky(MgCa)2xO3 as heterogeneous catalyst.

Fatty acid methyl esters (FAME) were produced from palm oil using eggshell modified with magnesium and potassium nitrates to form a composite, low-cost heterogeneous catalyst for transesterification. The catalyst, prepared by the combination of impregnation/co-precipitation was calcined at 830 °C for 4 h. Transesterification was conducted at a constant temperature of 65 °C in a batch reactor. Design of experiment (DOE) was used to optimize the reaction parameters, and the conditions that gave highest yield of FAME (85.8%) was 5.35 wt.% catalyst loading at 4.5 h with 16:1 methanol/oil molar ratio. The results revealed that eggshell, a solid waste, can be utilized as low-cost catalyst after modification with magnesium and potassium nitrates for biodiesel production.

Synthesis of fatty acid methyl ester from crude jatropha (Jatropha curcas Linnaeus) oil using aluminium oxide modified Mg-Zn heterogeneous catalyst.

The synthesis of fatty acid methyl esters (FAME) as a substitute to petroleum diesel was investigated in this study from crude jatropha oil (CJO), a non-edible, low-cost alternative feedstock, using aluminium modified heterogeneous basic oxide (Mg-Zn) catalyst. The transesterification reaction with methanol to methyl esters yielded 94% in 6h with methanol-oil ratio of 11:1, catalyst loading of 8.68 wt.% at 182°C and the properties of CJO fuel produced were determine and found to be comparable to the standards according to ASTM. In the range of experimental parameters investigated, it showed that the catalyst is selective to production of methyl esters from oil with high free fatty acid (FFA) and water content of 7.23% and 3.28%, respectively in a single stage process. Thus, jatropha oil is a promising feedstock for methyl ester production and large scale cultivation will help to reduce the product cost.