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Joana Reis - One of the best experts on this subject based on the ideXlab platform.
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Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis
Journal of Medicinal Chemistry, 2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Jeanne Mialet-perez, Eugenio Uriarte, Angelo Parini, Andrea Mattevi, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson's disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6-1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3',4'-dimethylphenyl)-4-oxo-4 H-chromene-3-carboxamide (1), N-(3'-chlorophenyl)-4-oxo-4 H-chromene-3-carboxamide (2), and N-(3'-fluorophenyl)-4-oxo-4 H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS).
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tight binding inhibition of human monoamine oxidase b by chromone analogs a kinetic crystallographic and biological analysis
Journal of Medicinal Chemistry, 2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Eugenio Uriarte, Angelo Parini, Jeanne Mialetperez, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson’s disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6–1.8 A resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (1), N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (2), and N-(3′-fluorophenyl)-4-oxo-4H-chromene-3-carboxamide (3), respectively. These...
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Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis
2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Jeanne Mialet-perez, Eugenio Uriarte, Angelo Parini, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson’s disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6–1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (1), N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (2), and N-(3′-fluorophenyl)-4-oxo-4H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS)
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discovery of new chemical entities for old targets insights on the lead optimization of chromone based monoamine oxidase b mao b inhibitors
Journal of Medicinal Chemistry, 2016Co-Authors: Joana Reis, Fernando Cagide, Tiago H. Silva, Alexandra Gaspar, Eugenio Uriarte, Carlos Fernandes, Daniel Chavarria, Fernando Remiao, Stefano Alcaro, Francesco OrtusoAbstract:The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure–activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme–inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physi...
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discovery of new chemical entities for old targets insights on the lead optimization of chromone based monoamine oxidase b mao b inhibitors
Journal of Medicinal Chemistry, 2016Co-Authors: Joana Reis, Fernando Cagide, Tiago H. Silva, Alexandra Gaspar, Eugenio Uriarte, Carlos Fernandes, Daniel Chavarria, Fernando Remiao, Stefano Alcaro, Francesco OrtusoAbstract:The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3'-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3',4'-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies.
Fernando Cagide - One of the best experts on this subject based on the ideXlab platform.
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Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis
Journal of Medicinal Chemistry, 2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Jeanne Mialet-perez, Eugenio Uriarte, Angelo Parini, Andrea Mattevi, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson's disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6-1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3',4'-dimethylphenyl)-4-oxo-4 H-chromene-3-carboxamide (1), N-(3'-chlorophenyl)-4-oxo-4 H-chromene-3-carboxamide (2), and N-(3'-fluorophenyl)-4-oxo-4 H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS).
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tight binding inhibition of human monoamine oxidase b by chromone analogs a kinetic crystallographic and biological analysis
Journal of Medicinal Chemistry, 2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Eugenio Uriarte, Angelo Parini, Jeanne Mialetperez, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson’s disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6–1.8 A resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (1), N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (2), and N-(3′-fluorophenyl)-4-oxo-4H-chromene-3-carboxamide (3), respectively. These...
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Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis
2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Jeanne Mialet-perez, Eugenio Uriarte, Angelo Parini, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson’s disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6–1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (1), N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (2), and N-(3′-fluorophenyl)-4-oxo-4H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS)
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discovery of new chemical entities for old targets insights on the lead optimization of chromone based monoamine oxidase b mao b inhibitors
Journal of Medicinal Chemistry, 2016Co-Authors: Joana Reis, Fernando Cagide, Tiago H. Silva, Alexandra Gaspar, Eugenio Uriarte, Carlos Fernandes, Daniel Chavarria, Fernando Remiao, Stefano Alcaro, Francesco OrtusoAbstract:The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure–activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme–inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physi...
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discovery of new chemical entities for old targets insights on the lead optimization of chromone based monoamine oxidase b mao b inhibitors
Journal of Medicinal Chemistry, 2016Co-Authors: Joana Reis, Fernando Cagide, Tiago H. Silva, Alexandra Gaspar, Eugenio Uriarte, Carlos Fernandes, Daniel Chavarria, Fernando Remiao, Stefano Alcaro, Francesco OrtusoAbstract:The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3'-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3',4'-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies.
Fernanda Borges - One of the best experts on this subject based on the ideXlab platform.
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Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis
Journal of Medicinal Chemistry, 2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Jeanne Mialet-perez, Eugenio Uriarte, Angelo Parini, Andrea Mattevi, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson's disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6-1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3',4'-dimethylphenyl)-4-oxo-4 H-chromene-3-carboxamide (1), N-(3'-chlorophenyl)-4-oxo-4 H-chromene-3-carboxamide (2), and N-(3'-fluorophenyl)-4-oxo-4 H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS).
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tight binding inhibition of human monoamine oxidase b by chromone analogs a kinetic crystallographic and biological analysis
Journal of Medicinal Chemistry, 2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Eugenio Uriarte, Angelo Parini, Jeanne Mialetperez, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson’s disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6–1.8 A resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (1), N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (2), and N-(3′-fluorophenyl)-4-oxo-4H-chromene-3-carboxamide (3), respectively. These...
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Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis
2018Co-Authors: Joana Reis, Fernando Cagide, Fernanda Borges, Nicola Manzella, Jeanne Mialet-perez, Eugenio Uriarte, Angelo Parini, Claudia BindaAbstract:Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson’s disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6–1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (1), N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (2), and N-(3′-fluorophenyl)-4-oxo-4H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS)
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synthesis of 6 aryl heteroaryl 4 oxo 4h chromene 2 carboxylic ethyl ester derivatives
Tetrahedron Letters, 2016Co-Authors: Carlos Fernandes, Alexandra Gaspar, Ligia R. Gomes, John N. Low, P Soares, Diana Martins, Fernanda BorgesAbstract:Abstract The development of new chemical entities represents an important challenge in pharmaceutical industry, being the use of privileged scaffolds for library design and drug discovery a valuable approach. Among the panoply of privileged structures, our research group has focused its attention on the chromone (4 H -benzopyran-4-one) scaffold due to its chemical versatility and ability to bind to multiple targets. With this endeavour we report an expedite two-step procedure for the synthesis of novel 6-aryl/heteroaryl-4-oxo-4 H -chromene-2-carboxylic ethyl ester. The new chromones were synthesized by a C–C Suzuki cross-coupling microwave-assisted reaction, using Pd(OAc) 2 as a catalyst, and a classic Claisen condensation followed by an intramolecular cyclization process.
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Discovery of two new classes of potent monoamine oxidase-B inhibitors by tricky chemistry
Chemical Communications, 2015Co-Authors: Fernando Cagide, Tiago H. Silva, Joana Reis, Alexandra Gaspar, Fernanda Borges, Ligia R. Gomes, John N. LowAbstract:The discovery of potent and selective monoamine oxidase-B inhibitors for the management of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases is still a challenging endeavor. Herein, we report the discovery of two new classes of potent and selective MAO-B inhibitors based on Chromane-2,4-dione and chromone-3-carboxamide scaffolds.
Vyacheslav Ya. Sosnovskikh - One of the best experts on this subject based on the ideXlab platform.
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uncatalyzed highly stereoselective addition of α morpholinostyrene to 3 nitro 2 trihalomethyl 2h chromenes synthesis of trans cis and trans trans 3 nitro 4 phenacyl 2 trihalomethyl Chromanes
ChemInform, 2016Co-Authors: Vladislav Yu. Korotaev, Alexey Yu. Barkov, Mikhail I Kodess, Igor B Kutyashev, Ivan V Kotovich, Vyacheslav Ya. SosnovskikhAbstract:Abstract Reactions of 2-R-3-nitro-2H-chromenes (R=CF3, CCl3, Ph) with α-morpholinostyrene in acetonitrile proceed diastereoselectively to give mainly trans–cis-2,3,4-trisubstituted Chromane enamines at room temperature and trans–trans-Chromane enamines at 60 °C as a result of nucleophilic addition at the C-4 atom of the chromene system. Acid hydrolysis of these compounds proceeded with retention of the configuration of the pyran ring and gave 4-phenacylChromanes. The stereochemistry of the products was established by X-ray diffraction analysis.
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highly regio and stereoselective addition of aminoenones to 2 substituted 3 nitro 2h chromenes unexpected synthesis of 5 trifluoromethyl 5h chromeno 3 4 b pyridines
Tetrahedron, 2015Co-Authors: Vladislav Yu. Korotaev, Alexey Yu. Barkov, Marina A Ezhikova, Mikhail I Kodess, Igor B Kutyashev, Ivan V Kotovich, Vyacheslav Ya. SosnovskikhAbstract:Reactions of 2-R-3-nitro-2H-chromenes (R=CF3, CCl3, Ph) with aminoenones derived from acetylacetone and cyclic amines (morpholine, piperidine) proceed diastereoselectively to give mainly cis–trans-2,3,4-trisubstituted Chromanes as a result of nucleophilic addition of the vinylogous β-methyl group at the C-4 atom of the chromene system. From these compounds, under acidic conditions, 4-acetoacetonyl-3-nitroChromanes and 5H-chromeno[3,4-b]pyridines, depending on the substituent at the 2-position, were obtained in moderate to good yields. Similar results, except for the synthesis of 5H-chromeno[3,4-b]pyridines, were obtained by replacing acetylacetone with benzoylacetone. The stereochemistry of the products was established by X-ray diffraction analysis.
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synthesis of 5 trifluoromethyl 5h chromeno 3 4 b pyridines from 3 nitro 2 trifluoromethyl 2h chromenes and aminoenones derived from acetylacetone and cyclic amines
Tetrahedron Letters, 2013Co-Authors: Vladislav Yu. Korotaev, Alexey Yu. Barkov, Vyacheslav Ya. SosnovskikhAbstract:Reactions of 3-nitro-2H-chromenes with aminoenones derived from acetylacetone and cyclic amines proceed diastereoselectively to give functionalized 2,3,4-trisubstituted Chromanes as a result of nucleophilic addition of the vinylogous b-methyl group at the C-4 atom of the chromene system. From these compounds, under acidic conditions, 5-(trifluoromethyl)-5H-chromeno[3,4-b]pyridines and 4-acetoacetonyl-3-nitro-2-(trichloromethyl/phenyl)Chromanes, depending on the substituent at the 2-position, were obtained in moderate to good yields.
Kristina Luthman - One of the best experts on this subject based on the ideXlab platform.
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a scaffold replacement approach towards new sirtuin 2 inhibitors
Bioorganic & Medicinal Chemistry, 2020Co-Authors: Tina Seifert, Marcus Malo, Tarja Kokkola, Johanna E L Steen, Kristian Meinander, Erik A A Wallen, Elina M Jarho, Kristina LuthmanAbstract:Abstract Sirtuins (SIRT1–SIRT7) are an evolutionary conserved family of NAD+-dependent protein deacylases regulating the acylation state of e-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.
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chroman 4 one and chromone based sirtuin 2 inhibitors with antiproliferative properties in cancer cells
Journal of Medicinal Chemistry, 2014Co-Authors: Tina Seifert, Marcus Malo, Tarja Kokkola, Erik A A Wallen, Elina M Jarho, Maria Fridensaxin, Maija Lahtelakakkonen, Karin Engen, Kristina LuthmanAbstract:Sirtuins (SIRTs) catalyze the NAD+-dependent deacetylation of Ne-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of α-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed bas...
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synthesis and evaluation of substituted chroman 4 one and chromone derivatives as sirtuin 2 selective inhibitors
Journal of Medicinal Chemistry, 2012Co-Authors: Maria Fridensaxin, Tina Seifert, Elina M Jarho, Marie Ryden Landergren, Tiina Suuronen, Maija Lahtelakakkonen, Kristina LuthmanAbstract:A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC50 of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.