This document summarizes the development of efficient protocols for synthesizing 1,2,3,4-tetrahydroisoquinolin-1-ones. Several methods were developed, including the use of Mitsunobu reactions, copper-catalyzed arylations, and SNAr reactions to install various substituents on the core scaffold. These methods proved to be versatile, efficient, and amenable to parallel synthesis, allowing for SAR exploration across different regions of the molecule.
The document provides information on HF cleavage and deprotection from resins. It discusses how HF is used to remove protecting groups from assembled peptides and release the resin. It describes the advantages of HF, materials needed, standard and low-high HF cleavage procedures, strategies to minimize side reactions, and provides examples of cleavage for different peptide sequences.
This document describes the identification of a new series of potent histone deacetylase (HDAC) inhibitors. The researchers designed substituted 2-piperazinyl-5-pyrimidylhydroxamic acids using a multicomponent Petasis reaction to introduce chemical diversity. Compounds in the new series exhibited HDAC inhibitory activity in the low nanomolar range and inhibited tumor cell growth similarly. The new compounds showed improved solubility over previous generations, making them promising starting points for developing new HDAC inhibitor drugs. Stereochemistry and substitution of the phenyl ring had little effect on inhibitory potency. The increased solubility of the compounds represents an important improvement for drug development.
C-terminal Sequencing of Protein : Novel Partial Acid Hydrolysis & Analysis b...Keiji Takamoto
The document describes a novel method for C-terminal sequencing of proteins using partial acid hydrolysis and mass spectrometry analysis. Peptides or proteins are hydrolyzed with vapors of strong organic acids like trifluoroacetic acid or hepta-fluorobutyric acid at high temperatures. This results in successive degradation of the C-terminal residues as seen by mass spectrometry. The degradation is believed to occur via formation of an oxazolone ring at the C-terminal amino acid, followed by removal of the C-terminal residue. Specific cleavages also occur at the peptide bonds preceding aspartic acid and serine residues. This method allows efficient C-terminal sequencing of proteins in small quantities directly from mass
In this work a new prodrug polymer was
prepared with two attachment groups (amid-ester), using di
functional spacer such as ethanol amine, which could react with
polyacrylic acid producing amide group, with remain ethanol
terminal group which could react with captopril acyl chloride,
producing ester group with extended the arm substituted drug to
improve the hydrolysis and to prevent the steric effect of polymer
chains. Many advantages enhanced the prodrug of polymer. The
prepared polymers were characterized by FTIR, 1H –NMR
spectroscopies. Controlled drug release was studied in different
pH values at 37℃, using UV. Spectra with comparing with
calibration curve. The modification percentage test was studied,and swelling percentage was calculated and all physical properties were observed.
solid phase synthesis Presentation by komalKomal Rajgire
The document summarizes solid phase synthesis. It begins with an introduction describing how solid phase synthesis involves coupling reagents to a solid support to perform multi-step reactions leading to a target molecule. It then discusses various aspects of planning solid phase synthesis such as suitable resin supports, linkers, protective groups, and monitoring reactions. Examples of resin types, linkers, and protective groups are provided. The document concludes by outlining advantages such as simplified purification and green chemistry principles, as well as disadvantages such as potential low reaction rates. Applications mentioned include combinatorial synthesis, peptide synthesis, and DNA synthesis.
plain 4 SYNTHESIS, PURIFICATION AND STABILITY STUDY OF ISLETAndrew Apals
This document outlines Andrew Apals' thesis defense presentation on the synthesis, purification, and stability study of the islet neogenesis-associated protein peptide (INGAP-P) and analogs. The presentation covers solid phase peptide synthesis of INGAP-P, linear and cyclic analogs. It also discusses reverse-phase HPLC method development for the separation and quantification of peptides in synthetic mixtures, including degradation studies of INGAP-P standards. The goal of the research is to develop purification methods to resolve INGAP-P from crude synthesis mixtures using analytical HPLC instrumentation.
The document discusses various side reactions that can occur during solid phase peptide synthesis (SPPS), including peptide fragmentation, deletion reactions, β-elimination reactions, rearrangements, cyclizations, modifications of amino acid side chains, and oxidations. Specific examples are provided for each category, such as acidolysis of Asp-Pro bonds and N-acetyl-N-alkyl peptides, β-elimination of cysteine and phosphorylated residues, acid- or base-catalyzed acyl shifts, aspartimide and asparagine deamidation, and disulfide scrambling or degradation. Factors affecting the side reactions like acidity, sequence dependence, and excipient impurities are also examined.
The document discusses solid phase peptide synthesis (SPPS) methods using different protecting groups. It describes the t-Boc and Fmoc protecting group strategies, comparing their advantages and disadvantages. The t-Boc strategy uses acid-labile protecting groups removed by TFA, while the Fmoc strategy uses a base-labile Fmoc group and acid-labile side chain protecting groups, allowing milder acidic conditions. The document outlines the different protocols used in SPPS, including resin attachment, amino acid coupling and protecting group removal steps. It also discusses side reactions that can occur and strategies to minimize them, such as using orthogonal protecting groups or modified amino acid derivatives.
The document provides information on HF cleavage and deprotection from resins. It discusses how HF is used to remove protecting groups from assembled peptides and release the resin. It describes the advantages of HF, materials needed, standard and low-high HF cleavage procedures, strategies to minimize side reactions, and provides examples of cleavage for different peptide sequences.
This document describes the identification of a new series of potent histone deacetylase (HDAC) inhibitors. The researchers designed substituted 2-piperazinyl-5-pyrimidylhydroxamic acids using a multicomponent Petasis reaction to introduce chemical diversity. Compounds in the new series exhibited HDAC inhibitory activity in the low nanomolar range and inhibited tumor cell growth similarly. The new compounds showed improved solubility over previous generations, making them promising starting points for developing new HDAC inhibitor drugs. Stereochemistry and substitution of the phenyl ring had little effect on inhibitory potency. The increased solubility of the compounds represents an important improvement for drug development.
C-terminal Sequencing of Protein : Novel Partial Acid Hydrolysis & Analysis b...Keiji Takamoto
The document describes a novel method for C-terminal sequencing of proteins using partial acid hydrolysis and mass spectrometry analysis. Peptides or proteins are hydrolyzed with vapors of strong organic acids like trifluoroacetic acid or hepta-fluorobutyric acid at high temperatures. This results in successive degradation of the C-terminal residues as seen by mass spectrometry. The degradation is believed to occur via formation of an oxazolone ring at the C-terminal amino acid, followed by removal of the C-terminal residue. Specific cleavages also occur at the peptide bonds preceding aspartic acid and serine residues. This method allows efficient C-terminal sequencing of proteins in small quantities directly from mass
In this work a new prodrug polymer was
prepared with two attachment groups (amid-ester), using di
functional spacer such as ethanol amine, which could react with
polyacrylic acid producing amide group, with remain ethanol
terminal group which could react with captopril acyl chloride,
producing ester group with extended the arm substituted drug to
improve the hydrolysis and to prevent the steric effect of polymer
chains. Many advantages enhanced the prodrug of polymer. The
prepared polymers were characterized by FTIR, 1H –NMR
spectroscopies. Controlled drug release was studied in different
pH values at 37℃, using UV. Spectra with comparing with
calibration curve. The modification percentage test was studied,and swelling percentage was calculated and all physical properties were observed.
solid phase synthesis Presentation by komalKomal Rajgire
The document summarizes solid phase synthesis. It begins with an introduction describing how solid phase synthesis involves coupling reagents to a solid support to perform multi-step reactions leading to a target molecule. It then discusses various aspects of planning solid phase synthesis such as suitable resin supports, linkers, protective groups, and monitoring reactions. Examples of resin types, linkers, and protective groups are provided. The document concludes by outlining advantages such as simplified purification and green chemistry principles, as well as disadvantages such as potential low reaction rates. Applications mentioned include combinatorial synthesis, peptide synthesis, and DNA synthesis.
plain 4 SYNTHESIS, PURIFICATION AND STABILITY STUDY OF ISLETAndrew Apals
This document outlines Andrew Apals' thesis defense presentation on the synthesis, purification, and stability study of the islet neogenesis-associated protein peptide (INGAP-P) and analogs. The presentation covers solid phase peptide synthesis of INGAP-P, linear and cyclic analogs. It also discusses reverse-phase HPLC method development for the separation and quantification of peptides in synthetic mixtures, including degradation studies of INGAP-P standards. The goal of the research is to develop purification methods to resolve INGAP-P from crude synthesis mixtures using analytical HPLC instrumentation.
The document discusses various side reactions that can occur during solid phase peptide synthesis (SPPS), including peptide fragmentation, deletion reactions, β-elimination reactions, rearrangements, cyclizations, modifications of amino acid side chains, and oxidations. Specific examples are provided for each category, such as acidolysis of Asp-Pro bonds and N-acetyl-N-alkyl peptides, β-elimination of cysteine and phosphorylated residues, acid- or base-catalyzed acyl shifts, aspartimide and asparagine deamidation, and disulfide scrambling or degradation. Factors affecting the side reactions like acidity, sequence dependence, and excipient impurities are also examined.
The document discusses solid phase peptide synthesis (SPPS) methods using different protecting groups. It describes the t-Boc and Fmoc protecting group strategies, comparing their advantages and disadvantages. The t-Boc strategy uses acid-labile protecting groups removed by TFA, while the Fmoc strategy uses a base-labile Fmoc group and acid-labile side chain protecting groups, allowing milder acidic conditions. The document outlines the different protocols used in SPPS, including resin attachment, amino acid coupling and protecting group removal steps. It also discusses side reactions that can occur and strategies to minimize them, such as using orthogonal protecting groups or modified amino acid derivatives.
Discovery-of-pyrimidyl-5-hydroxamic-acids-as-new-potent-histone-deacetylase-i...Peter ten Holte
This document describes the discovery of new potent histone deacetylase (HDAC) inhibitors containing a pyrimidyl-5-hydroxamic acid structure. A series of these compounds were prepared and tested for HDAC inhibitory activity and antiproliferative effects on cancer cells. The most potent compound contained an amino-2-pyrimidinyl linker and a pyridinyl moiety, inhibiting HDAC activity with an IC50 below 100 nM and reducing cancer cell proliferation in the low micromolar range. Replacing structural elements like the pyrimidinyl ring or changing the heterocyclic ring size generally resulted in lower enzymatic or antiproliferative potency. These results identify amino-2-py
The document describes the synthesis and characterization of new imidazole derivatives derived from D-erythroascorbic acid. D-erythroascorbic acid was modified through multi-step reactions to yield Schiff bases containing heterocyclic units like 1,3,4-oxadiazole and 1,3,4-thiadiazole. These Schiff bases were further derivatized to yield N-acyl, thiourea, and imidazole compounds. The structures of the synthesized compounds were characterized using techniques like elemental analysis, FTIR, NMR, and mass spectrometry. The compounds exhibited good antibacterial activity against Escherichia coli and Staphylococcus aureus.
Improved Stability of Formate Dehydrogenase by Coating with Didodecyldimethyl...researchinventy
Hydrophilic formate dehydrogenase (FDH) from candida boidinii was chemically modified by coating it with didodecyldimethylammonium bromide (DDAB). This coating changed the phase behavior of the enzyme, making it highly soluble in hydrophobic solvents and thereby offering the chance for biphasic enzyme recycling from hydrophilic substrates and products. Different coating procedures of FDH with DDAB were investigated and all proved suitable for efficient coating of the enzyme’s outer surface. A 50 mM Tris- (hydroxymethyl)-amminomethan (tris) buffer at pH 8 was chosen to make DDAB soluble and avoid aggregation. The reaction of NAD+ with uncoated and coated FDH to NADH and CO2 was monitored by UV-vis spectroscopy and kinetic parameters (rmax, Km, KI , EA) for the the FDH were determined. The coated enzyme resulted in a lower relative initial activity between 40-60% compared to the uncoated one. The stability of the coated enzyme (FDH*) was improved significantly and remained stable in long-term experiments, resulting in a deactivation rate kD smaller than 3% per day and a half-life time t1/2largerthan 23 days, while the deactivation rate of the uncoated enzyme was 260% per daywitha t1/2of 0.3 days. Both activation energies were similar, with 42 kJ mol-1 for the coated and 48 kJ mol-1 for the uncoated enzyme.This result suggests that there is not significant transport resistance originating from the DDAB coating layer. The reason for the significantly lower activity of the coated FDH probably stems from accumulation of formed CO2 in the coating layer, thereby preventing high equilibrium conversions
The document describes the synthesis of novel hydroxy naphthylchalcone compounds as potential inhibitors of the enzyme polyphenol oxidase (tyrosinase). Two of the synthesized compounds showed higher tyrosinase inhibitory activity than the positive control kojic acid. Kinetic analysis revealed the inhibition was reversible and competitive. Molecular docking studies confirmed the active inhibitors strongly interacted with residues in the active site of mushroom tyrosinase.
1) Novel compounds called O,O-diethyl 1-benzamido-2,2-biscarbamoylethanephosphonates were synthesized as substrates for HIV-1 protease (PR) to exploit activation of the phosphonate group.
2) One compound, O,O-diethyl 1-benzamido-2,2-bis[(1S)-N-(1-benzyl-2-hydroxyethyl)carbamoyl]ethanephosphonate, showed moderate anti-HIV activity in vitro. Its depsipeptide analogue inhibited HIV-1 PR with an IC50 of 31 μM.
3) The phosphonate group of these compounds was designed
Synthesis and characterization of resin copolymer derived from cardanol-furfu...ijceronline
International Journal of Computational Engineering Research (IJCER) is dedicated to protecting personal information and will make every reasonable effort to handle collected information appropriately. All information collected, as well as related requests, will be handled as carefully and efficiently as possible in accordance with IJCER standards for integrity and objectivity.
This study synthesized eight new fluorinated quinazolinone-sulphonamide hybrid compounds and evaluated their anticancer activity. One compound showed significant anticancer activity with low toxicity compared to the reference drug mitoxantrone. Biological assays also demonstrated moderate anticancer activity for the compounds compared to reference drugs. The compound with the best activity profile was identified for further evaluation as an anticancer agent.
1) The document reports on a computational and NMR study of a camphor-based chiral amino alcohol (2) and related compounds (1 and 3).
2) NMR analysis showed differences in chemical shifts between diastereotopic hydrogens H11a and H11b in compound 2, suggesting conformational restriction from an intramolecular hydrogen bond.
3) DFT calculations confirmed the most stable conformer of 2 features an intramolecular O-H-N hydrogen bond, restricting rotational mobility and accounting for the observed chemical shift differences between H11a and H11b.
The document summarizes the research goals and methods of Giuseppe Puzzo's PhD thesis on the production of biodegradable and biocompatible polymers for pharmaceutical applications. The research will explore using bacterial fermentation and microwave-assisted synthesis to obtain new polyhydroxyalkanoate polymers with improved yields, structures and properties compared to poly(3-hydroxybutyrate). Methods include using Pseudomonas aeruginosa to produce PHAs from long chain fatty acids and vegetable oils. New copolymers and terpolymers will also be synthesized using microwave-assisted transesterification reactions.
The document describes the carbon nanotube-gold nanohybrid (AuCNT) catalyzed N-formylation of various primary and secondary amines using aqueous formaldehyde. Key findings include:
1) AuCNT catalyzes the room temperature N-formylation of various primary and secondary amines with aqueous formaldehyde, affording formamides in excellent yields.
2) The reaction proceeds with low catalyst loading (0.34 mol%), excellent chemoselectivity, and recyclability of the AuCNT catalyst.
3) Control experiments confirm the AuCNT nanohybrid is the active catalytic species, and the reaction proceeds through a hemiaminal intermediate that is oxidized to the
This document describes a study that modified cassava starch with soybean oil maleate (SOMA) and used the modified starch as a filler in poly(lactic acid) (PLA) composites. SOMA was synthesized by grafting soybean oil with maleic anhydride, and then used to modify cassava starch, resulting in SOMA-g-STARCH. Various ratios of PLA and SOMA-g-STARCH were compounded and tested. The compatibility, morphology, thermal properties, and mechanical properties of the composites were characterized. The results showed that compositions with 90:10 and 80:20 ratios of PLA:SOMA-g-STARCH had the best compatibility, surface
Phytochemical investigation of the methanolic extract of Launaea intybacea yielded eleven compounds, which were characterized using NMR, mass spectrometry, and by comparison to reported data. The compounds showed antioxidant activity in DPPH radical scavenging assays and inhibitory effects against acetylcholinesterase, butyrylcholinesterase, and lipoxygenase enzymes. This is the first report of these bioactive compounds isolated from L. intybacea.
Chemistry of peptide (BPHARM,MPHARM,MSC,BSC)Shikha Popali
THE PRESENTATION DESCRIBING BOND FORMATION OF AMINO ACIDS AND PROTEINS AND COUPLING REAGENTS IN PEPTIDE SYNTHESIS FOLLOWED BY CARBODIMIDES, PHOSPHONIUM AND AMMONIUM SALTS.
This document summarizes a palladium-catalyzed method for fluorinating arylboronic acid derivatives. Key points:
- A Pd(II) complex is used as a precatalyst to catalyze the fluorination of various aryl trifluoroborates and other arylboron reagents.
- The reaction proceeds through a single-electron transfer pathway involving an isolated and characterized Pd(III) intermediate.
- A wide variety of functional groups are tolerated and the aryl fluoride products are obtained in good yields and purity.
- The reaction is operationally simple and scalable to the multigram level, providing a practical method for synthesizing aryl fluorides.
The document describes the synthesis and antimicrobial screening of some pyrazolyl heterocycles. Specifically, it details the synthesis of compounds 3, 4, 5, and 6 through various reactions between 1-phenyl-3-(2-pyridyl)-1H-pyrazole-4-carboxaldehyde and acetophenone derivatives. Compound 3 undergo oxidative cyclization to form compounds 4 and 5. Compound 3 also undergoes condensation with hydrazine to form compound 6. The structures of compounds 3, 4, 5, and 6 were characterized using spectral methods. These compounds were then tested for antimicrobial activity against various bacteria and fungi, with some compounds showing moderate to good activity.
Degradation of PLA at Mesophillic and thermophillic conditionsSabahat Ali
This document summarizes research on the degradation of polylactic acid (PLA) under mesophilic and thermophilic conditions. Key findings include:
1) Mesophilic bacteria like Pseudomonas geniculata and Streptomyces pavanii were found to degrade PLA films at 25-40°C, with S. pavanii showing higher degradation.
2) PLA degradation was higher under thermophilic (41-122°C) conditions compared to mesophilic (20-45°C) due to PLA-degrading enzymes working best at high temperatures. Up to 90% of PLA weight loss was observed at thermophilic temperatures within 12 days of
International Journal of Engineering Research and Applications (IJERA) is a team of researchers not publication services or private publications running the journals for monetary benefits, we are association of scientists and academia who focus only on supporting authors who want to publish their work. The articles published in our journal can be accessed online, all the articles will be archived for real time access.
Our journal system primarily aims to bring out the research talent and the works done by sciaentists, academia, engineers, practitioners, scholars, post graduate students of engineering and science. This journal aims to cover the scientific research in a broader sense and not publishing a niche area of research facilitating researchers from various verticals to publish their papers. It is also aimed to provide a platform for the researchers to publish in a shorter of time, enabling them to continue further All articles published are freely available to scientific researchers in the Government agencies,educators and the general public. We are taking serious efforts to promote our journal across the globe in various ways, we are sure that our journal will act as a scientific platform for all researchers to publish their works online.
Utilization of food processing waste by ThraustochytridsRuss Sam
1) The study evaluated the ability of the mangrove isolate Schizochytrium mangrovei KF6 to utilize various food wastes for growth and production of docosahexaenoic acid (DHA).
2) S. mangrovei grew well in a glucose yeast extract medium, producing the highest DHA yield of 3094 mg/L or 203 mg/g after 4 days.
3) The fungus was also able to grow on and utilize different food wastes including bread crusts, okara powder, and brewing grain waste to produce DHA, though in lower quantities than in the glucose medium.
This document describes a new method for quantifying poly(3-hydroxybutyrate) (PHB) in microbial cells using headspace solid-phase microextraction (SPME) coupled with gas chromatography. The method involves either methanolyzing or hydrolyzing PHB in samples to form methyl 3-hydroxybutyrate (Me-3-HB) or crotonic acid, respectively. These products are then extracted using SPME and analyzed by gas chromatography. The new SPME-based methods provide accurate results, are easier to perform than existing methods, and avoid use of hazardous chlorinated solvents. The document compares the new methods to the commonly used methanolysis/chloroform method and finds excellent agreement between all
Novel coumarin isoxazoline derivatives: Synthesis and study of antibacterial ...Ratnakaram Venkata Nadh
A highly efficient and mild protocol for the syntheses of ethyl-3-
[7-benzyloxy-4-methyl-2-oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-
isoxazole carboxylates and ethyl-3-[7-benzyloxy-3-chloro-4-methyl-2-
oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-isoxazole carboxylates in
good yields via [3 þ 2] cycloaddition of in situ–generated nitrile
oxides from 7-benzyloxy-4-methyl-coumarin hydroxymoylchlorides
and 7-benzyloxy-3-chloro-4-methyl-coumarin hydroxymoylchlorides
respectively with ethyl-3-aryl prop-2-enoate has been developed.
The new compounds are screened for antibacterial activity.
This document summarizes the chemical synthesis of 2-amino-4-heteroarylpyrimidines and related compounds for use as JNK1 inhibitors. Key steps include:
1) Microwave-induced SNAr reactions of primary amines with 2-methylsulfonylpyrimidines or 2-chloropyrimidines to access initial targets.
2) Elaboration of pendant piperidine functionality using silica-bound reagents in microwave reductive amination and amide bond formation.
3) Exploration of variations to the core pyrimidine scaffold and piperidine substitutions using efficient parallel synthesis methods.
Discovery-of-pyrimidyl-5-hydroxamic-acids-as-new-potent-histone-deacetylase-i...Peter ten Holte
This document describes the discovery of new potent histone deacetylase (HDAC) inhibitors containing a pyrimidyl-5-hydroxamic acid structure. A series of these compounds were prepared and tested for HDAC inhibitory activity and antiproliferative effects on cancer cells. The most potent compound contained an amino-2-pyrimidinyl linker and a pyridinyl moiety, inhibiting HDAC activity with an IC50 below 100 nM and reducing cancer cell proliferation in the low micromolar range. Replacing structural elements like the pyrimidinyl ring or changing the heterocyclic ring size generally resulted in lower enzymatic or antiproliferative potency. These results identify amino-2-py
The document describes the synthesis and characterization of new imidazole derivatives derived from D-erythroascorbic acid. D-erythroascorbic acid was modified through multi-step reactions to yield Schiff bases containing heterocyclic units like 1,3,4-oxadiazole and 1,3,4-thiadiazole. These Schiff bases were further derivatized to yield N-acyl, thiourea, and imidazole compounds. The structures of the synthesized compounds were characterized using techniques like elemental analysis, FTIR, NMR, and mass spectrometry. The compounds exhibited good antibacterial activity against Escherichia coli and Staphylococcus aureus.
Improved Stability of Formate Dehydrogenase by Coating with Didodecyldimethyl...researchinventy
Hydrophilic formate dehydrogenase (FDH) from candida boidinii was chemically modified by coating it with didodecyldimethylammonium bromide (DDAB). This coating changed the phase behavior of the enzyme, making it highly soluble in hydrophobic solvents and thereby offering the chance for biphasic enzyme recycling from hydrophilic substrates and products. Different coating procedures of FDH with DDAB were investigated and all proved suitable for efficient coating of the enzyme’s outer surface. A 50 mM Tris- (hydroxymethyl)-amminomethan (tris) buffer at pH 8 was chosen to make DDAB soluble and avoid aggregation. The reaction of NAD+ with uncoated and coated FDH to NADH and CO2 was monitored by UV-vis spectroscopy and kinetic parameters (rmax, Km, KI , EA) for the the FDH were determined. The coated enzyme resulted in a lower relative initial activity between 40-60% compared to the uncoated one. The stability of the coated enzyme (FDH*) was improved significantly and remained stable in long-term experiments, resulting in a deactivation rate kD smaller than 3% per day and a half-life time t1/2largerthan 23 days, while the deactivation rate of the uncoated enzyme was 260% per daywitha t1/2of 0.3 days. Both activation energies were similar, with 42 kJ mol-1 for the coated and 48 kJ mol-1 for the uncoated enzyme.This result suggests that there is not significant transport resistance originating from the DDAB coating layer. The reason for the significantly lower activity of the coated FDH probably stems from accumulation of formed CO2 in the coating layer, thereby preventing high equilibrium conversions
The document describes the synthesis of novel hydroxy naphthylchalcone compounds as potential inhibitors of the enzyme polyphenol oxidase (tyrosinase). Two of the synthesized compounds showed higher tyrosinase inhibitory activity than the positive control kojic acid. Kinetic analysis revealed the inhibition was reversible and competitive. Molecular docking studies confirmed the active inhibitors strongly interacted with residues in the active site of mushroom tyrosinase.
1) Novel compounds called O,O-diethyl 1-benzamido-2,2-biscarbamoylethanephosphonates were synthesized as substrates for HIV-1 protease (PR) to exploit activation of the phosphonate group.
2) One compound, O,O-diethyl 1-benzamido-2,2-bis[(1S)-N-(1-benzyl-2-hydroxyethyl)carbamoyl]ethanephosphonate, showed moderate anti-HIV activity in vitro. Its depsipeptide analogue inhibited HIV-1 PR with an IC50 of 31 μM.
3) The phosphonate group of these compounds was designed
Synthesis and characterization of resin copolymer derived from cardanol-furfu...ijceronline
International Journal of Computational Engineering Research (IJCER) is dedicated to protecting personal information and will make every reasonable effort to handle collected information appropriately. All information collected, as well as related requests, will be handled as carefully and efficiently as possible in accordance with IJCER standards for integrity and objectivity.
This study synthesized eight new fluorinated quinazolinone-sulphonamide hybrid compounds and evaluated their anticancer activity. One compound showed significant anticancer activity with low toxicity compared to the reference drug mitoxantrone. Biological assays also demonstrated moderate anticancer activity for the compounds compared to reference drugs. The compound with the best activity profile was identified for further evaluation as an anticancer agent.
1) The document reports on a computational and NMR study of a camphor-based chiral amino alcohol (2) and related compounds (1 and 3).
2) NMR analysis showed differences in chemical shifts between diastereotopic hydrogens H11a and H11b in compound 2, suggesting conformational restriction from an intramolecular hydrogen bond.
3) DFT calculations confirmed the most stable conformer of 2 features an intramolecular O-H-N hydrogen bond, restricting rotational mobility and accounting for the observed chemical shift differences between H11a and H11b.
The document summarizes the research goals and methods of Giuseppe Puzzo's PhD thesis on the production of biodegradable and biocompatible polymers for pharmaceutical applications. The research will explore using bacterial fermentation and microwave-assisted synthesis to obtain new polyhydroxyalkanoate polymers with improved yields, structures and properties compared to poly(3-hydroxybutyrate). Methods include using Pseudomonas aeruginosa to produce PHAs from long chain fatty acids and vegetable oils. New copolymers and terpolymers will also be synthesized using microwave-assisted transesterification reactions.
The document describes the carbon nanotube-gold nanohybrid (AuCNT) catalyzed N-formylation of various primary and secondary amines using aqueous formaldehyde. Key findings include:
1) AuCNT catalyzes the room temperature N-formylation of various primary and secondary amines with aqueous formaldehyde, affording formamides in excellent yields.
2) The reaction proceeds with low catalyst loading (0.34 mol%), excellent chemoselectivity, and recyclability of the AuCNT catalyst.
3) Control experiments confirm the AuCNT nanohybrid is the active catalytic species, and the reaction proceeds through a hemiaminal intermediate that is oxidized to the
This document describes a study that modified cassava starch with soybean oil maleate (SOMA) and used the modified starch as a filler in poly(lactic acid) (PLA) composites. SOMA was synthesized by grafting soybean oil with maleic anhydride, and then used to modify cassava starch, resulting in SOMA-g-STARCH. Various ratios of PLA and SOMA-g-STARCH were compounded and tested. The compatibility, morphology, thermal properties, and mechanical properties of the composites were characterized. The results showed that compositions with 90:10 and 80:20 ratios of PLA:SOMA-g-STARCH had the best compatibility, surface
Phytochemical investigation of the methanolic extract of Launaea intybacea yielded eleven compounds, which were characterized using NMR, mass spectrometry, and by comparison to reported data. The compounds showed antioxidant activity in DPPH radical scavenging assays and inhibitory effects against acetylcholinesterase, butyrylcholinesterase, and lipoxygenase enzymes. This is the first report of these bioactive compounds isolated from L. intybacea.
Chemistry of peptide (BPHARM,MPHARM,MSC,BSC)Shikha Popali
THE PRESENTATION DESCRIBING BOND FORMATION OF AMINO ACIDS AND PROTEINS AND COUPLING REAGENTS IN PEPTIDE SYNTHESIS FOLLOWED BY CARBODIMIDES, PHOSPHONIUM AND AMMONIUM SALTS.
This document summarizes a palladium-catalyzed method for fluorinating arylboronic acid derivatives. Key points:
- A Pd(II) complex is used as a precatalyst to catalyze the fluorination of various aryl trifluoroborates and other arylboron reagents.
- The reaction proceeds through a single-electron transfer pathway involving an isolated and characterized Pd(III) intermediate.
- A wide variety of functional groups are tolerated and the aryl fluoride products are obtained in good yields and purity.
- The reaction is operationally simple and scalable to the multigram level, providing a practical method for synthesizing aryl fluorides.
The document describes the synthesis and antimicrobial screening of some pyrazolyl heterocycles. Specifically, it details the synthesis of compounds 3, 4, 5, and 6 through various reactions between 1-phenyl-3-(2-pyridyl)-1H-pyrazole-4-carboxaldehyde and acetophenone derivatives. Compound 3 undergo oxidative cyclization to form compounds 4 and 5. Compound 3 also undergoes condensation with hydrazine to form compound 6. The structures of compounds 3, 4, 5, and 6 were characterized using spectral methods. These compounds were then tested for antimicrobial activity against various bacteria and fungi, with some compounds showing moderate to good activity.
Degradation of PLA at Mesophillic and thermophillic conditionsSabahat Ali
This document summarizes research on the degradation of polylactic acid (PLA) under mesophilic and thermophilic conditions. Key findings include:
1) Mesophilic bacteria like Pseudomonas geniculata and Streptomyces pavanii were found to degrade PLA films at 25-40°C, with S. pavanii showing higher degradation.
2) PLA degradation was higher under thermophilic (41-122°C) conditions compared to mesophilic (20-45°C) due to PLA-degrading enzymes working best at high temperatures. Up to 90% of PLA weight loss was observed at thermophilic temperatures within 12 days of
International Journal of Engineering Research and Applications (IJERA) is a team of researchers not publication services or private publications running the journals for monetary benefits, we are association of scientists and academia who focus only on supporting authors who want to publish their work. The articles published in our journal can be accessed online, all the articles will be archived for real time access.
Our journal system primarily aims to bring out the research talent and the works done by sciaentists, academia, engineers, practitioners, scholars, post graduate students of engineering and science. This journal aims to cover the scientific research in a broader sense and not publishing a niche area of research facilitating researchers from various verticals to publish their papers. It is also aimed to provide a platform for the researchers to publish in a shorter of time, enabling them to continue further All articles published are freely available to scientific researchers in the Government agencies,educators and the general public. We are taking serious efforts to promote our journal across the globe in various ways, we are sure that our journal will act as a scientific platform for all researchers to publish their works online.
Utilization of food processing waste by ThraustochytridsRuss Sam
1) The study evaluated the ability of the mangrove isolate Schizochytrium mangrovei KF6 to utilize various food wastes for growth and production of docosahexaenoic acid (DHA).
2) S. mangrovei grew well in a glucose yeast extract medium, producing the highest DHA yield of 3094 mg/L or 203 mg/g after 4 days.
3) The fungus was also able to grow on and utilize different food wastes including bread crusts, okara powder, and brewing grain waste to produce DHA, though in lower quantities than in the glucose medium.
This document describes a new method for quantifying poly(3-hydroxybutyrate) (PHB) in microbial cells using headspace solid-phase microextraction (SPME) coupled with gas chromatography. The method involves either methanolyzing or hydrolyzing PHB in samples to form methyl 3-hydroxybutyrate (Me-3-HB) or crotonic acid, respectively. These products are then extracted using SPME and analyzed by gas chromatography. The new SPME-based methods provide accurate results, are easier to perform than existing methods, and avoid use of hazardous chlorinated solvents. The document compares the new methods to the commonly used methanolysis/chloroform method and finds excellent agreement between all
Novel coumarin isoxazoline derivatives: Synthesis and study of antibacterial ...Ratnakaram Venkata Nadh
A highly efficient and mild protocol for the syntheses of ethyl-3-
[7-benzyloxy-4-methyl-2-oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-
isoxazole carboxylates and ethyl-3-[7-benzyloxy-3-chloro-4-methyl-2-
oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-isoxazole carboxylates in
good yields via [3 þ 2] cycloaddition of in situ–generated nitrile
oxides from 7-benzyloxy-4-methyl-coumarin hydroxymoylchlorides
and 7-benzyloxy-3-chloro-4-methyl-coumarin hydroxymoylchlorides
respectively with ethyl-3-aryl prop-2-enoate has been developed.
The new compounds are screened for antibacterial activity.
This document summarizes the chemical synthesis of 2-amino-4-heteroarylpyrimidines and related compounds for use as JNK1 inhibitors. Key steps include:
1) Microwave-induced SNAr reactions of primary amines with 2-methylsulfonylpyrimidines or 2-chloropyrimidines to access initial targets.
2) Elaboration of pendant piperidine functionality using silica-bound reagents in microwave reductive amination and amide bond formation.
3) Exploration of variations to the core pyrimidine scaffold and piperidine substitutions using efficient parallel synthesis methods.
The document provides information for a Kindergarten open house at an international school. It outlines the agenda for the evening which includes introductions of teachers and their families, an overview of the curriculum and philosophy, and specialists the students will have. It discusses the Kindergarten team, units of inquiry, dispositions, transdisciplinary skills, and areas of development. It also covers communication, literacy and math components, encouraging qualities in students, and housekeeping items.
This document provides a summary of language learning tasks designed for a kindergarten class in Colombia. The objectives are to develop intercultural awareness through folk tales, increase fluency through songs and projects, and use the target language. Tasks include building vocabulary about the sun and moon, previewing and reading the story "I Am La Luna", singing and acting out a song, using target language structures, and drawing and collage projects. Some aspects went well, like student engagement, but others were challenging, such as pronunciation and generating target language. Improvements would focus on repetitive practice and dividing large groups.
The document discusses the benefits of exercise for mental health. Regular physical activity can help reduce anxiety and depression and improve mood and cognitive function. Exercise causes chemical changes in the brain that may help protect against mental illness and improve symptoms.
The children in the play area began cooking pretend foods and decided to turn their kitchen into a restaurant. They took on roles like cooks, waiters and customers. The restaurant they named was the "Spicy Food Restaurant" where only spicy foods like sausages and bread with chillies were served. The children made signs, menus, and props to enhance their role playing. They also visited a real cafeteria to observe restaurant roles and setups before making their own pancakes in the play restaurant.
This document summarizes the development of efficient protocols for the synthesis of 1,2,3,4-tetrahydroisoquinolin-1-ones. Specifically, it describes:
1) A concise 5-step synthesis of a key phenol intermediate from 4-benzyloxybenzaldehyde.
2) Three parallel arrays utilizing the phenol intermediate to explore structure-activity relationships, including a Mitsunobu reaction, copper-catalyzed arylation, and nucleophilic aromatic substitution.
3) The need to further optimize the key 5-step synthesis to enable more diverse SAR exploration of the chemical series.
This document describes an efficient synthetic route to produce ethyl 2-aryl-4-hydroxy-1,3(2H,4H)-dioxoisoquinoline-4-carboxylates, which are known to inhibit auxin transport in plants and have plant growth regulating properties. The synthesis involves condensing anilines with homophthalic anhydride to form intermediates, which are then modified through various steps including acylation, enolate formation, alcoholysis, and oxygenation to produce the target compounds. Several of the target compounds showed potent auxin transport inhibition and plant growth regulating activity in tests.
This document describes research on improving the purification of a cytoplasmic hydrogenase enzyme (SHI) from the hyperthermophilic archaeon Pyrococcus furiosus. Key points:
1) A polyhistidine tag was added to SHI allowing single-step purification via affinity chromatography, yielding a 50-fold increase in enzyme compared to the native multi-step process.
2) In addition to the full tetrameric SHI enzyme, a trimeric intermediate form lacking the catalytic subunit was also purified. This intermediate retained NADPH oxidation activity, confirming the proposed SHI maturation pathway.
3) Overexpression of the tagged SHI in P. furiosus and its high-yield
1) Torulaspora delbrueckii was used to biotransform 30g of benzaldehyde into 22.9g of L-phenylacetylcarbinol (L-PAC) in a 5L stirred tank reactor.
2) L-PAC was then converted to ephedrine in two microwave-assisted steps: first L-PAC was transformed to 2-(methylimino)-1-phenyl-1-propanol, then this was reduced to ephedrine.
3) The identities of the products were confirmed using 1H NMR and FT-IR analysis, demonstrating a facile synthesis of ephedrine from benzaldehyde using biocatalysis and microwave-assisted chemistry.
This document summarizes research into the HemQ enzyme from Staphylococcus aureus, which catalyzes the final step in the biosynthesis of heme b in some bacteria. The researchers sought to identify reaction intermediates on the pathway from coproheme III to heme b. They found that the first decarboxylation rapidly produces harderoheme III as an intermediate, while the second decarboxylation controls the overall rate. Both harderoheme isomers III and IV reacted when bound to HemQ. While H2O2 is the presumed biological oxidant, peracetic acid could also drive the reaction, suggesting possible iron-mediated reaction mechanisms.
This document describes the design, synthesis, and evaluation of novel thrombin inhibitors incorporating P3-P4 lactam sulfonamide moieties. The inhibitors were designed to exploit interactions with thrombin's S2 and S3 sites to improve selectivity over related serine proteases. A series of 5-7 membered lactam rings were synthesized and incorporated a P1 argininal group. X-ray crystallography of one inhibitor bound to thrombin confirmed the predicted binding mode. In vitro testing showed several inhibitors had low nanomolar IC50 values against thrombin and good selectivity over trypsin and factor Xa. Overall, the lactam sulfonamides represent a new class of orally bioavailable
This document discusses the role of dehydration catalyst acid properties on one-step DME synthesis using physical mixtures. It summarizes the results of experiments testing various solid acid catalysts for methanol dehydration and one-step DME synthesis from syngas. The main findings are:
1) Catalyst acidity, determined by pyridine adsorption IR spectroscopy, affected activity for methanol dehydration, with stronger acid sites correlating to higher rates.
2) In one-step DME synthesis, addition of an acid catalyst to the methanol synthesis catalyst strongly increased CO conversion.
3) The determining rate of direct DME synthesis appears to be controlled by the acid properties, specifically the strength
This document summarizes the one-pot synthesis of tri- and tetra-substituted imidazoles using 3-picolinic acid as an organocatalyst. A variety of substituted imidazoles were obtained in good yields under mild conditions. The method provides advantages such as short reaction times, high yields, and an easy experimental procedure. The author concludes that this simple method could serve as an effective approach for synthesizing highly substituted imidazole systems.
This document summarizes an investigation into using an enzymatic catalyst to catalyze the esterification of telechelic polymers, specifically poly(butadiene) and poly(ethylene oxide), in order to generate macromolecular chain transfer agents (CTAs) for synthesizing block copolymers. Experiments were conducted to esterify a hydroxyl-functionalized poly(butadiene) with a carboxylic acid functional RAFT agent using Novozym 435 catalyst. NMR and GPC analysis indicated some esterification occurred, though the molecular weight increase was small. More investigation is needed to optimize the reaction conditions to fully synthesize the macromolecular CTA. The goal is to develop a mild method to
This document describes a one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones using 4-nitrophthalic acid as a catalyst under solvent-free conditions. Various aldehydes, 1,3-dicarbonyl compounds, and urea or thiourea reacted smoothly in good to excellent yields. The reaction conditions were optimized to use a 2 mol% catalyst loading at 90°C for 30 minutes. 4-Nitrophthalic acid proved to be an effective and inexpensive catalyst for this Biginelli reaction, providing advantages over other reported catalysts such as higher yields, simpler workup, and an environmentally friendly procedure. The products were characterized
1. A new RP-HPLC method was developed and validated for the estimation of Clopidogrel bisulphate in bulk drug and pharmaceutical formulations.
2. The method involved using a C18 column, mobile phase of acetonitrile and phosphate buffer at a ratio of 60:40, and detection at 224 nm.
3. The method was found to be linear, precise, accurate, specific, robust and suitable for the routine analysis of Clopidogrel bisulphate in quality control.
Method Development and Validation of Clopidogrel Bisulphate by Reverse Phase-...SriramNagarajan15
A new, simple sensitive, rapid, accurate and precise RP-HPLC method was developed for the estimation of Clopidogrel bisulphate in bulk drug and pharmaceutical formulation. Clopidogrel bisulphate was chromatographed on a reverse phase C18column (150 mm x 4.5 mm, i.d 5μm) in a mobile phase consisting of acetonitrile and phosphate buffer (pH: 3.0) in the ratio of 60:40 % v/v. The mobile phase was pumped at a flow rate of 1 ml/min with detection at 224 nm. The detector response was linear in the concentration of 50-150 μg /ml. The limit of detection and limit of quantitation was found to be 1.3 and 4.2 µg/ml, respectively. The intra and inter day variation was found to be less than 2%. The mean recovery of the drug from the solution was 99.79%. The proposed method is simple, fast, accurate, precise and reproducible hence, it can be applied for routine quality control analysis of Clopidogrel bisulphate in bulk drug and pharmaceutical formulation. Key words: Clopidogrel bisulphate, RP-HPLC, Validation, Accuracy, Precision.
Method Development and Validation of Clopidogrel Bisulphate by Reverse Phase-...SriramNagarajan15
A new, simple sensitive, rapid, accurate and precise RP-HPLC method was developed for the estimation of Clopidogrel bisulphate in bulk drug and pharmaceutical formulation. Clopidogrel bisulphate was chromatographed on a reverse phase C18column (150 mm x 4.5 mm, i.d 5μm) in a mobile phase consisting of acetonitrile and phosphate buffer (pH: 3.0) in the ratio of 60:40 % v/v. The mobile phase was pumped at a flow rate of 1 ml/min with detection at 224 nm. The detector response was linear in the concentration of 50-150 μg /ml. The limit of detection and limit of quantitation was found to be 1.3 and 4.2 µg/ml, respectively. The intra and inter day variation was found to be less than 2%. The mean recovery of the drug from the solution was 99.79%. The proposed method is simple, fast, accurate, precise and reproducible hence, it can be applied for routine quality control analysis of Clopidogrel bisulphate in bulk drug and pharmaceutical formulation. Key words: Clopidogrel bisulphate, RP-HPLC, Validation, Accuracy, Precision.
1. A new RP-HPLC method was developed and validated for the estimation of Clopidogrel bisulphate in bulk drug and pharmaceutical formulations.
2. The method involved using a C18 column, mobile phase of acetonitrile and phosphate buffer at a ratio of 60:40, and detection at 224 nm.
3. The method was found to be linear, precise, accurate, specific, robust and suitable for the routine analysis of Clopidogrel bisulphate in quality control labs.
Solution And Solid Phase Synthesis Publicationadotse
This document describes the solution- and solid-phase synthesis of peptide-substituted thiazolidinediones as potential ligands for peroxisome proliferator-activated receptors (PPARs). Initial studies focused on the low-yielding solution-phase synthesis of two target compounds. Improved yields were obtained using solid-phase synthesis and protecting the thiazolidinedione nitrogen. A small library of nine resin-bound peptide-substituted thiazolidinediones was then synthesized to examine structural features that facilitate PPAR binding and identify new PPAR activators/inhibitors.
This document describes the development of an improved synthesis for a 2,3-disubstituted 4,7-diazaindole compound. Key improvements included using an iron-catalyzed cross-coupling reaction to prepare 2-propylpyrazine in over 60% yield, avoiding issues with the original ethylation process. Additionally, a modified Chichibabin cyclization was developed where methylation of the ketone occurred prior to cyclization, improving yields and purity. The optimized processes were successfully scaled to the pilot plant level to produce kilogram quantities of the target molecule.
This document discusses the optimization of supercritical carbon dioxide extraction (SCE) conditions for extracting c-linolenic acid (GLA) from Spirulina platensis. Response surface methodology (RSM) was used to optimize three extraction parameters: pressure, time, and ethanol concentration. SCE with ethanol as a co-solvent was found to significantly increase GLA yields compared to SCE alone. RSM analysis identified a pressure of 400 bars, extraction time of 1 hour, and minimum ethanol concentration of 13.7 ml per 16 g of biomass as optimal conditions for extracting 102% of the GLA content compared to conventional solvent extraction.
A graphene/hemin hybrid material as an efficient green catalyst for stereosel...Pawan Kumar
The document describes a study investigating a hemin/graphene composite catalyst for the stereoselective olefination of aldehydes using ethyl diazoacetate.
1) A hemin/graphene oxide composite was prepared and found to efficiently catalyze the olefination of aromatic aldehydes with high (E)-selectivity, showing its potential as a heterogeneous catalyst.
2) The catalyst could be easily recovered from the reaction mixture and reused several times without significant loss of activity or selectivity.
3) A variety of substituted aromatic and alicyclic aldehydes underwent olefination using this catalyst, providing moderate to high product yields and stereoselectivity.
The document summarizes the production and characterization of glucose and ethanol from sugarcane bagasse. It discusses:
1) Pretreatment methods for bagasse including physico-chemical, chemical, biological and hydrolysis to separate lignin and increase accessibility of cellulose.
2) Production of glucose by hydrolyzing cellulose and production of ethanol through fermentation processes like SSF, SHF, DMC and SSCF.
3) Characterization methods for analyzing glucose concentration, sugar conversion, crystallinity, and ethanol yield through techniques like HPLC, SEM and UV spectrophotometry.
The conclusion recommends dilute acid pretreatment and enzymatic hydrolysis as they require fewer steps and
How to Make a Field Mandatory in Odoo 17Celine George
In Odoo, making a field required can be done through both Python code and XML views. When you set the required attribute to True in Python code, it makes the field required across all views where it's used. Conversely, when you set the required attribute in XML views, it makes the field required only in the context of that particular view.
हिंदी वर्णमाला पीपीटी, hindi alphabet PPT presentation, hindi varnamala PPT, Hindi Varnamala pdf, हिंदी स्वर, हिंदी व्यंजन, sikhiye hindi varnmala, dr. mulla adam ali, hindi language and literature, hindi alphabet with drawing, hindi alphabet pdf, hindi varnamala for childrens, hindi language, hindi varnamala practice for kids, https://www.drmullaadamali.com
Walmart Business+ and Spark Good for Nonprofits.pdfTechSoup
"Learn about all the ways Walmart supports nonprofit organizations.
You will hear from Liz Willett, the Head of Nonprofits, and hear about what Walmart is doing to help nonprofits, including Walmart Business and Spark Good. Walmart Business+ is a new offer for nonprofits that offers discounts and also streamlines nonprofits order and expense tracking, saving time and money.
The webinar may also give some examples on how nonprofits can best leverage Walmart Business+.
The event will cover the following::
Walmart Business + (https://business.walmart.com/plus) is a new shopping experience for nonprofits, schools, and local business customers that connects an exclusive online shopping experience to stores. Benefits include free delivery and shipping, a 'Spend Analytics” feature, special discounts, deals and tax-exempt shopping.
Special TechSoup offer for a free 180 days membership, and up to $150 in discounts on eligible orders.
Spark Good (walmart.com/sparkgood) is a charitable platform that enables nonprofits to receive donations directly from customers and associates.
Answers about how you can do more with Walmart!"
it describes the bony anatomy including the femoral head , acetabulum, labrum . also discusses the capsule , ligaments . muscle that act on the hip joint and the range of motion are outlined. factors affecting hip joint stability and weight transmission through the joint are summarized.
Leveraging Generative AI to Drive Nonprofit InnovationTechSoup
In this webinar, participants learned how to utilize Generative AI to streamline operations and elevate member engagement. Amazon Web Service experts provided a customer specific use cases and dived into low/no-code tools that are quick and easy to deploy through Amazon Web Service (AWS.)
How to Setup Warehouse & Location in Odoo 17 InventoryCeline George
In this slide, we'll explore how to set up warehouses and locations in Odoo 17 Inventory. This will help us manage our stock effectively, track inventory levels, and streamline warehouse operations.
Temple of Asclepius in Thrace. Excavation resultsKrassimira Luka
The temple and the sanctuary around were dedicated to Asklepios Zmidrenus. This name has been known since 1875 when an inscription dedicated to him was discovered in Rome. The inscription is dated in 227 AD and was left by soldiers originating from the city of Philippopolis (modern Plovdiv).
Gender and Mental Health - Counselling and Family Therapy Applications and In...PsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Beyond Degrees - Empowering the Workforce in the Context of Skills-First.pptxEduSkills OECD
Iván Bornacelly, Policy Analyst at the OECD Centre for Skills, OECD, presents at the webinar 'Tackling job market gaps with a skills-first approach' on 12 June 2024
1. This article appeared in a journal published by Elsevier. The attached
copy is furnished to the author for internal non-commercial research
and education use, including for instruction at the authors institution
and sharing with colleagues.
Other uses, including reproduction and distribution, or selling or
licensing copies, or posting to personal, institutional or third party
websites are prohibited.
In most cases authors are permitted to post their version of the
article (e.g. in Word or Tex form) to their personal website or
institutional repository. Authors requiring further information
regarding Elsevier’s archiving and manuscript policies are
encouraged to visit:
http://www.elsevier.com/copyright
2. Author's personal copy
Chemically-enabled synthesis of 1,2,3,4-tetrahydroisoquinolin-1-ones
Paul S. Humphries *, Gayatri Balan, Bruce M. Bechle, Edward L. Conn, Kenneth J. Dirico, Yu Hui,
Robert M. Oliver, James A. Southers, Xiaojing Yang
Pfizer Global R&D, CVMED Chemistry, Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
Article history:
Received 5 February 2009
Accepted 20 February 2009
Available online 25 February 2009
a b s t r a c t
We have developed a number of efficient protocols for the facile synthesis of 1,2,3,4-tetrahydroisoquin-
olin-1-ones. This synthetic methodology allowed concise and efficient exploration of the SAR in all areas
of the molecule. A number of these methods proved to be versatile, efficient and amenable to parallel
synthesis.
Ó 2009 Elsevier Ltd. All rights reserved.
G protein-coupled receptor 40 (GPR40) belongs to a family of
fatty acid (FA) binding GPCRs, which include GPR40, GPR41,
GPR43, and GPR120.1
GPR41 and GPR43 are activated by short-
chain FAs, GPR40 is activated by medium- and long-chain FAs,
and GPR120 is activated by long-chain FAs.2
GPR40 is highly ex-
pressed in pancreatic b-cells and insulin-secreting cell lines.
GPR40-deficient b-cells secrete less insulin in response to FAs,
and loss of GPR40 protects mice from obesity-induced hyper-insu-
linemia, hyperglycemia, and glucose intolerance. Conversely, over-
expression of GPR40 in b-cells of mice leads to impaired b-cell
function, hyperinsulinemia, and diabetes.3
These results suggest
that GPR40 plays an important role in linking obesity and type 2
diabetes.
As part of an ongoing GPR40 drug discovery program in our lab-
oratories, compounds 1 and 2 were identified from high-through-
put screening (HTS) and possessed attractive pharmacological
properties as well as structural features amenable to optimization
by rapid parallel synthesis (Fig. 1).
We initially wanted to explore the SAR of the terminal cyclo-
hexyl and phenyl moieties of 1 and 2. In order to do this in an effi-
cient manner, we required a concise synthesis of phenol
intermediate 7. This intermediate was accessed in a straightfor-
ward fashion following the five step protocol below (Scheme 1).4
4-Benxyloxybenzaldehyde 3 was condensed with propylamine to
afford imine 4 in excellent yield. Treatment of imine 4 with hom-
ophthalic anhydride resulted in the formation of cis-lactam 5 in
moderate yield along with minor amounts of trans-lactam 6.5
The thermodynamically less stable isomer 5 could be epimerized
under acidic conditions, resulting in the exclusive formation of
trans-lactam 6 in excellent yield.6
Esterification of acid 6 with iodo-
methane afforded the intermediate methyl ester, which was subse-
quently debenzylated utilizing boron tribromide to yield the
required phenol intermediate 7.7
Our first parallel chemistry effort required a Mitsunobu reaction
between phenol 7 and a variety of alkyl alcohols (Scheme 2).8
This
reaction was attempted utilizing polymer-supported triphenyl-
phosphine, but with no success.9
It was also found that DMF was
required as a co-solvent, due to the poor solubility of template 7
in THF alone. Diisopropyl azodicarboxylate (DIAD) was found to
be optimal when compared with DEAD, DMAD and PPh3CN. The
resulting products 8 were taken on crude into the ensuing sapon-
ification reaction to afford the required acids 9. In singleton exper-
iments, the crude acids 9 were subjected to an SPE ‘catch and
release’ work-up with SAX cartridges.10
This work-up allowed for
the products to be isolated in pure form, free from any residual
DMF solvent or triphenylphosphine oxide by-products. Utilizing
this procedure, hit compound 1 was obtained in a 75% yield over
the two steps. A small array ($185) of diverse alkyl alcohols were
subjected to this synthetic sequence (exchanging a base-acid wash
for the SPE work-up) with a 53% success rate.
Our next parallel array required a method for obtaining diaryl
ethers 11 from phenol 7 (Scheme 3). Utilizing elegant methodology
developed in the Evans laboratories, copper-promoted arylation of
phenol 7 was carried out with a diverse set of arylboronic acids to
yield required products 10.11
Once again, the resulting products 10
were taken on crude into the saponification reaction to afford the
required acids 11. Utilizing this methodology, hit compound 2
was obtained in a 71% yield over the two steps. A small array
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.157
* Corresponding author. Tel.: +1 860 705 0559.
E-mail address: phumphri@gmail.com (P.S. Humphries).
Figure 1. Initial hits 1 and 2 from high-throughput screening.
Tetrahedron Letters 50 (2009) 2140–2143
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
3. Author's personal copy
($110) of diverse arylboronic acids were subjected to this syn-
thetic sequence with a 85% success rate.
The final parallel library to utilize phenol 7 involved SNAr reac-
tions with 2-bromoheteroaryls to obtain the required products 13
(Scheme 4) This step was optimized under a variety of conditions,
utilizing 2-bromopyridine as our partner of choice. Ullman-type
coupling of phenol 7, in the presence of catalyst 14, afforded 12,
which was saponified to give 13 (where HetAr = 2-pyridyl) in
85% yield.12
A small array ($20) of 2-bromoheteroaryls were sub-
jected to this synthetic sequence with a 100% success rate.
The next endeavor required more diverse SAR exploration of the
chemical series (Scheme 5). To achieve this undertaking, we
needed to optimize the chemistry in Scheme 1 in order to allow
for it to be utilized in a number of parallel arrays. Two of the most
immediate challenges were the solubility of the reagents/products
in the existing solvents and the requirement for Dean–Stark condi-
tions on formation of the imine (e.g., 4) Solutions to these chal-
lenges involved utilizing conditions similar to reductive
aminations by choosing methanol as the solvent of choice for imine
formation. The poor solubility of homophthalic anhydride necessi-
tated the use of DMF as the solvent for the formation of the cis- and
Scheme 1. Reagents and conditions: (a) C3H7NH2, 4 ÅA
0
MS, CH2Cl2, rt, 16 h, 100%; (b) homophthalic anhydride, CH3CN, 60 °C, 16 h, 50%; (c) AcOH, 120 °C, 16 h, 95%; (d) MeI,
K2CO3, Me2CO, rt, 16 h, 90%; (e) BBr3, CH2Cl2, rt, 16 h, 90%.
Scheme 2. Reagents and conditions: (a) ROH, PPh3, DIAD, THF, DMF, 80 °C, 16 h; (b)
LiOH, THF, MeOH, H2O, rt, 16 h.
Scheme 3. Reagents and conditions: (a) ArB(OH)2, Cu(OAc)2, Et3 N, Py, 1,2-DCE,
DMF, 4 ÅA
0
MS, air, 50 °C, 16 h; (b) LiOH, THF, MeOH, H2O, rt, 16 h.
Scheme 4. Reagents and conditions: (a) 2-Br-HetAr, CuI (cat.), 14 (cat.), K3PO4,
MeCN, 100 °C, 16 h; (b) LiOH, THF, MeOH, H2O, rt, 16 h.
P. S. Humphries et al. / Tetrahedron Letters 50 (2009) 2140–2143 2141
4. Author's personal copy
trans-lactams (e.g., 5 and 6). The resulting mixture was converted
to all trans-lactam (e.g., 6) by subjection to strong base, rather than
the original acidic conditions. Two libraries were executed utilizing
this synthetic sequence with a success rate of 67% (varying R2) and
71% (varying R1).
Diversification of the left-hand phenyl ring required an efficient
synthesis of diverse homophthalic anhydrides. A representative
synthetic scheme from this exercise is shown below (Scheme 6).
Acid 18 was subjected to copper-catalyzed coupling with the anion
of dimethyl malonate to afford diester 19, which was taken on
crude. Decarboxylation of 19 was achieved under acidic conditions
to yield required bis-acid 20 in moderate yield over two steps.13
Dehydrative cyclization of 20, utilizing 22,14
resulting in the effi-
cient formation of anhydride 21 in excellent yield.15
Attempts to
achieve this transformation utilizing acetyl chloride,16
acetic anhy-
dride,17
or thionyl chloride18
resulted in lower yields. A number of
other substituted anhydrides were also synthesized in a similar
fashion.
SAR exploration also required us to synthesize the a-methyl-
carboxylic acid 25 and it’s diastereomer 30. Intermediate ester 23
(obtained via Scheme 5) was deprotonated and the resulting eno-
late was subjected to iodomethane to afford the single diastereo-
mer 24 in 92% yield. Relative stereochemistry was confirmed by
the observed NOE (2.5%) between the C-3 methine and the C-4
methyl group. This facial selectivity is also in line with that re-
ported by others.19
Saponification of 24 yielded required acid 25
in a straightforward fashion (Scheme 7).
Due to the complete facial selectivity in the formation of 24, ac-
cess to diastereomer 30 required the synthesis of anyhdride 29
(Scheme 8). Esterification of bis-acid 26 afforded bis-ester 27.
Deprotonation of 27, treatment of the resulting enolate with iodo-
methane, followed by saponification afforded 28 in good yield.20
Dehydrative cyclization, utilizing 22, occurred in moderate yield
to form required anyhdride 29.
Formation of the imine from 4-phenoxybenzaldehyde and pro-
pylamine, followed by treatment with anyhdride 29 afforded a mix-
ture of two diastereomers 30 and 25. 1
H NMR analysis of the crude
reaction mixture revealed a ratio of 1.4–1.7:1 favoring diastereomer
30, which was isolated in 25% yield. Diastereomer 25 was found to be
Scheme 6. Reagents and conditions: (a) NaH, CuBr2 (cat.), CH2(CO2Me)2, 70 °C, 2 h;
(b) HCl, 110 °C C, 48 h, 50% (two steps); (c) 22, CH2Cl2, rt, 1 h, 93%.
Scheme 7. Reagents and conditions: (a) LDA, THF, À78 °C, MeI, 20 min, 92%; (b)
LiOH, THF, MeOH, H2O, rt, 16 h, 95%.
Scheme 8. Reagents and conditions: (a) Me2SO4, K2CO3, 1,4-dioxane, 70 °C, 16 h,
87%; (b) LDA, THF, À78 °C, MeI, HMPA, 30 min, 75%; (c) LiOH, 1,4-dioxane, MeOH,
H2O, 50 °C, 16 h, 62%; (d) 22, CH2Cl2, rt, 1 h, 52%.
Scheme 9. Reagents and conditions: (a) 4-phenoxybenzaldehyde, propylamine,
MeOH, rt, 16 h then 29, DMF, rt, 16 h, 30 = 25% and 25 = 17%.
Scheme 5. Reagents and conditions: (a) MeOH, rt, 16 h then homophthalic
anhydride, DMF, rt, 16 h then 1 N aq NaOH, rt, 16 h.
2142 P. S. Humphries et al. / Tetrahedron Letters 50 (2009) 2140–2143
5. Author's personal copy
identical to that obtained by the method in Scheme 7. Unlike 25, dia-
stereomer 30 showed no observable NOE between the C-3 methine
and the C-4 methyl group (Scheme 9).
In summary, we have developed a number of efficient protocols
for the facile synthesis of 1,2,3,4-tetrahydroisoquinolin-1-ones.
This synthetic methodology allowed concise and efficient explora-
tion of the SAR in all areas of the molecule. A number of these
methods proved to be versatile, efficient and amenable to parallel
synthesis.
Acknowledgements
The authors would like to thank Chris Limberakis for stimulat-
ing discussions and feedback on this manuscript.
References and notes
1. (a) Hirasawa, A.; Hara, T.; Katsuma, S.; Adachi, T.; Tsujimoto, G. Biol. Pharm. Bull.
2008, 31, 1847; (b) Bernard, J. Curr. Opin. Inv. Drugs 2008, 9, 1078; (c) Telvekar,
V. N.; Kundaikar, H. S. Curr. Drug Targets 2008, 9, 899; (d) Costanzi, S.;
Neumann, S.; Gershengorn, M. C. J. Biol. Chem. 2008, 283, 16269; (e) Winzell, M.
S.; Ahren, B. Pharmacol. Ther. 2007, 116, 437; (f) Rayasam, G. V.; Tulasi, V. K.;
Davis, J. A.; Bansal, V. S. Exp. Opin. Ther. Targets 2007, 11, 661.
2. (a) Briscoe, C. P.; Tadayyon, M.; Andrews, J. L.; Benson, W. G.; Chambers, J. K.;
Eilert, M. M.; Ellis, C.; Elshourbagy, N. A.; Goetz, A. S.; Minnick, D. T.; Murdock,
P. R.; Sauls, H. R.; Shabon, U.; Spinage, L. D.; Strum, J. C.; Szekeres, P. G.; Tan, K.
B.; Way, J. M.; Ignar, D. M.; Wilson, S.; Muir, A. I. J. Biol. Chem. 2003, 278, 11303;
(b) Itoh, Y.; Kawamata, Y.; Harada, M.; Kobayashi, M.; Fujii, R.; Fukusumi, S.;
Ogi, K.; Hosoya, M.; Tanaka, Y.; Uejima, H.; Tanaka, H.; Maruyama, M.; Satoh,
R.; Okubo, S.; Kizawa, H.; Komatsu, H.; Matsumura, F.; Noguchi, Y.; Shinohara,
T.; Hinuma, S.; Fujisawa, Y.; Fujino, M. Nature 2003, 422, 173; (c) Brown, A. J.;
Goldsworthy, S. M.; Barnes, A. A.; Eilert, M. M.; Tcheang, L.; Daniels, D.; Muir, A.
I.; Wigglesworth, M. J.; Kinghorn, I.; Fraser, N. J.; Pike, N. B.; Strum, J. C.;
Steplewski, K. M.; Murdock, P. R.; Holder, J. C.; Marshall, F. H.; Szekeres, P. G.;
Wilson, S.; Ignar, D. M.; Foord, S. M.; Wise, A.; Dowell, S. J. J. Biol. Chem. 2003,
278, 11312.
3. Steneberg, P.; Rubins, N.; Bartoov-Shifman, R.; Walker, M. D.; Edlund, H. Cell
Metab. 2005, 1, 245.
4. All new compounds were characterized by full spectroscopic data, yields refer
to chromatographed material with purity >95%.
5. (a) Ryckebusch, A.; Garcin, D.; Lansiaux, A.; Goossens, J.-F.; Baldeyrou, B.;
Houssin, R.; Bailly, C.; Henichart, J.-P. J. Med. Chem. 2008, 51, 3617; (b) Morrell,
A.; Placzek, M.; Parmley, S.; Antony, S.; Dexheimer, T. S.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2007, 50, 4419; (c) Ng, P. Y.; Tang, Y.; Knosp, W.
M.; Stadler, H. S.; Shaw, J. T. Angew. Chem., Int. Ed. 2007, 46, 5352; (d) Morrell,
A.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. J. Med. Chem. 2006, 49,
7740.
6. (a) Cushman, M.; Gentry, J.; Dekow, F. J. Org. Chem. 1977, 42, 1111; (b)
Cushman, M.; Mohan, P. Tetrahedron Lett. 1985, 26, 4563.
7. Paliakov, E.; Strekowski, L. Tetrahedron Lett. 2004, 45, 4093.
8. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380; (b)
Mitsunobu, O. Synthesis 1981, 1; (c) Hughes, D. L. Org. React. 1992, 42, 335; (d)
Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127.
9. Humphries, P. S.; Do, Q.-Q. T.; Wilhite, D. M. Beilstein J. Org. Chem. 2006, 2, 21.
10. Isolute SAX cartridges were purchased from Biotage AB (www.biotage.com).
11. (a) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937; (b)
Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3, 1029.
12. Cristau, H.-J.; Cellier, P. P.; Hamada, S.; Spindler, J.-F.; Taillefer, M. Org. Lett.
2004, 6, 913.
13. Alcaraz, L.; Furber, M.; Purdie, M.; Springthorpe, B. WO 2003/068743 A1, 2003;
Chem. Abstr. 2003, 139, 197375.
14. Evans, D. A.; Janey, J. M. Org. Lett. 2001, 3, 2125.
15. Lio, K.; Ramesh, N. G.; Okajima, A.; Higuchi, K.; Fujioka, H.; Akai, S.; Kita, Y. J.
Org. Chem. 2000, 65, 89.
16. (a) Tsou, H.-R.; Otteng, M.; Tran, T.; Floyd, M. B.; Reich, M.; Birnberg, G.;
Kutterer, K.; Ayral-Kaloustian, S.; Ravi, M.; Nilakantan, R.; Grillo, M.; McGinnis,
J. P.; Rabindran, S. K. J. Med. Chem. 2008, 51, 3507; (b) Vankatram, A.; Colley, T.;
DeRuiter, J.; Smith, F. J. Het. Chem. 2005, 42, 297.
17. (a) Bauta, W. E.; Lovett, D. P.; Cantrell, W. R.; Burke, B. D. J. Org. Chem. 2003, 68,
5967; (b) Bauta, W. E.; Cantrell, W. R.; Lovet, D. P. WO 2003/004486 A2, 2003;
Chem. Abstr. 2003, 138, 106599.
18. Oezcan, S.; Balci, M. Tetrahedron 2008, 64, 5531.
19. Xiao, X.; Miao, Z.-H.; Antony, S.; Pommier, Y.; Cushman, M. Bioorg. Med. Chem.
Lett. 2005, 15, 2795.
20. (a) Kita, Y.; Akai, S.; Ajimura, N.; Yoshigi, M.; Tsugoshi, T.; Yasuda, H.; Tamura,
Y. J. Org. Chem. 1986, 51, 4150; (b) Yamaguchi, M.; Hasebe, K.; Higashi, H.;
Uchida, M.; Irie, A.; Minami, T. J. Org. Chem. 1990, 55, 1611.
P. S. Humphries et al. / Tetrahedron Letters 50 (2009) 2140–2143 2143