This document describes the design, synthesis, and evaluation of a series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines as potential inhibitors of phosphodiesterase 4 (PDE4) and cancer cell growth. A ligand- and phase transfer catalyst-free intramolecular Heck reaction was used to synthesize the target compounds. Some compounds showed significant inhibition of PDE4B and growth inhibition of oral cancer cells in vitro. They also showed acceptable safety profiles in zebrafish embryos, but no apoptosis was observed. The goal was to develop PDE4 inhibitors that do not inhibit luciferase, which could produce false positives in assays.
This document describes the synthesis and anti-proliferative evaluation of novel mefenamic acid-based indole analogues. A series of analogues were designed and synthesized using a palladium-catalyzed coupling-cyclization reaction between mefenamic acid-derived alkynes and various iodoindoles. The compounds were evaluated for growth inhibition against normal and cancer cell lines. Several analogues showed selective inhibition of oral cancer cells, with one compound (5g) found to be particularly promising as an anti-proliferative agent.
This document reviews 3,4-dihydropyrimidines thione, their chemistry and pharmacological potentials. It begins with background on pyrimidine structures and properties. It then discusses the chemical properties of pyrimidines and derivatives, including electrophilic and nucleophilic reactions. Biological importance is explained by pyrimidine's presence in nucleic acids, vitamins, and other biologically active compounds. Dihydropyrimidines are introduced as compounds obtained from cyclocondensation reactions. Several studies evaluating dihydropyrimidines as calcium channel blockers, antihypertensives, antibacterials, antifungals, and antioxidants are summarized.
This document discusses metathesis reactions and their applications in organic synthesis. It begins with definitions and examples of different types of metathesis reactions including alkene, alkyne, and enyne metathesis. It then covers the key catalysts used, such as Grubbs and Schrock catalysts, as well as the 2005 Nobel Prize awarded for the development of metathesis reactions. The document concludes by outlining several important applications of metathesis in synthesizing biologically active compounds and natural products.
This document describes a new solid-phase synthesis method for producing peptide and peptidomimetic compounds containing a P1-aldehyde group. The method involves attaching N-protected aldehyde precursors to a novel Hydrazino-Carbonyl-Amino-Methylated polystyrene resin (HCAM resin) via a semicarbazone linkage. The attached compounds can then undergo further synthetic steps before being cleaved from the resin via acidic hydrolysis to obtain the final P1-aldehyde products in good overall yields and purity. The method allows for the efficient production and screening of combinatorial libraries of such compounds.
The document describes the design, synthesis, and testing of novel lipopeptide conjugates as potential antimicrobial agents. A library of conjugates was designed based on a template consisting of a hydrophobic moiety, dipeptide, and spermidine. Conjugates containing linoleic acid exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships revealed that optimal activity required a hydrophobicity of 50-70% and a minimum charge of +2. Active conjugates were found to have different modes of action, damaging bacterial cell membranes and DNA. Two conjugates showed selective membrane disruption of pathogenic MRSA and were identified as promising leads for further optimization and development as antimicrobial agents.
This document describes a study that synthesized novel 2,3-dihydro-1H-inden-1-one chalcone-like compounds and their hydroxyl derivatives to evaluate their inhibitory effects on mushroom tyrosinase activity. Two compounds, 2a and 2b, inhibited tyrosinase's diphenolase activity in a dose-dependent manner, with IC50 values lower than the positive control, kojic acid. Kinetic analysis showed that compounds 2a and 2b are reversible competitive inhibitors of tyrosinase. Compound 2b, with a 3,4-dihydroxy group resembling the substrate L-DOPA, exhibited the most potent inhibition, suggesting hydroxy-substituted 2,
This document describes a one-pot, three-component reaction to synthesize densely substituted benzofurans from methyl ketones, phenols, and nucleophiles. Specifically, it details:
1) The reaction of phenylglyoxal monohydrate, phenols like sesamol, and indoles produces benzofurans in good to excellent yields with acid catalysis.
2) Replacing phenylglyoxal with methyl ketones and using I2/DMSO allows an in situ generation of arylglyoxal from the methyl ketone for the reaction.
3) Various substituted benzofurans can be synthesized from different methyl ketones, phenols
This document describes the design, synthesis, and evaluation of a series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines as potential inhibitors of phosphodiesterase 4 (PDE4) and cancer cell growth. A ligand- and phase transfer catalyst-free intramolecular Heck reaction was used to synthesize the target compounds. Some compounds showed significant inhibition of PDE4B and growth inhibition of oral cancer cells in vitro. They also showed acceptable safety profiles in zebrafish embryos, but no apoptosis was observed. The goal was to develop PDE4 inhibitors that do not inhibit luciferase, which could produce false positives in assays.
This document describes the synthesis and anti-proliferative evaluation of novel mefenamic acid-based indole analogues. A series of analogues were designed and synthesized using a palladium-catalyzed coupling-cyclization reaction between mefenamic acid-derived alkynes and various iodoindoles. The compounds were evaluated for growth inhibition against normal and cancer cell lines. Several analogues showed selective inhibition of oral cancer cells, with one compound (5g) found to be particularly promising as an anti-proliferative agent.
This document reviews 3,4-dihydropyrimidines thione, their chemistry and pharmacological potentials. It begins with background on pyrimidine structures and properties. It then discusses the chemical properties of pyrimidines and derivatives, including electrophilic and nucleophilic reactions. Biological importance is explained by pyrimidine's presence in nucleic acids, vitamins, and other biologically active compounds. Dihydropyrimidines are introduced as compounds obtained from cyclocondensation reactions. Several studies evaluating dihydropyrimidines as calcium channel blockers, antihypertensives, antibacterials, antifungals, and antioxidants are summarized.
This document discusses metathesis reactions and their applications in organic synthesis. It begins with definitions and examples of different types of metathesis reactions including alkene, alkyne, and enyne metathesis. It then covers the key catalysts used, such as Grubbs and Schrock catalysts, as well as the 2005 Nobel Prize awarded for the development of metathesis reactions. The document concludes by outlining several important applications of metathesis in synthesizing biologically active compounds and natural products.
This document describes a new solid-phase synthesis method for producing peptide and peptidomimetic compounds containing a P1-aldehyde group. The method involves attaching N-protected aldehyde precursors to a novel Hydrazino-Carbonyl-Amino-Methylated polystyrene resin (HCAM resin) via a semicarbazone linkage. The attached compounds can then undergo further synthetic steps before being cleaved from the resin via acidic hydrolysis to obtain the final P1-aldehyde products in good overall yields and purity. The method allows for the efficient production and screening of combinatorial libraries of such compounds.
The document describes the design, synthesis, and testing of novel lipopeptide conjugates as potential antimicrobial agents. A library of conjugates was designed based on a template consisting of a hydrophobic moiety, dipeptide, and spermidine. Conjugates containing linoleic acid exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships revealed that optimal activity required a hydrophobicity of 50-70% and a minimum charge of +2. Active conjugates were found to have different modes of action, damaging bacterial cell membranes and DNA. Two conjugates showed selective membrane disruption of pathogenic MRSA and were identified as promising leads for further optimization and development as antimicrobial agents.
This document describes a study that synthesized novel 2,3-dihydro-1H-inden-1-one chalcone-like compounds and their hydroxyl derivatives to evaluate their inhibitory effects on mushroom tyrosinase activity. Two compounds, 2a and 2b, inhibited tyrosinase's diphenolase activity in a dose-dependent manner, with IC50 values lower than the positive control, kojic acid. Kinetic analysis showed that compounds 2a and 2b are reversible competitive inhibitors of tyrosinase. Compound 2b, with a 3,4-dihydroxy group resembling the substrate L-DOPA, exhibited the most potent inhibition, suggesting hydroxy-substituted 2,
This document describes a one-pot, three-component reaction to synthesize densely substituted benzofurans from methyl ketones, phenols, and nucleophiles. Specifically, it details:
1) The reaction of phenylglyoxal monohydrate, phenols like sesamol, and indoles produces benzofurans in good to excellent yields with acid catalysis.
2) Replacing phenylglyoxal with methyl ketones and using I2/DMSO allows an in situ generation of arylglyoxal from the methyl ketone for the reaction.
3) Various substituted benzofurans can be synthesized from different methyl ketones, phenols
The document describes the synthesis of novel (2-nitro-1-phenoxypropane-1, 3-diyl) dibenzene compounds from Baylis-Hillman derivatives. Specifically, it details (1) the synthesis of Baylis-Hillman adducts from nitroolefins, (2) performing Friedel-Crafts reactions on the adducts to form diaryl compounds, and (3) treating the diaryl compounds with phenol under K2CO3 to form the title (2-nitro-1-phenoxypropane-1, 3-diyl) dibenzene compounds. The reactions produced the target compounds in good yields ranging from 60-75%.
Hypervalent refers to the main group elements that breaks the octet rule and firmly has more than right electrons in it's valence shell. These are non - metallic oxidation reagents.
This document describes research on the synthesis of anti-1,2-diols using aldehyde α-oxygenation followed by organometallic addition. Contrary to previous reports, the researchers found this method produces anti-diols, not syn-diols. They demonstrated the scope of the reaction using different organometallic reagents and applied it to synthesize stereoisomers of oxylipins from a plant, determining the stereochemistry of two natural products. The synthesis involved aldehyde α-oxygenation, organometallic addition, functional group manipulations and comparisons to natural products to assign stereochemistry.
The document summarizes a study that analyzed 4 genetically engineered strains of Clostridium thermocellum with differing pathways for converting phosphoenolpyruvate (PEP) to pyruvate. The strains were cultured and their metabolite concentrations and reversibility of reactions were measured to calculate free energy changes. Strain 1138 diverted flux through the malate shunt, strain 1163 expressed an exogenous pyruvate kinase, and strain 1251 expressed pyruvate kinase and deleted PPDK and the malate shunt. Strain 1163 had higher GDP and GTP, suggesting its PEP to oxaloacetate conversion was more efficient. Further optimizing the PEP to pyruvate pathway, such as
The document summarizes the Biginelli reaction, which was discovered in 1893 by Italian chemist Pietro Biginelli. It involves the acid-catalyzed cyclocondensation of beta-keto esters, aldehydes, and urea or thiourea in alcohols to produce dihydropyrimidinones (DHPMs). DHPMs have potential pharmaceutical applications and several exhibit biological activities. The document discusses the reaction mechanism, recent advances like asymmetric synthesis and solid-phase approaches, and applications of DHPMs such as in pharmacology and natural product synthesis.
The document describes a concise total synthesis of the prolyl endopeptidase inhibitor eurystatin A via a novel multi-step strategy. Key steps include:
1) A three-component Passerini reaction between suitably protected alaninal, leucine isonitrile, and ornithine components to deliver adducts 10a,b in high yield.
2) Orthogonal N-deprotection of 10a led, via a smooth O- to N-acyl migration, to 11, which constitutes the entire skeleton of the eurystatins.
3) Subsequent deprotection, macrocyclization, elaboration, and final oxidation steps efficiently afforded
1) A series of mefenamic acid-derived 1,2,3-triazole compounds were designed and synthesized via a greener copper-catalyzed azide-alkyne cycloaddition reaction. This yielded a library of 20 novel compounds in good to excellent yields.
2) Three compounds (5d, 5p, and 5q) showed promising apoptotic activity in zebrafish embryos, inducing apoptosis in a dose-dependent manner. Compound 5p showed consistent activity up to 30 mM without causing mortality.
3) One of these compounds may have potential medicinal value based on its apoptotic properties and safety profile observed in zebrafish screening. Further optimization and testing of these
This document reports on a ligand-free multi-component reaction for linking a quinoxaline framework to a benzimidazole nucleus to generate novel hybrid molecules as potential inducers of apoptosis. The reaction involves N-(prop-2-ynyl)quinoxalin-2-amine derivatives, 2-iodoanilines, and tosyl azide in the presence of copper iodide and triethylamine in DMSO. This produces the target hybrid molecules containing a quinoxaline-benzimidazole linkage in good yields within 30 minutes. Some of the synthesized compounds showed encouraging apoptosis inducing properties in zebrafish embryos.
This document describes an enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz (1) in 62% overall yield over seven steps. A key step is an enantioselective addition of Li-cyclopropyl acetylide (4a) to p-methoxybenzyl-protected ketoaniline 3a, mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a), that establishes the stereogenic center of efavirenz with high stereocontrol (96-98% ee). The synthesis proceeds through preparation of starting materials, an optimized enantioselective alkynylation reaction, and subsequent transformations
This document summarizes research on the effects of heme ring oxygenation on the structure and function of cytochrome c peroxidase (CcP). Specifically, it describes the synthesis of 4-mesoporphyrinone (mesopone) and its incorporation into CcP to form a hybrid protein called MpCcP. Testing found that MpCcP had similar peroxidase activity to wild-type CcP with cytochrome c, but varied activity with other substrates. Structural analysis via X-ray crystallography provided the first structural characterization of an oxygenated heme protein and found only the S-isomer of mesopone in the crystallized protein despite using a mixture of isomers.
Synthesis and Catalytic Application of Chiral 1,1′-Bi-2-naphtholand Biphenant...DrMAdamSayah
Synthesis and Catalytic Application of Chiral 1,1′-Bi-2-naphtholand Biphenanthrol-Based Pincer Complexes- Selective Allylation of Sulfonimines with Allyl Stannane and Allyl Trifluoroborate
1) The document describes the total synthesis of the natural product 10-hydroxyasimicin, which contains a bis-THF motif in its central core.
2) A key step was the development of a template approach to link two alkenol building blocks and induce stereocontrol during ring-closing metathesis to generate the bis-THF framework.
3) The synthesis involved coupling the building blocks, ring-closing metathesis, asymmetric dihydroxylation, macrocycle opening and elaboration to install side chains, and final coupling and deprotection to yield the target natural product.
This document summarizes the convergent stereoselective synthesis of (-)-deoxypukalide, the enantiomer of a degradation product of the natural product pukalide. Key steps include a novel intraannular furan synthesis using a 4-oxopropargylic β-keto ester and silica gel to form a 3-carboxy 2,5-bridged furan in 96% yield. The synthesis features a "furan-last" strategy employing molecular mechanics calculations to direct stereodefining steps. Installation of the embedded butenolide moiety is achieved to complete the total synthesis of (-)-deoxypukalide, which is confirmed by X-
This document summarizes an investigation into using lysine-functionalized dendrimers as potential detoxification agents for the organophosphate pesticide dichlorvos. Zeroth-, first-, and second-generation polyester dendrimers were synthesized with exactly 4, 8, and 16 lysine groups respectively on their periphery. The dendrimers were found to be water-soluble and showed low toxicity to cell lines. They were also able to efficiently capture dichlorvos, demonstrating their potential as antidotes to maintain acetylcholinesterase activity in cases of organophosphate poisoning.
The document summarizes the Passerini reaction and its use in synthesizing α-hydroxy-β-amino acid derivatives and related compounds. It describes how treating α-amino aldehydes with trifluoroacetic acid (TFA) and a pyridine-type base generates α-hydroxy-β-amino amide products in good yields with retention of stereochemistry. A variety of amino acid derivatives have been synthesized using this method. The products have applications as protease inhibitors, natural products, and imaging agents.
1) Chalcones are α,β-unsaturated carbonyl compounds formed via the Claisen-Schmidt reaction between benzaldehyde and acetophenone. They contain two aromatic rings joined by an α,β unsaturated carbonyl group.
2) Chalcones exhibit various pharmacological activities including antioxidant, antibacterial, antifungal, anticancer, and antidepressant properties. Their activity is influenced by substitutions on the aromatic rings. Halogen and methoxy groups often enhance biological activity.
3) Studies have shown that chalcones can act as free radical scavengers and inhibit lipid peroxidation, demonstrating their antioxidant properties. Substitutions like hydroxyl and methoxy groups in
OBC epoxidations paper - Queen Mary University LONDON UK - Thomas FollierThomas Follier
This document reports on a study of the catalytic activity of manganese complexes with two similar polyamine ligands (7 and 8) that differ by the presence of a secondary or tertiary nitrogen, in the epoxidation of styrene. Ligand 7 showed the highest activity with MnSO4 and H2O2, while ligand 8 was most effective with Mn(OTf)2, MnCl2, and Mn(ClO4)2 using peracetic acid. Kinetic analysis indicated the structural differences in the ligands lead to differences in the nature of the active species formed. Ligand 7 with MnSO4 produced the epoxide in 78% yield, while ligand 8 with Mn(OT
The bulbs and aerial parts of Zephyranthes concolor were found to contain six alkaloids: chlidanthine, galanthamine, galanthamine N-oxide, lycorine, galwesine, and epinorgalanthamine. High resolution 1H and 13C NMR spectra were recorded for chlidanthine, which was identified through 2D NMR experiments and X-ray crystallography. Chlidanthine and galanthamine N-oxide showed acetylcholinesterase inhibitory activity, though weaker than galanthamine. The alkaloids also showed poor anti-HIV activity and low cytotoxicity.
1) Ranchers in Idaho observed lambs born with cyclopia (one eye) due to ewes grazing on corn lily plants. Cyclopamine was identified as the compound responsible and was later found to inhibit the Hedgehog signaling pathway.
2) Nakiterpiosin and nakiterpiosinone were isolated from cyanobacterial sponges and shown to inhibit cancer cell growth. Their unique C-nor-D-homosteroid skeleton presented synthetic challenges.
3) The authors developed a convergent synthesis of nakiterpiosin involving a carbonylative Stille coupling and a photo-Nazarov cyclization. Model studies led them to propose a revised structure for n
1) Ranchers in Idaho observed lambs born with cyclopia (one eye) due to ewes grazing on corn lily plants. Cyclopamine was identified as the compound responsible and was later found to inhibit the Hedgehog signaling pathway.
2) Nakiterpiosin and nakiterpiosinone were isolated from cyanobacterial sponges and shown to inhibit cancer cell growth. Their unique C-nor-D-homosteroid skeleton presented synthetic challenges.
3) The authors developed a convergent synthesis of nakiterpiosin involving a carbonylative Stille coupling and a photo-Nazarov cyclization. Model studies led them to propose a revised structure for n
This document discusses the author's experiences undergoing IVF treatment at two clinics in India - Dr. Nayna Patel’s Akanksha Clinic in Anand and Kiran IVF in Hyderabad. It covers their experiences with the doctors and clinic processes, surrogate contracts and profiles, donor egg information, lodging, transportation, costs, IVF drug protocols, and immigration details. More information can be found at www.ourindiaivf.com.
The front cover of Hip-Hop Weekly (HHW) magazine uses informal layout and images of celebrities Rihanna and Chris Brown to target a young audience. Though the text layout appears disorganized, the font sizes follow conventional order of importance. The large headline about the celebrities hints at gossip or rumors, suggesting HHW converges music and tabloid content. The £2.95 price indicates the target audience is lower-middle class 17-24 year olds who regularly purchase the weekly magazine. Though both genders are represented on the non-sexualized cover, internal content more often sexualizes women, implying the audience is somewhat male-dominated.
The document describes the synthesis of novel (2-nitro-1-phenoxypropane-1, 3-diyl) dibenzene compounds from Baylis-Hillman derivatives. Specifically, it details (1) the synthesis of Baylis-Hillman adducts from nitroolefins, (2) performing Friedel-Crafts reactions on the adducts to form diaryl compounds, and (3) treating the diaryl compounds with phenol under K2CO3 to form the title (2-nitro-1-phenoxypropane-1, 3-diyl) dibenzene compounds. The reactions produced the target compounds in good yields ranging from 60-75%.
Hypervalent refers to the main group elements that breaks the octet rule and firmly has more than right electrons in it's valence shell. These are non - metallic oxidation reagents.
This document describes research on the synthesis of anti-1,2-diols using aldehyde α-oxygenation followed by organometallic addition. Contrary to previous reports, the researchers found this method produces anti-diols, not syn-diols. They demonstrated the scope of the reaction using different organometallic reagents and applied it to synthesize stereoisomers of oxylipins from a plant, determining the stereochemistry of two natural products. The synthesis involved aldehyde α-oxygenation, organometallic addition, functional group manipulations and comparisons to natural products to assign stereochemistry.
The document summarizes a study that analyzed 4 genetically engineered strains of Clostridium thermocellum with differing pathways for converting phosphoenolpyruvate (PEP) to pyruvate. The strains were cultured and their metabolite concentrations and reversibility of reactions were measured to calculate free energy changes. Strain 1138 diverted flux through the malate shunt, strain 1163 expressed an exogenous pyruvate kinase, and strain 1251 expressed pyruvate kinase and deleted PPDK and the malate shunt. Strain 1163 had higher GDP and GTP, suggesting its PEP to oxaloacetate conversion was more efficient. Further optimizing the PEP to pyruvate pathway, such as
The document summarizes the Biginelli reaction, which was discovered in 1893 by Italian chemist Pietro Biginelli. It involves the acid-catalyzed cyclocondensation of beta-keto esters, aldehydes, and urea or thiourea in alcohols to produce dihydropyrimidinones (DHPMs). DHPMs have potential pharmaceutical applications and several exhibit biological activities. The document discusses the reaction mechanism, recent advances like asymmetric synthesis and solid-phase approaches, and applications of DHPMs such as in pharmacology and natural product synthesis.
The document describes a concise total synthesis of the prolyl endopeptidase inhibitor eurystatin A via a novel multi-step strategy. Key steps include:
1) A three-component Passerini reaction between suitably protected alaninal, leucine isonitrile, and ornithine components to deliver adducts 10a,b in high yield.
2) Orthogonal N-deprotection of 10a led, via a smooth O- to N-acyl migration, to 11, which constitutes the entire skeleton of the eurystatins.
3) Subsequent deprotection, macrocyclization, elaboration, and final oxidation steps efficiently afforded
1) A series of mefenamic acid-derived 1,2,3-triazole compounds were designed and synthesized via a greener copper-catalyzed azide-alkyne cycloaddition reaction. This yielded a library of 20 novel compounds in good to excellent yields.
2) Three compounds (5d, 5p, and 5q) showed promising apoptotic activity in zebrafish embryos, inducing apoptosis in a dose-dependent manner. Compound 5p showed consistent activity up to 30 mM without causing mortality.
3) One of these compounds may have potential medicinal value based on its apoptotic properties and safety profile observed in zebrafish screening. Further optimization and testing of these
This document reports on a ligand-free multi-component reaction for linking a quinoxaline framework to a benzimidazole nucleus to generate novel hybrid molecules as potential inducers of apoptosis. The reaction involves N-(prop-2-ynyl)quinoxalin-2-amine derivatives, 2-iodoanilines, and tosyl azide in the presence of copper iodide and triethylamine in DMSO. This produces the target hybrid molecules containing a quinoxaline-benzimidazole linkage in good yields within 30 minutes. Some of the synthesized compounds showed encouraging apoptosis inducing properties in zebrafish embryos.
This document describes an enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz (1) in 62% overall yield over seven steps. A key step is an enantioselective addition of Li-cyclopropyl acetylide (4a) to p-methoxybenzyl-protected ketoaniline 3a, mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a), that establishes the stereogenic center of efavirenz with high stereocontrol (96-98% ee). The synthesis proceeds through preparation of starting materials, an optimized enantioselective alkynylation reaction, and subsequent transformations
This document summarizes research on the effects of heme ring oxygenation on the structure and function of cytochrome c peroxidase (CcP). Specifically, it describes the synthesis of 4-mesoporphyrinone (mesopone) and its incorporation into CcP to form a hybrid protein called MpCcP. Testing found that MpCcP had similar peroxidase activity to wild-type CcP with cytochrome c, but varied activity with other substrates. Structural analysis via X-ray crystallography provided the first structural characterization of an oxygenated heme protein and found only the S-isomer of mesopone in the crystallized protein despite using a mixture of isomers.
Synthesis and Catalytic Application of Chiral 1,1′-Bi-2-naphtholand Biphenant...DrMAdamSayah
Synthesis and Catalytic Application of Chiral 1,1′-Bi-2-naphtholand Biphenanthrol-Based Pincer Complexes- Selective Allylation of Sulfonimines with Allyl Stannane and Allyl Trifluoroborate
1) The document describes the total synthesis of the natural product 10-hydroxyasimicin, which contains a bis-THF motif in its central core.
2) A key step was the development of a template approach to link two alkenol building blocks and induce stereocontrol during ring-closing metathesis to generate the bis-THF framework.
3) The synthesis involved coupling the building blocks, ring-closing metathesis, asymmetric dihydroxylation, macrocycle opening and elaboration to install side chains, and final coupling and deprotection to yield the target natural product.
This document summarizes the convergent stereoselective synthesis of (-)-deoxypukalide, the enantiomer of a degradation product of the natural product pukalide. Key steps include a novel intraannular furan synthesis using a 4-oxopropargylic β-keto ester and silica gel to form a 3-carboxy 2,5-bridged furan in 96% yield. The synthesis features a "furan-last" strategy employing molecular mechanics calculations to direct stereodefining steps. Installation of the embedded butenolide moiety is achieved to complete the total synthesis of (-)-deoxypukalide, which is confirmed by X-
This document summarizes an investigation into using lysine-functionalized dendrimers as potential detoxification agents for the organophosphate pesticide dichlorvos. Zeroth-, first-, and second-generation polyester dendrimers were synthesized with exactly 4, 8, and 16 lysine groups respectively on their periphery. The dendrimers were found to be water-soluble and showed low toxicity to cell lines. They were also able to efficiently capture dichlorvos, demonstrating their potential as antidotes to maintain acetylcholinesterase activity in cases of organophosphate poisoning.
The document summarizes the Passerini reaction and its use in synthesizing α-hydroxy-β-amino acid derivatives and related compounds. It describes how treating α-amino aldehydes with trifluoroacetic acid (TFA) and a pyridine-type base generates α-hydroxy-β-amino amide products in good yields with retention of stereochemistry. A variety of amino acid derivatives have been synthesized using this method. The products have applications as protease inhibitors, natural products, and imaging agents.
1) Chalcones are α,β-unsaturated carbonyl compounds formed via the Claisen-Schmidt reaction between benzaldehyde and acetophenone. They contain two aromatic rings joined by an α,β unsaturated carbonyl group.
2) Chalcones exhibit various pharmacological activities including antioxidant, antibacterial, antifungal, anticancer, and antidepressant properties. Their activity is influenced by substitutions on the aromatic rings. Halogen and methoxy groups often enhance biological activity.
3) Studies have shown that chalcones can act as free radical scavengers and inhibit lipid peroxidation, demonstrating their antioxidant properties. Substitutions like hydroxyl and methoxy groups in
OBC epoxidations paper - Queen Mary University LONDON UK - Thomas FollierThomas Follier
This document reports on a study of the catalytic activity of manganese complexes with two similar polyamine ligands (7 and 8) that differ by the presence of a secondary or tertiary nitrogen, in the epoxidation of styrene. Ligand 7 showed the highest activity with MnSO4 and H2O2, while ligand 8 was most effective with Mn(OTf)2, MnCl2, and Mn(ClO4)2 using peracetic acid. Kinetic analysis indicated the structural differences in the ligands lead to differences in the nature of the active species formed. Ligand 7 with MnSO4 produced the epoxide in 78% yield, while ligand 8 with Mn(OT
The bulbs and aerial parts of Zephyranthes concolor were found to contain six alkaloids: chlidanthine, galanthamine, galanthamine N-oxide, lycorine, galwesine, and epinorgalanthamine. High resolution 1H and 13C NMR spectra were recorded for chlidanthine, which was identified through 2D NMR experiments and X-ray crystallography. Chlidanthine and galanthamine N-oxide showed acetylcholinesterase inhibitory activity, though weaker than galanthamine. The alkaloids also showed poor anti-HIV activity and low cytotoxicity.
1) Ranchers in Idaho observed lambs born with cyclopia (one eye) due to ewes grazing on corn lily plants. Cyclopamine was identified as the compound responsible and was later found to inhibit the Hedgehog signaling pathway.
2) Nakiterpiosin and nakiterpiosinone were isolated from cyanobacterial sponges and shown to inhibit cancer cell growth. Their unique C-nor-D-homosteroid skeleton presented synthetic challenges.
3) The authors developed a convergent synthesis of nakiterpiosin involving a carbonylative Stille coupling and a photo-Nazarov cyclization. Model studies led them to propose a revised structure for n
1) Ranchers in Idaho observed lambs born with cyclopia (one eye) due to ewes grazing on corn lily plants. Cyclopamine was identified as the compound responsible and was later found to inhibit the Hedgehog signaling pathway.
2) Nakiterpiosin and nakiterpiosinone were isolated from cyanobacterial sponges and shown to inhibit cancer cell growth. Their unique C-nor-D-homosteroid skeleton presented synthetic challenges.
3) The authors developed a convergent synthesis of nakiterpiosin involving a carbonylative Stille coupling and a photo-Nazarov cyclization. Model studies led them to propose a revised structure for n
This document discusses the author's experiences undergoing IVF treatment at two clinics in India - Dr. Nayna Patel’s Akanksha Clinic in Anand and Kiran IVF in Hyderabad. It covers their experiences with the doctors and clinic processes, surrogate contracts and profiles, donor egg information, lodging, transportation, costs, IVF drug protocols, and immigration details. More information can be found at www.ourindiaivf.com.
The front cover of Hip-Hop Weekly (HHW) magazine uses informal layout and images of celebrities Rihanna and Chris Brown to target a young audience. Though the text layout appears disorganized, the font sizes follow conventional order of importance. The large headline about the celebrities hints at gossip or rumors, suggesting HHW converges music and tabloid content. The £2.95 price indicates the target audience is lower-middle class 17-24 year olds who regularly purchase the weekly magazine. Though both genders are represented on the non-sexualized cover, internal content more often sexualizes women, implying the audience is somewhat male-dominated.
El documento trata sobre los conceptos de metacognición, aprendizaje significativo, compromiso de aprendizaje y autoeficacia en el aprendizaje. Explica que la metacognición implica conocer la propia cognición y regular las actividades intelectuales. El aprendizaje significativo produce una retención duradera al relacionar nueva información con conocimientos previos. El compromiso de aprendizaje requiere la participación activa del estudiante. Y la autoeficacia en el aprendizaje depende de factores como la etapa prof
This document is a program written by Armando Henriquez for a computing class at Universidad Fermin Toro in Cabudare, Venezuela in November 2013. The program uses functions to evaluate whether an input character is an alphabetic character or numeric digit. The user is prompted to input a character, which is then passed to the Eval function to check the character's value and print the corresponding output.
This document provides information about igneous rocks, including:
- Igneous rocks form from the crystallization of magma, which is molten rock located beneath the Earth's surface or lava on the surface.
- There are two main types of igneous rocks: extrusive rocks, which solidify on the surface, and intrusive rocks, which solidify underground.
- Factors like cooling rate and mineral composition determine the texture of the igneous rock, ranging from glassy to phaneritic.
- Igneous rocks can be classified based on their composition as felsic, intermediate, or mafic rocks like granite, andesite, and basalt respectively.
Pagina 53 a 56 conflicto del canal de beagleMario Suarez
El documento describe el conflicto del Canal de Beagle entre Argentina y Chile en 1978-1979, incluyendo las posiciones beligerantes de algunos sectores militares argentinos como Massera y Menéndez que querían la guerra, en contraste con Videla que se oponía. También discute el rol de la Iglesia católica y el Papa Juan Pablo II en mediar el conflicto y evitar una guerra, así como las consecuencias económicas de las políticas neoliberales impulsadas por la dictadura militar argentina.
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Pagina 52 doctrina de seguridad nacional canal encuentroMario Suarez
La doctrina de seguridad nacional promovió la persecución, tortura y muerte de personas bajo la falsa premisa de una lucha contra el comunismo. Instructores militares franceses trajeron esta doctrina a la Argentina en 1959 y enseñaron que la aplicación del terror, incluida la tortura y muerte de inocentes, era necesaria para derrotar al enemigo. La dictadura militar argentina que gobernó entre 1976-1983 aplicó estos métodos represivos contra la población siguiendo las enseñanzas de la doctrina de
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technique as well as conventional heating. The S∩N donor benzothiazolines, 1-
(2-furanyl) ethanone benzothiazoline (Bzt1N
∩
SH), 1-(2-thienyl) ethanone
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New Schiff base ligand (E)-6-(2-(4-
(dimethylamino)benzylideneamino)-2-phenylacetamido)-3,3-
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic
acid = (HL) Figure(1) was prepared via condensation of
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molar ratio reactions with metal ions and HL, 2NA on reaction
with MCl2 .nH2O salt yields complexes corresponding to the
formulas [M(L)(NA)2Cl] ,where M =
Fe(II),Co(II),Ni(II),Cu(II),and Zn(II) and NA=nicotinamide.
The 1H-NMR, FT-IR, UV-Vis and elemental analysis
were used for the characterization of the ligand. The complexes
were structurally studied through AAS, FT-IR, UV-Vis,
chloride contents, conductance, and magnetic susceptibility
measurements. All complexes are non-electrolytes in DMSO
solution. Octahedral geometries have been suggested for each
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tridentates and the deprotonated enolic form is preferred for
coordination. In order to evaluate the effect of the bactericidal
activity, these synthesized complexes, in comparison to the un
complexed Schiff base has been screened against bacterial
species, Staphy
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7 synthesis, characterisation and antimicrobial activity of schiff base of 7 ...BIOLOGICAL FORUM
ABSTRACT: Compounds having 2-quinolone moiety are associated with interesting biological activities. In the present study, we synthesized Schiff bases of 7-hydroxy-3-methyl-2-quinolone and their antibacterial activity was evaluated by wells diffusion method. Schiff bases of 7-hydroxy-3-methyl-2-quinolone (1 to 5 named as Q2aa-Q2ae) were prepared by refluxing 7-hydroxy-3-methyl-2-quinolone with substituted aromatic aldehydes. The final test compounds were purified and characterized by IR, 1HNMR and Mass Spectral studies. M.P. of these compounds was confirmed by open capillary method instrument chemline cl 725. They were evaluated for antibacterial activity. Compounds were active against Klebsiella pneumonia and Enterococcus faecalis. While ciprofloxacin was used as standards.
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.
This presentation includes basic of PCOS their pathology and treatment and also Ayurveda correlation of PCOS and Ayurvedic line of treatment mentioned in classics.
A review of the growth of the Israel Genealogy Research Association Database Collection for the last 12 months. Our collection is now passed the 3 million mark and still growing. See which archives have contributed the most. See the different types of records we have, and which years have had records added. You can also see what we have for the future.
LAND USE LAND COVER AND NDVI OF MIRZAPUR DISTRICT, UPRAHUL
This Dissertation explores the particular circumstances of Mirzapur, a region located in the
core of India. Mirzapur, with its varied terrains and abundant biodiversity, offers an optimal
environment for investigating the changes in vegetation cover dynamics. Our study utilizes
advanced technologies such as GIS (Geographic Information Systems) and Remote sensing to
analyze the transformations that have taken place over the course of a decade.
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of extensive research and worry. As the global community grapples with swift urbanization,
population expansion, and economic progress, the effects on natural ecosystems are becoming
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significant role in maintaining the ecological equilibrium of our planet.Land serves as the foundation for all human activities and provides the necessary materials for
these activities. As the most crucial natural resource, its utilization by humans results in different
'Land uses,' which are determined by both human activities and the physical characteristics of the
land.
The utilization of land is impacted by human needs and environmental factors. In countries
like India, rapid population growth and the emphasis on extensive resource exploitation can lead
to significant land degradation, adversely affecting the region's land cover.
Therefore, human intervention has significantly influenced land use patterns over many
centuries, evolving its structure over time and space. In the present era, these changes have
accelerated due to factors such as agriculture and urbanization. Information regarding land use and
cover is essential for various planning and management tasks related to the Earth's surface,
providing crucial environmental data for scientific, resource management, policy purposes, and
diverse human activities.
Accurate understanding of land use and cover is imperative for the development planning
of any area. Consequently, a wide range of professionals, including earth system scientists, land
and water managers, and urban planners, are interested in obtaining data on land use and cover
changes, conversion trends, and other related patterns. The spatial dimensions of land use and
cover support policymakers and scientists in making well-informed decisions, as alterations in
these patterns indicate shifts in economic and social conditions. Monitoring such changes with the
help of Advanced technologies like Remote Sensing and Geographic Information Systems is
crucial for coordinated efforts across different administrative levels. Advanced technologies like
Remote Sensing and Geographic Information Systems
9
Changes in vegetation cover refer to variations in the distribution, composition, and overall
structure of plant communities across different temporal and spatial scales. These changes can
occur natural.
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How to Setup Warehouse & Location in Odoo 17 InventoryCeline George
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69. synthesis, ex vivo and in silico studies of 3 cyano-2-pyridone derivatives with vasorelaxant activity
1. European Journal of Medicinal Chemistry 70 (2013) 669e676
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, ex vivo and in silico studies of 3-cyano-2-pyridone
derivatives with vasorelaxant activity
Fernando Hernández a, Arturo Sánchez a, Priscila Rendón-Vallejo b, César Millán-Pacheco c,
Yolanda Alcaraz d, Francisco Delgado e, Miguel A. Vázquez a, *, Samuel Estrada-Soto b, *
a
Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Gto. 36050, Mexico
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mor. 62209, Mexico
Facultad de Ciencias, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mor. 62209, Mexico
d
Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Gto. 36050, Mexico
e
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala, 11340 México, D. F., Mexico
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2013
Received in revised form
3 October 2013
Accepted 7 October 2013
Available online 14 October 2013
An efficient and simple synthesis of 3-cyano-2-pyridone derivatives (6aef) through 3,4-dihydropyridin2-one oxidation process is described. A greener method to synthesize 3,4-dihydropyridin-2-one has also
been developed by rearranging 4H-pyran (4aef) derivatives in aqueous medium applying H2SO4 as the
catalyst source and microwave irradiation. The vasorelaxant activity of 3-cyano-2-pyridone derivatives
(6aef) was proved on isolated thoracic aorta rat rings with and without endothelium (þE and ÀE,
respectively) pre-contracted with noradrenaline (0.1 mM). All compounds exhibited significant
concentration-dependent and endothelium-independent vasorelaxant effects being the nitro derivatives
(6a and f) and compound 6d the most potent with EC50 of 7, 4.4 and 5 mM, respectively. Finally, a previously described 3D model of the central pore of human L-type calcium channel (LCC), modified to be on
agreement with NCBI sequence NP_005174.2 for subunit alpha-1F isoform 1, was used to dock most
active compounds. 6a, d and f lowest affinity energy structures were found docked in the same cavity
conformed by IS6, IS5, IP and IIS6 helices. Nifedipine lowest energy structure was found in the cavity
formed by IIS6, IIS5, IIP and IIIS6. Although nifedipine docked in a different cavity, the superposition of
both, allowed us to observe that they were almost the same cavities, indicating that there exist subtle
steric differences that lead to a different docking for nifedipine. All compounds docked with similar free
energy of binding.
Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords:
4H-Pyrans
2-Pyridones
Microwave irradiation
Vasorelaxant activity
Docking score
L-type calcium channel
1. Introduction
Cardiovascular disease (CVD) has been recognized as the most
common leading cause of mortality in developed countries. The
underlying risk factors that trigger CVD are metabolic disorders
(atherogenic dyslipidemia), obesity (induced by physical inactivity
and caloric diet), diabetes and hypertension [1,2]. In this context,
hypertension is one of the most prevalent causes that origin CVD by
development of an impaired vascular relaxation process for
appearance of endothelial dysfunction and oxidative stress [3].
Antihypertensive drugs influence arterial blood pressure at four
* Corresponding authors.
E-mail addresses: mvazquez@ugto.mx
(S. Estrada-Soto).
(M.A.
Vázquez),
enoch@uaem.mx
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.10.018
effectors’ sites: the resistance vessels, the capacitance vessels, the
heart, and the kidney [4].
So, new antihypertensive agents with new or known therapeutic targets are needed to control hypertension more effectively,
with less adverse effects and neutral impact on known cardiovascular risk factors. Thus, in an attempt to found novel antihypertensive compounds with vasorelaxant activity, we decided to
design 3-cyano-2-pyridone hybrids derivatives as calcium channel
blockers and possible PD3 and PD4 inhibitors taken in account
nifedipine, milrinone and amrinone [5e8]. 2-pyridones constituted
an important type of heterocyclic that have shown variety of biological activities [5]. They work as specific phosphodiesterase
(PDE3) inhibitors and are good alternative to classic digitalis glycosides for the acute treatment of congestive heart failure (CHF) i.e.
amrinone and milrinone (Fig. 1) [6,7]. In addition, nifedipine (Fig. 1)
is a dihydropyridine L-type calcium channel (LCC) blocker. Its main
uses are as an antianginal (especially in Prinzmetal’s angina) and
2. 670
F. Hernández et al. / European Journal of Medicinal Chemistry 70 (2013) 669e676
Table 1
Comparison of different sources of energy for conversion of 4a to 5a.a
Entry
antihypertensive, although a large number of other indications
have recently been found for this agent, such as Raynaud’s phenomenon, premature labor, and painful spasms of the esophagus
such as in cancer and tetanus patients. It is also commonly used for
the small subset of pulmonary hypertension patients whose
symptoms respond to calcium channel blockers [8].
The most common method used to synthetize 2-pyridones is the
Michael addition of acetonitrile derivatives to an appropriate a,bunsaturated carbonyl substrate and subsequent hydrolytic cyclization followed by oxidative aromatization [9e11]. Alternatively, b-oxo
amides under Vilsmeier conditions are used to produce 2-pyridones
[12]. Other notable methods starting from the Blaise reaction intermediate were reported [13]. However, many of the established
methods carried out this procedure under harsh reaction conditions.
On the other hand, one of the objectives in modern synthetic organic
chemistry includes leading reactions with effective, clean, and
environmentally safer methodologies. It is appropriate to mention
that the revision of fundamental synthetic reactions using different
energy source [14], represents one of the main subjects of our
research group in order to contribute to the development of environmentally benign methods. Thus, various reactions have been
studied: among them the Knoevenagel condensation [15e17], the
Biginelli reaction [18], the formation of N-benzylideneanilines [19],
4H-pyran [20], and the DielseAlder reaction [21].
2. Results and discussion
2.1. Chemistry
Our group previously reported the synthesis of 4H-pyrans derivatives and 2-pyridones using infrared irradiation [20], and we
projected that a rearrangement of 4aef, and subsequent oxidation
reaction, would provide a synthetic route for 3-cyano-2-pyridone
(6aef) under microwave irradiation (Scheme 1).
T ( C)
Reaction time
Yield (%)b
1
2
3
4
Fig. 1. Structure of milrinone, amrinone and nifedipine.
Source energy
Infrared (50 V)
Conventional
Microwave
Room temperature
80
80
100
25
7 min
30 min
5 min
7h
80
72
86
8
a
All entries were carried out using p-toluenesulphonic acid as catalyst in ethanol
as solvent.
b
Determined by 1H NMR of the recrystallization of crude reaction, corresponding
to the mixture of trans/cis adducts.
It was envisaged sequential ring-opening followed by ringclosure process of 4H-pyran 4a. To find a suitable catalyst for this
rearrangement, we initially screened the reaction with p-toluenesulphonic acid as catalyst [22], using microwave irradiation as energy source at 100 C, for 5 min, in the absence of solvent. The
desired pyridone 5a was obtained as a mixture of diastereoisomers
trans/cis in low yield (60%), as judged from 1H NMR (300 MHz)
analysis of the crude reaction (Supplementary information).
In an attempt to obtain a homogeneous reaction by improved
the adduct obtained, the reaction was performed with CHCl3, THF,
CH3CN, dioxane, water and ethanol to found the right catalytic
activity of acid and the best suited medium of transformation. We
found that the reaction using ethanol (86% yields) as the solvent
resulted in higher yields than any other solvent.
To demonstrate the efficiency and applicability of the microwave irradiation we also compared different sources of energy. The
comparison of the yields and reaction times shows that by using
infrared [23] and microwaves irradiation the reaction time is
shortened and the product yielded is increased (Table 1, entry 1, 3).
In addition, we screened a number of Brönsted acids for efficient
ring-opening/ring-closing of 4a. Also, it was studied the catalytic
activity of iodine (Lewis acid) over the reaction using microwave
irradiation. Hydrochloric acid was found slightly better (yield 79%),
however best results were obtained with sulfuric acid (yield 95%).
The latter catalyst in 10 mol% was sufficient to push the reaction
forward, nevertheless and increasing in the amounts of catalyst
(30 mol%) did not improved the yield (95%). Reducing the amount
of catalyst to 5 mol%, resulted in a lower yield (65%). Moreover, the
inclusion of iodine in the reaction resulted in a poor conversion of
5a (yield 57%). Thus, reactions were carried out with 10 mol% of the
catalyst and microwave irradiation was used as the energy source.
The use of optimal experimental conditions described later
(microwave irradiation, 5 min, 100 C, H2SO4eEtOH) for the
Table 2
Relation between diastereoisomers trans/cis 5aef by NMR.
Entry
Yield (%)a
Adducts (trans/cis)
1
2
3
4
5
6
Scheme 1.
Product
5a
5b
5c
5d
5e
5f
95
87
95
88
83
92
84/16
82/18
84/16
89/11
80/20
82/18
a
Determined after re-crystallization by 1H NMR, corresponding to the mixture of
trans/cis adducts.
3. F. Hernández et al. / European Journal of Medicinal Chemistry 70 (2013) 669e676
reactions of different 4H-pyrans 4bef afforded good yields for 3,4dihydropyridin-2-ones 5bef as a mixture trans/cis adducts. The
results (Table 2, entries 1e6) indicated that aryl or heteroaryl
functional groups were all suitable for the reaction.
Compounds 5aef were isolated as a mixture trans/cis adducts,
like its precursors, these had the same number of signals in the
proton-decoupled 13C NMR spectrum. Its 1H NMR spectrum for 5a
shows the appearance of two new sets of signals at w10.80e
10.40 ppm to the protons NH (trans/cis), w5.05e4.57 ppm (trans
J ¼ 7.5 Hz) and 4.67e4.35 ppm (cis J ¼ 5.5 Hz). Furthermore, the
infrared spectrums of 5aef displayed carbonyl absorptions at
w1721 and 1662 cmÀ1, in contrast to the carbonyl absorption at
w1676 cmÀ1 for 4aef.
The ring-opening/ring-closing of 4a proved to be an efficient
process for building the 3,4-dihydropyridin-2-ones scaffold. That
pyridine-2-ones 5aef possesses a core, which may be expected to
undergo an oxidation reaction.
In order to support the aromatization the adduct 5a was reacted
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), in ethanol
as the solvent, the test was performed with microwave energy as an
alternative source (100 C/14 psi, ethanol, 5 min), the conversion is
efficient (91% yield).
In order to investigate the scope and limitations of this oxidation
reaction, as well as to identify the possible effect induced by other
substrates on the formation of compounds 6bef, we carried out the
reaction with substrates 5bef under the same reaction conditions.
A similar behavior was observed with respect to 5a, leading to
adducts 6bef as single products in comparable yields (Table 3). It is
evident that the reaction proceeded smoothly for both electro rich
and electro deficient aryl and heteroaryl aldehydes with reasonably
good yield. The spectral data and physical properties of 6aef are
showed in the Supplementary information.
2.2. Vasorelaxant effect of compounds 6aef
On the other hand, compounds 6aef showed a significant vasorelaxant activity in a concentration-dependent manner on the
contraction induced by noradrenaline (0.1 mM, NA) (Table 4) on
aorta rat rings. Compounds 6a, d and f were the most potent, and
revealed an endothelium-independent effect (Fig. 2aec). All compounds tested were less potent than positive control nifedipine
and carbachol, respectively. An endothelium-independent relaxation is related with a smooth muscle cells activity, which interferes
on contraction processes such as a-adrenoceptors antagonism,
calcium channel blockade, potassium channel opening, cAMP or
Table 3
Synthesis of 5-cyano-pyridin-2-ones 6aef.a
Comp.
R1
Yield (%)b
m.p [ C]
6a
6b
6c
6d
6e
6f
4-NO2C6H4
C4H3O
C5H4N
C4H3S
3-ClC6H4
2,4-(NO2)2C6H3
91.0
90.0
84.0
94.0
95.0
85.0
208e210
223e225
174e176
212e214
230e232
268e269
a
The compounds (5aef) (1 mmol), DDQ (1 mmol) were irradiated with microwaves in 3 mL ethanol at 100 C for 5 min.
b
Isolated yield of the pure product.
671
Table 4
Relaxatory effects induced by 6aef on the contraction induced by NA (0.1 mM).
With endothelium (Eþ)
Without endothelium (EÀ)
Contractile agent: NA 0.1 mM
Compound
EC50 (mM)
Efficacy (%)
6a
6b
6c
6d
6e
6f
Carbachol
Nifedipine
7
22
270
5
85
4.4
0.30
ND
98
100
85.47
100
97
97
74.06
ND
Æ
Æ
Æ
Æ
Æ
Æ
Æ
1.96
4.18
1.86
2.1
2.06
3.1
5.7
EC50 (mM)
Efficacy (%)
8.2
31
178
12
62
3.6
ND
0.03
95
93
86.40
99
99
99
ND
97.0
Æ
Æ
Æ
Æ
Æ
Æ
0.69
1.77
1.84
0.69
2.1
2.1
Æ 2.48
cGMP increment, or Ca2þ-CaM complex activity inhibition [24,25].
As we described previously, 3-cyano-2-pyridone hybrids derivatives were designed as calcium channel blockers and possible
PD3 and PD4 inhibitors, taken in account nifedipine (L-type calcium
channel blocker), milrinone and amrinone (PD3 and PD4 inhibitors)
with potential vasorelaxant and antihypertensive effects. So, we
expect that some of these compounds showed vasorelaxant effect
by an interference with LCC as described for nifedipine and other
LCC blockers structurally related.
2.3. Molecular docking of compounds 6a, d, f and nifedipine on
human L-type calcium channel
In order to explain the possible blockade of LCC of compounds
6a, d and f as nifedipine does, they were docked on human calcium
L-type channel to test their binding affinities. Docking studies were
done over all inner cavities facing to cytoplasm without any bias to
a specific cavity. Fig. 3 shows the aminoacids sequence of the helices where compounds docked by Vina. Recently, Pandey et al. [26]
showed a theoretical model for N-type calcium channel. They
found that their model was in agreement with previous studies on
LCC [27,28]. In current work, we have used aminoacids numeration
as proposed by Pandey et al. [26] for N-type, to facilitate any
comparison between their results than obtained by us.
Compounds 6a, d and f lowest affinity energy structures were
found docked in the same cavity conformed by IS6, IS5, IP and IIS6
helices (Fig. 4). Whereas, nifedipine lowest energy structure was
found in the cavity formed by IIS6, IIS5, IIP and IIIS6. Although
nifedipine docked in a different cavity, cavities superposition
allowed us to observed that they where almost the same indicating
that there exists subtle steric differences that lead to a different
docking for nifedipine (Fig. 4c). Pandey et al. [26] found that
MetIP.49, GluIP.50, ThrIP.48 and GluIIP.50 interact with nifedipine by
hydrogen bonds. While, we found that nifedipine interact with
those conserved aminoacids on L-type channel (TIIP,48, GIIP,49 and
EIIP,50). Van der Waals interactions, that Pandey et al. [26] found,
included SerIS6.15, LeuIIS6.18, ThrIIP.48, GlyIIP.49, PheIIIS6.11, PheIIIS6.14,
ProIIIS6.15, PheIIIS6.18, PheIIIS6.22 and ValIIIS6.19. In present study, we did
not found the same residues (due in part to the length of the helices
used on the model employed), however, residues that we found
were located on positions near to those proposed before [27]. For
example, IIIS6 residues were located on positions from V9 to P15;
while, we found residues in contact with nifedipine by Van der
Waals interactions in the same range of aminoacids (I11 and I14).
I11 and I14 were known positions on 1,4-dihydropyridines (as
nifedipine) bind [28]. Based on previous results [26e28], we proposed that Autodock Vina reproduced completely the reported
interaction between nifedipine and L-type calcium channel.
Compounds 6a, d and f are closely structurally related and these
were found on the lowest binding affinity energy obtained by
4. 672
F. Hernández et al. / European Journal of Medicinal Chemistry 70 (2013) 669e676
0
Relaxation (%)
20
40
60
80
100
1 E -4
1 E -3
0 .0 1
0 .1
[ µM ]
1
10
100
0
Relaxation (%)
20
40
60
80
100
3. Experimental
1 E -4
1 E -3
0 .0 1
0 .1
1
10
10 0
[ µM ]
20
40
60
80
100
1 E -4
1 E -3
0 .0 1
0 .1
3.1. Chemistry
Melting points were determined on an Electrothermal digital
90100 melting point apparatus and were uncorrected. The progress
of the reaction and the purity of compounds were monitored by TLC
with E. Merck silica gel 60-F254 coated aluminum sheets, in nhexane/ethyl acetate (7:3), and visualized by a 254 nm UV lamp. IR
spectra were recorded on a PerkineElmer Spectrum 100 FT-IR
spectrophotometer. NMR spectra were recorded, for solutions
in DMSO-d6 and CDCl3 with Me4Si as internal standard, on
Varian Gemini (300 MHz) and Varian VNMR System (500 MHz)
instruments. High-resolution mass spectra (HRMS) were obtained
with a JSM-GCMate II mass spectrometer, and electron impact
techniques (70 eV) were employed. The 4H-pyrans were reported
previously [20], and were used to obtained the products 6aef. CEM
discover-SP microwave reactor was used for these reactions.
0
Relaxation (%)
molecular representations (Fig. 5), 6a and f cyano group faces into
the protein; meanwhile portsides faced to the aqueous side of the
calcium channel (interacting by hydrogen bond with NIIS6.15 side
chain). 6a, d and f bowspirit group faced to the cavity side (this
group had interactions with IIIIS6.11, IIIIS6.14 {residues that have effects on dihydropyridines binding} [28] and GIIS6.14) avoiding
possible steric clashes of the NO2 in ortho position from nifedipine.
On the other hand, compound 6f shows two NO2 groups at the
bowspirit side that may provide a strong negative side, which
could be neutralized by the presence of positive ions. These two
NO2 groups and their negative charge might be the reason why
Autodock Vina found the cavity formed by IS6, IS5, IP and IIS6 a
better location for 6f. In this cavity, there exist an additional NIIS6.15
that could form hydrogen bonds with a NO2 groups. Compound 6f
were docked with the bowspirit side facing into the protein side of
the channel, but the cyano group was located on a position that is
not able to make the same hydrogen bond with NIIS6.15 side.
Compound 6d docked their stern group into the protein cavity as
nifedipine does, but the lack of an esther group (instead of the
cyano on 6d) reduced the number of hydrophobic interactions
with protein residues that might influenced its binding affinity for
protein.
In conclusion, it was designed and synthesized some hybrid
milrinoneenifedipine analogs by greener method with significant
potent and efficient vasorelaxant effect that could be used as Hit for
the development of new analogs with more potency and efficacy
than described here. Also, computational studies allowed us to
hypothesize that more active compounds are acting as LCC
blockers, which suggest that our compounds could be used in the
treatment of hypertension and related diseases.
1
10
100
[ µM ]
Fig. 2. Concentrationeresponse curves of most active compounds 6a, d and f on aorta
rat rings pre-contracted with NA (0.1 mM).
Autodock Vina (À6.3, À6.6, À5.8 and À6.5 kcal/mol for nifedipine,
6a, d and f, respectively). Using Goldmann and Stoltefuss [29]
nomenclature (portside, bowspirit, starboard and stern), 6a,
d and f have a cyano and carbonyl group in the starboat side and
they differ in the bowspirit group. 6a has a NO2 group in para position, while 6f shows two NO2 substituents in ortho and para,
respectively. Moreover, 6d change from a bencyl group to a 2thienyl cycle. As noted in the 2D interaction diagrams and 3D
3.1.1. General procedure for the preparation of ethyl-5-cyano-2methyl-6-oxo-4-hetero and carboaryl-1,4,5,6-tetrahydropyridine-3carboxylate (5aef)
3.1.1.1. Method A. A mixture of 4H-pyran 4aef (1.50 mmol) and
concentrated sulfuric acid (10 mol%) in EtOH (3 mL) was irradiated
with infrared until at 80 C (50 V) for 15 min. The progress of the
reaction was monitored by TLC (hexane/EtOAc, 7:3). The reaction
was continued to carry out a recrystallization using a proportion
H2O/EtOH (95/5) to obtain the mixture of the two diastereoisomers.
The obtained solid was collected by vacuum filtration; the product
was allowed to dry and then quantified.
3.1.1.2. Method B. In a pressure tube for microwave reactions was
placed 4H-pyran 4aef (1.50 mmol) and 3 mL of EtOH added. To the
reaction mixture was added concentrated sulfuric acid (10 mol%).
5. F. Hernández et al. / European Journal of Medicinal Chemistry 70 (2013) 669e676
673
Fig. 3. Aminoacid sequence for L-type calcium channel where nifedipine, 6a, d and f where found docked. Aminoacid sequence for N-type calcium channel for its corresponding
helices is shown. Aminoacid sequence and numeration where taken from Pandey et al. [26]. Blue color on N-type sequences shows those residues that Pandey et al. [26] found that
interact with nifedipine, and which, we also found that interact with it on L-type calcium channel. (For interpretation of the references to color in this figure legend, the reader is
referred to the web version of this article.)
The reaction mixture was irradiated with microwave irradiation
until a reaction temperature of 100 C for 5 min, 39 psi, 10 W. The
end of the reaction was confirmed by TLC using a 7:3 (Hex/AcOEt).
The reaction was continued to carry out a recrystallization using a
proportion H2O/EtOH (95/5) to obtain the mixture of the two diastereoisomers. The obtained solid was collected by vacuum
filtration; the product was allowed to dry and then quantified.
3.1.2. General procedure for the preparation of ethyl-5-cyano-2methyl-6-oxo-4-hetero and carbo aryl-1,6-dihydropyridine-3carboxylate (6aef)
3.1.2.1. Method A. A mixture of 1,4,5,6-tetrahydropyridine (5aef).
(1.52 mmol), ethanol (3 mL) and DDQ (1.52 mmol) was irradiated
with infrared until at 80 C (50 V) for 10 min. The progress of the
reaction was monitored by TLC (EtOAc/hexane 5:5). The reaction
was purificated by chromatography column (hexane/AcOEt, 1/1).
The obtained solid was collected after vacuum.
3.1.2.2. Method B. A mixture of 1,4,5,6-tetrahydropyridine (5aef).
(1.52 mmol), ethanol (3 mL) and DDQ (1.52 mmol) was irradiated
with microwaves until at 100 C, 39 psi, 10 W for 5 min. The
progress of the reaction was monitored by TLC (EtOAc/hexane 5:5).
The reaction was purificated by chromatography column (hexane/
AcOEt, 1:1). The obtained solid was collected after vacuum.
3.1.3. Ethyl-5-cyano-2-methyl-4-(4-nitrophenyl)-6-oxo-1,6dihydropyridine-3-carboxylate (6a)
Yield: 91%; brown solid; mp 208e210 C; IR (KBr): 2254, 1651,
1283 cmÀ1; 1H NMR (DMSO-d6, 200 MHz) d 13.13 (s, 1H), 8.46 (d,
J ¼ 8.4 Hz, 2H), 7.74 (d, 2H, J ¼ 8.4 Hz), 3.92 (q, 2H, J ¼ 7 Hz), 2.54 (s, 3H),
0.80 (t, 3H, J ¼ 7 Hz); 13C NMR (CDCl3, 50 MHz): d 164.2, 159.4, 157.8,
154.9, 147.9, 142.8, 128.9, 123.6, 115.0, 110.9, 101.0, 61.05, 18.7, 13.1;
HRMS (EIþ) calculated for C16H13N3O5: 327.0855, found 327.0855.
3.1.4. Ethyl-5-cyano-4-(furan-2-yl)-2-methyl-6-oxo-1,6dihydropyridine-3-carboxylate (6b)
Yield: 90%; yellow solid; mp 223e225 C; IR (KBr): 3118, 2226,
1653 cmÀ1; 1H NMR (DMSO-d6, 200 MHz) d 7.93 (1H, d, J ¼ 1.6 Hz),
7.24 (1H, d, J ¼ 3.8 Hz), 6.07 (1H, m), 4.10 (2H, q, J ¼ 7 Hz), 2.35 (3H,
s), 1.05 (3H, t, J ¼ 7 Hz), 13C NMR (CDCl3, 50 MHz): d 165.3, 160.1,
152.8, 146.3, 146.1, 145.1, 115.8, 115.6, 112.6, 109.6, 96.1, 61.4, 17.9,
13.7; HRMS (EIþ) calculated for C14H12N2O4: 272.0797, found
272.0797.
3.1.5. Ethyl-5-cyano-2-methyl-6-oxo-4-(pyridin-4-yl)-1,6dihydropyridine-3-carboxylate (6c)
Yield: 84%; brown solid; mp 174e176 C; IR (KBr): 2928, 2228,
1678 cmÀ1; 1H NMR (DMSO-d6, 200 MHz) d 8.71 (d, J ¼ 5.4 Hz, 2H),
7.08 (d, J ¼ 5.6 Hz, 2H), 3.82 (q, J ¼ 7 Hz, 2H), 2.64 (3H, s), 0.71 (3H, t,
J ¼ 7 Hz), 13C NMR (CDCl3, 50 MHz): d 164.2, 159.5, 157.1, 155.0,
149.8, 144.1, 121.9, 114.9, 110.7, 100.7, 61.1, 18.6, 12.9; HRMS (EIþ)
calculated for C15H13N3O3: 283.0956, found 283.0923.
3.1.6. Ethyl-5-cyano-2-methyl-4-(2-thienyl)-6-oxo-1,6dihydropyridine-3-carboxylate (6d)
Yield: 94%; brown solid; mp 212e214 C; IR (KBr): 2991, 2221,
1655, 1285 cmÀ1; 1H NMR (DMSO-d6, 200 MHz) d 13.00 (1H, s), 7.86
(d, J ¼ 4.8 Hz, 1H), 7.31 (s, 1H), 7.20 (t, J ¼ 4.2 Hz, 1H), 3.92 (q,
J ¼ 7 Hz 2H), 2.36 (s, 3H), 0.89 (t, J ¼ 7 Hz, 3H); 13C NMR (CDCl3,
50 MHz): d 165.0, 159.7; 152.7, 151.7, 134.9, 129.8, 129.5, 127.7, 115.4,
112.5, 100.6, 61.3, 18.1, 13.3; HRMS (EIþ) calculated for C14H12N2O3S:
288.0568, found 288.0569.
3.1.7. Ethyl-4-(3-chlorophenyl)-5-cyano-2-methyl-6-oxo-1,6dihydropyridine-3-carboxylate (6e)
Yield: 95%; red solid; mp 230e232 C; IR (KBr): 3331, 2229,
1646 cmÀ1; 1H NMR (DMSO-d6, 200 MHz) d 7.59 (m, 1H), 7.48 (m,
2H), 7.26 (m, 1H), 3.83 (q, J ¼ 7 Hz, 2H), 2.41 (s, 3H), 0.77 (t,
J ¼ 7 Hz, 3H); 13C NMR (CDCl3, 50 MHz): d 164.5, 159.6, 157.9,
153.9, 138.0, 130.5, 129.3, 127.0, 126.1, 115.2, 111.6, 100.9, 60.9, 18.4,
13.1; HRMS (EIþ) calculated for C16H13ClN2O3: 316.7390, found
316.7381.
3.1.8. Ethyl-5-cyano-4-(2,4-dinitrophenyl)-2-methyl-6-oxo-1,6dihydropyridine-3-carboxylate (6f)
Yield: 85%; red solid; mp 268e269 C; IR (KBr): 2231, 1677,
1282 cmÀ1; 1H NMR (DMSO-d6, 200 MHz) d 9.02 (d, J ¼ 1.8, 1H), 8.74
(1H, d, J ¼ 8.4 Hz), 7.83 (d, J ¼ 8.4 Hz, 1H), 3.92 (2H, q, J ¼ 7 Hz); 2.62
(3H, s); 0.90 (t, J ¼ 7 Hz, 3H); 13C NMR (CDCl3, 50 MHz): d 162.9,
158.9, 157.2, 156.7, 147.8, 146.3, 137.9, 131.3, 128.4, 119.6, 113.9, 108.3,
100.8, 60.9, 19.8, 13.2; HRMS (EIþ) calculated for C16H12N4O7:
372.0706, found 372.0700.
6. 674
F. Hernández et al. / European Journal of Medicinal Chemistry 70 (2013) 669e676
3.2. Vasorelaxant activity
All animals were sacrificed by cervical dislocation and the
thoracic aorta was removed, cleaned, and cut in about 3e5 mm
length rings. In addition, for some aortic rings the endothelium
layer was removed by manual procedures. Then, each piece of
tissue was suspended in a tissue chamber containing Krebs
Fig. 4. a) Top view and b) side view of calcium channel model with ligands docked.
The ligands are shown on sticks. Nifedipine, 6a and d were docked in the same
location. c) Superposition of those helices (white ribbon for cavity conformed for IIS6,
IIS5, IIP and IIIS6 helices and green ribbon for cavity of IS6, IS5, IP and IIS6 helices) that
conformed the cavities where compounds were docked. Ligands are shown on sticks
(nifedipine in blue, 6a in red, 6d in orange and 6f in yellow). (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of this
article.)
Fig. 5. Proteineligand interactions diagrams (left) and its corresponding molecular structure representation (right). Circles on green represents non-polar interactions and pink circles polar interactions. (For interpretation of the references
to color in this figure legend, the reader is referred to the web version of this
article.)
7. F. Hernández et al. / European Journal of Medicinal Chemistry 70 (2013) 669e676
solution at 37 C, continuously gassed with O2/CO2 (9:1). Tissues
were placed under a resting tension of 3.0 g and allowed to stabilize for 60 min. The contractions were recorded with an isometrical force transducer Grass FT 03 (Astromed, West Warwick,
RI), connected to a MP100 Manager Biopac System polygraph
(Biopac Instruments, Santa Barbara, CA). After the stabilization
period the tissues were stimulated with NA (0.1 mM) during
10 min and they were washed with fresh Krebs solution. This
procedure was repeated three times at 30 min intervals before
starting the experiments. The absence or presence of endothelium layer was confirmed by the lack of the relaxant response
induced by carbachol (1 mM) in the last contraction to assess
viability. Finally, all tissues were contracted with NA and test
samples (pure compounds or positive control) were added to the
bath in quarter-log cumulative concentrations (evaluation
period). The relaxant effect of the samples was determined by its
ability to induce a maximal vascular contraction before and after
their addition.
3.3. Docking
Lipkind’s molecular model of calcium channel L-type was
kindly obtained from Prof. Mancilla-Percino et al., 2010 [30].
The sequence present on the original structure was modified to
be on agreement with NCBI sequence NP_005174.2 for subunit
alpha-1F isoform 1. Missing hydrogens were built and the final
channel structure energy minimized with 250 steps of steepest
descent method using Amber ff99SB parameters [31] as
implemented on Chimera USCF software [32]. Nifedipine, 6a,
d and f compounds were built using Avogadro software version
1.1.0 [33]. Geometry optimization of each ligand was done using
RM1 method for MOPAC [34] as implemented on Avogadro.
Pymol [35] and Autodock/Vina plugin for PyMOL were used to
prepare all the necessary files for docking [36]. Only polar
atoms were used for protein. Protein grid was centered at (0.5,
0.42, 5.2) with dimensions of the grid of 28 Â 32 Â 22 with a
A
spacing of 1 between grid points with exhaustiveness of 48.
Docking was performed by Autodock Vina version 1.1.2 [37].
Proteineligand diagram interactions were done using Discovery
Studio Visualizer [38] and all molecular structures with VMD
[39].
Acknowledgments
This study was financed by a grant from “Apoyo a la Mejora del
Perfil Individual del profesorado de tiempo completo (Fondo para la
Consolidación de las Universidades Públicas Estatales y con Apoyo
Solidario Ejercicio 2009)” and Faculty of Pharmacy Budgets (FECES
2011 and 2012). F.H. thanks CONACyT for a graduate scholarship
(no. 482137) M.A.V. acknowledges CONACyT (grant 168474) and
UGto-DAIP (grant 281/13).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.10.018.
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