Background: Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a prog... more Background: Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a program to discover natural inhibitors of carcinogenesis. Zapote blanco, the fruit of Casimiroa edulis, is consumed in many parts of the world. Zapotin is a non-toxic inducer of cellular differentiation, apoptosis and cell cycle arrest with cultured HL-60 promyelocytic cells. Materials and methods: An efficient chemical synthesis for zapotin was devised. Using this synthetic material, activity was examined in the two-stage mouse skin carcinogenesis model. Results: Topical zapotin significantly inhibited 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced mouse skin tumorigenesis, using the anti-initiation and anti-promotion protocols. Conclusion: Encouraging results from previous and current in vivo studies warrant further investigation of the chemopreventive activity of zapotin.
Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for... more Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure‐based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB‐ID: 4ZGA), the S‐enantiomer (Gscore = −13.168 kcal/mol) of the bound ligand PAT‐494 scored better than its R‐enantiomer (Gscore = −9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT‐494. Accordingly, the docking‐based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L‐tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 an...
L'invention concerne des composes flavonoides substitues et des formulations pharmaceutiques ... more L'invention concerne des composes flavonoides substitues et des formulations pharmaceutiques de composes flavonoides. Des procedes de preparation des composes flavonoides, et des procedes de traitement du cancer chez des mammiferes utilisant les composes flavonoides decrits ou les formulations pharmaceutiques de ceux-ci sont egalement decrits.
A series of novel bicyclic, substituted pyrimidinone compounds were designed, synthesized and cha... more A series of novel bicyclic, substituted pyrimidinone compounds were designed, synthesized and characterized. In vitro antiproliferative activity of the synthesized compounds was evaluated against six different human cancer cell lines using MTT assay. Among all twenty four compounds tested, compound 22 (N-([1,1'-biphenyl]-4-yl)-2-((3-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2-a]pyrimidin-2-yl)oxy)acetamide) exhibited significant cell growth inhibition of human liver cancer cells HepG2 with GIC 50 (50% growth inhibitory concentration) value of 120 + 10 nM and was found to be selective over healthy human embryonic kidney (HEK) cell line (33.1% inhibition at 20 μM). Further studies demonstrated that compound 22 induced cell apoptosis in HepG2 cells and resulted in similar effect to Staurosporine, a well known proapoptopic compound widely used to induce apoptosis in various cancer cell lines. Compound 22 also rendered acceptable aqueous solubility (3.5 + 0.37 μM, at pH 7.4) and attractive metabolic stability against human liver microsomes with a half-life of 34.63 + 0.33 minutes. Based on the similarity observed between the known tankyrase-1 inhibitors available in literature and compound 22, in silico docking study was performed and the results suggested that the compound interacted with the key amino acid residues present in the tankyrase-1 enzyme active site.
A new, convenient synthesis of dibenzo[b,e]azepin-6-ones and seven-membered sultam derivatives ha... more A new, convenient synthesis of dibenzo[b,e]azepin-6-ones and seven-membered sultam derivatives have been envisaged via Pd-catalyzed regioselective intramolecular Heck reaction of the corresponding easily accessible precursors. This protocol has been successfully implemented to synthesize N-methyldarenzepine in four steps and in good yield. Moreover, one of the intermediates has been utilized for the synthesis of a new analogue of darenzepine. Preliminary modeling studies were performed to investigate the binding potential to muscarinic acetylcholine receptor (M4).
Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a program to disco... more Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a program to discover natural inhibitors of carcinogenesis. Zapote blanco, the fruit of Casimiroa edulis, is consumed in many parts of the world. Zapotin is a non-toxic inducer of cellular differentiation, apoptosis and cell cycle arrest with cultured HL-60 promyelocytic cells. An efficient chemical synthesis for zapotin was devised. Using this synthetic material, activity was examined in the two-stage mouse skin carcinogenesis model. Topical zapotin significantly inhibited 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced mouse skin tumorigenesis, using the anti-initiation and anti-promotion protocols. Encouraging results from previous and current in vivo studies warrant further investigation of the chemopreventive activity of zapotin.
We describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely te... more We describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely tethered aldehyde, [b] the effect of a Lewis acid upon the course of TMM chemistry, [c] examples of exclusive intramolecular cycloaddition, competitive cycloaddition and ATC, and exclusive ATC, and [d] a set of predictive guidelines with which to assess whether cycloaddition or ATC will be the preferred path, and when the two processes will be competitive. Remarkably, a wide variety of structures can be obtained simply by varying the length of the tether within the diazenes investigated. DFT calculations were used to probe the energy surfaces for both atom transfer and cycloaddition. The transition structure for atom transfer involving the captodative system indicates that it occurs earlier along the reaction coordinate than for a system having only one radical stabilizing group. This is consistent with the existence of an exothermic process leading from the initial diyl to the captodatively stabilized distonic diyl. Gratifyingly, theory agrees with observation and provides substantial insight into the chemistry. this paper we describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely tethered aldehyde, [b] the effect of a Lewis acid upon the course of TMM chemistry, [c] examples of exclusive intramolecular cycloaddition, competitive cycloaddition and ATC, and exclusive ATC, and [d] a set of predictive guidelines with which to assess whether cycloaddition or ATC will be the preferred path, and when the two processes will be competitive.
An efficient method has been developed to synthesize zapotin (5,6,2′,6′-tetramethoxyflavone), a c... more An efficient method has been developed to synthesize zapotin (5,6,2′,6′-tetramethoxyflavone), a component of the edible fruit Casimiroa edulis, on multi-gram scale. The synthesis utilizes a regioselective C-acylation of a dilithium dianion derived from a substituted o-hydroxyactophenone to afford a β-diketone intermediate that can be cyclized to zapotin in good overall yield, thus avoiding the inefficient Baker-Venkataraman rearrangement pathway. Zapotin was found to induce both cell differentiation and apoptosis with cultured human promyelocytic leukemia cells (HL-60 cells). In addition, the compound inhibits 12-O-tetradecanoylphorbol 13-acetate (TPAc)-induced ornithine decarboxylase (ODC) activity with human bladder carcinoma cells (T24 cells), and TPA-induced nuclear factor-kappa B (NF-κB) activity with human hepatocellular liver carcinoma cells (HepG2 cells). These data suggest that zapotin merits further investigation as a potential cancer chemopreventive agent.
An efficient and economical synthesis of the naturally occurring aromatase inhibitor abyssinone I... more An efficient and economical synthesis of the naturally occurring aromatase inhibitor abyssinone II was performed. The synthesis features an optimized aromatic prenylation reaction in which an arylcopper intermediate is reacted with prenyl bromide to afford a key intermediate that was converted to a prenylated aromatic aldehyde. Condensation of the aldehyde with an o-hydroxyacetophenone under Claisen-Schmidt conditions afforded a chalcone that was deprotected and cyclized in the presence of sodium acetate in refluxing ethanol to afford (+/-)-abyssinone II. The synthesis proved to be versatile enough to provide an array of abyssinone II derivatives that were evaluated as aromatase inhibitors. Methylation of the 4'-hydroxyl group of (+/-)-abyssinone II resulted in a significant increase in aromatase inhibitory activity, and further smaller increases in activity resulted from the methylation of the 7-hydroxyl group and removal of the prenyl side chain. As a result of these structural changes, the most active flavanone of the series was 20 times more potent than (+/-)-abyssinone II (IC50 40.95 microM).
An efficient method has been developed to synthesize casimiroin (1), a component of the edible fr... more An efficient method has been developed to synthesize casimiroin (1), a component of the edible fruit of Casimiroa edulis, on a multigram scale in good overall yield. The route was versatile enough to provide an array of compound 1 analogues that were evaluated as QR2 and aromatase inhibitors. In addition, X-ray crystallography studies of QR2 in complex with compound 1 and one of its more potent analogs has provided insight into the mechanism of action of this new series of QR2 inhibitors. The initial biological investigations suggest that compound 1 and its analogues merit further investigation as potential chemopreventive or chemotherapeutic agents.
An efficient protocol for the synthesis of chiral polyhydroxy diacetylenic alcohols from chiral 4... more An efficient protocol for the synthesis of chiral polyhydroxy diacetylenic alcohols from chiral 4,5-O-isopropylidene propargyl chlorides using strong bases is described and is useful for the synthesis of biologically active natural products.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Background: Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a prog... more Background: Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a program to discover natural inhibitors of carcinogenesis. Zapote blanco, the fruit of Casimiroa edulis, is consumed in many parts of the world. Zapotin is a non-toxic inducer of cellular differentiation, apoptosis and cell cycle arrest with cultured HL-60 promyelocytic cells. Materials and methods: An efficient chemical synthesis for zapotin was devised. Using this synthetic material, activity was examined in the two-stage mouse skin carcinogenesis model. Results: Topical zapotin significantly inhibited 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced mouse skin tumorigenesis, using the anti-initiation and anti-promotion protocols. Conclusion: Encouraging results from previous and current in vivo studies warrant further investigation of the chemopreventive activity of zapotin.
Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for... more Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure‐based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB‐ID: 4ZGA), the S‐enantiomer (Gscore = −13.168 kcal/mol) of the bound ligand PAT‐494 scored better than its R‐enantiomer (Gscore = −9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT‐494. Accordingly, the docking‐based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L‐tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 an...
L'invention concerne des composes flavonoides substitues et des formulations pharmaceutiques ... more L'invention concerne des composes flavonoides substitues et des formulations pharmaceutiques de composes flavonoides. Des procedes de preparation des composes flavonoides, et des procedes de traitement du cancer chez des mammiferes utilisant les composes flavonoides decrits ou les formulations pharmaceutiques de ceux-ci sont egalement decrits.
A series of novel bicyclic, substituted pyrimidinone compounds were designed, synthesized and cha... more A series of novel bicyclic, substituted pyrimidinone compounds were designed, synthesized and characterized. In vitro antiproliferative activity of the synthesized compounds was evaluated against six different human cancer cell lines using MTT assay. Among all twenty four compounds tested, compound 22 (N-([1,1'-biphenyl]-4-yl)-2-((3-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2-a]pyrimidin-2-yl)oxy)acetamide) exhibited significant cell growth inhibition of human liver cancer cells HepG2 with GIC 50 (50% growth inhibitory concentration) value of 120 + 10 nM and was found to be selective over healthy human embryonic kidney (HEK) cell line (33.1% inhibition at 20 μM). Further studies demonstrated that compound 22 induced cell apoptosis in HepG2 cells and resulted in similar effect to Staurosporine, a well known proapoptopic compound widely used to induce apoptosis in various cancer cell lines. Compound 22 also rendered acceptable aqueous solubility (3.5 + 0.37 μM, at pH 7.4) and attractive metabolic stability against human liver microsomes with a half-life of 34.63 + 0.33 minutes. Based on the similarity observed between the known tankyrase-1 inhibitors available in literature and compound 22, in silico docking study was performed and the results suggested that the compound interacted with the key amino acid residues present in the tankyrase-1 enzyme active site.
A new, convenient synthesis of dibenzo[b,e]azepin-6-ones and seven-membered sultam derivatives ha... more A new, convenient synthesis of dibenzo[b,e]azepin-6-ones and seven-membered sultam derivatives have been envisaged via Pd-catalyzed regioselective intramolecular Heck reaction of the corresponding easily accessible precursors. This protocol has been successfully implemented to synthesize N-methyldarenzepine in four steps and in good yield. Moreover, one of the intermediates has been utilized for the synthesis of a new analogue of darenzepine. Preliminary modeling studies were performed to investigate the binding potential to muscarinic acetylcholine receptor (M4).
Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a program to disco... more Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a program to discover natural inhibitors of carcinogenesis. Zapote blanco, the fruit of Casimiroa edulis, is consumed in many parts of the world. Zapotin is a non-toxic inducer of cellular differentiation, apoptosis and cell cycle arrest with cultured HL-60 promyelocytic cells. An efficient chemical synthesis for zapotin was devised. Using this synthetic material, activity was examined in the two-stage mouse skin carcinogenesis model. Topical zapotin significantly inhibited 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced mouse skin tumorigenesis, using the anti-initiation and anti-promotion protocols. Encouraging results from previous and current in vivo studies warrant further investigation of the chemopreventive activity of zapotin.
We describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely te... more We describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely tethered aldehyde, [b] the effect of a Lewis acid upon the course of TMM chemistry, [c] examples of exclusive intramolecular cycloaddition, competitive cycloaddition and ATC, and exclusive ATC, and [d] a set of predictive guidelines with which to assess whether cycloaddition or ATC will be the preferred path, and when the two processes will be competitive. Remarkably, a wide variety of structures can be obtained simply by varying the length of the tether within the diazenes investigated. DFT calculations were used to probe the energy surfaces for both atom transfer and cycloaddition. The transition structure for atom transfer involving the captodative system indicates that it occurs earlier along the reaction coordinate than for a system having only one radical stabilizing group. This is consistent with the existence of an exothermic process leading from the initial diyl to the captodatively stabilized distonic diyl. Gratifyingly, theory agrees with observation and provides substantial insight into the chemistry. this paper we describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely tethered aldehyde, [b] the effect of a Lewis acid upon the course of TMM chemistry, [c] examples of exclusive intramolecular cycloaddition, competitive cycloaddition and ATC, and exclusive ATC, and [d] a set of predictive guidelines with which to assess whether cycloaddition or ATC will be the preferred path, and when the two processes will be competitive.
An efficient method has been developed to synthesize zapotin (5,6,2′,6′-tetramethoxyflavone), a c... more An efficient method has been developed to synthesize zapotin (5,6,2′,6′-tetramethoxyflavone), a component of the edible fruit Casimiroa edulis, on multi-gram scale. The synthesis utilizes a regioselective C-acylation of a dilithium dianion derived from a substituted o-hydroxyactophenone to afford a β-diketone intermediate that can be cyclized to zapotin in good overall yield, thus avoiding the inefficient Baker-Venkataraman rearrangement pathway. Zapotin was found to induce both cell differentiation and apoptosis with cultured human promyelocytic leukemia cells (HL-60 cells). In addition, the compound inhibits 12-O-tetradecanoylphorbol 13-acetate (TPAc)-induced ornithine decarboxylase (ODC) activity with human bladder carcinoma cells (T24 cells), and TPA-induced nuclear factor-kappa B (NF-κB) activity with human hepatocellular liver carcinoma cells (HepG2 cells). These data suggest that zapotin merits further investigation as a potential cancer chemopreventive agent.
An efficient and economical synthesis of the naturally occurring aromatase inhibitor abyssinone I... more An efficient and economical synthesis of the naturally occurring aromatase inhibitor abyssinone II was performed. The synthesis features an optimized aromatic prenylation reaction in which an arylcopper intermediate is reacted with prenyl bromide to afford a key intermediate that was converted to a prenylated aromatic aldehyde. Condensation of the aldehyde with an o-hydroxyacetophenone under Claisen-Schmidt conditions afforded a chalcone that was deprotected and cyclized in the presence of sodium acetate in refluxing ethanol to afford (+/-)-abyssinone II. The synthesis proved to be versatile enough to provide an array of abyssinone II derivatives that were evaluated as aromatase inhibitors. Methylation of the 4'-hydroxyl group of (+/-)-abyssinone II resulted in a significant increase in aromatase inhibitory activity, and further smaller increases in activity resulted from the methylation of the 7-hydroxyl group and removal of the prenyl side chain. As a result of these structural changes, the most active flavanone of the series was 20 times more potent than (+/-)-abyssinone II (IC50 40.95 microM).
An efficient method has been developed to synthesize casimiroin (1), a component of the edible fr... more An efficient method has been developed to synthesize casimiroin (1), a component of the edible fruit of Casimiroa edulis, on a multigram scale in good overall yield. The route was versatile enough to provide an array of compound 1 analogues that were evaluated as QR2 and aromatase inhibitors. In addition, X-ray crystallography studies of QR2 in complex with compound 1 and one of its more potent analogs has provided insight into the mechanism of action of this new series of QR2 inhibitors. The initial biological investigations suggest that compound 1 and its analogues merit further investigation as potential chemopreventive or chemotherapeutic agents.
An efficient protocol for the synthesis of chiral polyhydroxy diacetylenic alcohols from chiral 4... more An efficient protocol for the synthesis of chiral polyhydroxy diacetylenic alcohols from chiral 4,5-O-isopropylidene propargyl chlorides using strong bases is described and is useful for the synthesis of biologically active natural products.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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