Marcus Malo - Academia.edu (original) (raw)

Papers by Marcus Malo

Journal of Medicinal Chemistry, Nov 21, 2016

Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-s... more Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.

ACS Chemical Neuroscience, Dec 18, 2019

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associat... more Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N-desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M 1 receptor (M 1) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M 1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesised to establish a structureactivity relationship (SAR) at the M 1 receptor as an indication of potential pro-cognitive properties. In vitro evaluation revealed a narrow SAR in which M 1 agonist activity was established by functionalisation in the 4-and 8-positions in the tricyclic core. In vivo behavioural response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M 1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M 1 agonist activity. Co-treatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f, in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential pro-cognitive activity.

Dopamine (DA) is an endogenous neurotransmitter acting in the central nervous system. DA plays a ... more Dopamine (DA) is an endogenous neurotransmitter acting in the central nervous system. DA plays a key role in many vital brain functions such as behavior, cognition, motor activity, learning, and reward. Dopamine receptors belong to the rhodopsin like family of G-protein coupled receptors (GPCRs). There are five subtypes of DA receptors (D1-D5), which are further divided into two main families based on sequence similarities and their coupling to intracellular signaling (D1and D2-like receptors). Dopamine agonists mimic the effects of the natural neurotransmitter and it has been found that selective dopamine D2 or D1 and mixed D1/D2 agonists are useful in the treatment of Parkinson disease. As D2 (but not D1) agonists have shown undesirable dyskinetic effects it is of highest interest to understand the reasons behind D1/D2 agonist selectivity. This thesis is focused on the identification of structural features that determine the selectivity of D1 and D2 receptor agonists for their respective receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor, and excluded volumes where no heavy atoms are permitted. The sets of D1 and D2 ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. 3D receptor models in their agonist bound state were also generated for dopamine D1 and D2, in order to get improved insight into agonist binding. The constructed D1 and D2 agonist pharmacophore models were superimposed into their corresponding receptor model. The arrangement of pharmacophoric features were in agreement with the position of the agonist key interacting amino acids in the binding site, with exception of one hydrogen bond accepting/donating feature in the D2 model and the positioning of the excluded volumes in both models. Both pharmacophore models were refined to better reflect the shape of the binding pocket and had similar pharmacophore hit rate when screening the test sets of dopamine ligands. Several key factors for D1/D2 agonist selectivity were identified. In addition, a semi-empirical method to model transmembrane proteins with focus on the ligand binding site has been developed. The method was evaluated by generating a β1-adrenergic receptor model which had an RMSD of 1.6 Å for all heavy atoms in the binding site relative the crystal structure. A D2 receptor model with an agonist present was constructed, but this model was unable to discriminate actives from inactives in a docking study.

ChemMedChem, Feb 1, 2010

The inside cover picture shows apomorphine docked into the dopamine D2 receptor pharmacophore mod... more The inside cover picture shows apomorphine docked into the dopamine D2 receptor pharmacophore model. The solid spheres represent excluded volumes (grey), H bond acceptors/donors (cyan), functionalities interacting with the protonated amino group (Asp-TM3) (red), and projected features of the p-system normals (orange). The mesh spheres represent a cation feature (blue) and an aromatic centroid feature (orange). For more details, see the Full Paper by P. Svensson, et al. on p. 232 ff.

Journal of Organic Chemistry, Jun 17, 2021

This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoa... more This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoates. The reaction is a BBr 3-promoted cyclization of 1,6-ketoesters (1) to five-membered diketo compounds (2). The synthesis is interesting as it constitutes one of the few examples of modular stereoselective synthesis of structures with a cis-oriented vicinal diphenylethylene. The core structure of 2 can be smoothly derivatized, which makes it a promising synthetic building block for further stereoselective synthetic applications.

Journal of Computer-aided Molecular Design, Mar 1, 2013

Prediction of 3D structures of membrane proteins, and of G-protein coupled receptors (GPCRs) in p... more Prediction of 3D structures of membrane proteins, and of G-protein coupled receptors (GPCRs) in particular, is motivated by their importance in biological systems and the difficulties associated with experimental structure determination. In the present study, a novel method for the prediction of 3D structures of the membrane-embedded region of helical membrane proteins is presented. A large pool of candidate models are produced by repacking of the helices of a homology model using Monte Carlo sampling in torsion space, followed by ranking based on their geometric and ligand-binding properties. The trajectory is directed by weak initial

The Journal of Organic Chemistry, 2021

This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoa... more This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoates. The reaction is a BBr 3-promoted cyclization of 1,6-ketoesters (1) to five-membered diketo compounds (2). The synthesis is interesting as it constitutes one of the few examples of modular stereoselective synthesis of structures with a cis-oriented vicinal diphenylethylene. The core structure of 2 can be smoothly derivatized, which makes it a promising synthetic building block for further stereoselective synthetic applications.

ACS Chemical Neuroscience, 2019

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associat... more Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N-desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M 1 receptor (M 1) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M 1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesised to establish a structureactivity relationship (SAR) at the M 1 receptor as an indication of potential pro-cognitive properties. In vitro evaluation revealed a narrow SAR in which M 1 agonist activity was established by functionalisation in the 4-and 8-positions in the tricyclic core. In vivo behavioural response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M 1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M 1 agonist activity. Co-treatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f, in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential pro-cognitive activity.

Bioorganic & Medicinal Chemistry, 2019

Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD +-dependent protein deacylases... more Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD +-dependent protein deacylases regulating the acylation state of ε-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.

Journal of Medicinal Chemistry, 2016

Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-s... more Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.

European Journal of Medicinal Chemistry, 2016

A scaffold approach has been used to develop somatostatin β-turn mimetics based on chroman-4-one ... more A scaffold approach has been used to develop somatostatin β-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II´ β-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2-and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have K i-values in the low µM range when evaluated for their affinity for the sst2 and sst4 receptors.

ACS chemical neuroscience, May 17, 2016

Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack ... more Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose-response. Apomorphine increased the distance of each swim...

Journal of Medicinal Chemistry, 2016

The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR−Nurr1) and is a pr... more The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR−Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC 50 of 8.2) and RXR−Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.

Journal of medicinal chemistry, Jan 11, 2014

Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N(ε)-acetyl lysines on various pr... more Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N(ε)-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 th...

Journal of Medicinal Chemistry, Nov 21, 2016

Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-s... more Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.

ACS Chemical Neuroscience, Dec 18, 2019

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associat... more Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N-desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M 1 receptor (M 1) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M 1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesised to establish a structureactivity relationship (SAR) at the M 1 receptor as an indication of potential pro-cognitive properties. In vitro evaluation revealed a narrow SAR in which M 1 agonist activity was established by functionalisation in the 4-and 8-positions in the tricyclic core. In vivo behavioural response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M 1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M 1 agonist activity. Co-treatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f, in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential pro-cognitive activity.

Dopamine (DA) is an endogenous neurotransmitter acting in the central nervous system. DA plays a ... more Dopamine (DA) is an endogenous neurotransmitter acting in the central nervous system. DA plays a key role in many vital brain functions such as behavior, cognition, motor activity, learning, and reward. Dopamine receptors belong to the rhodopsin like family of G-protein coupled receptors (GPCRs). There are five subtypes of DA receptors (D1-D5), which are further divided into two main families based on sequence similarities and their coupling to intracellular signaling (D1and D2-like receptors). Dopamine agonists mimic the effects of the natural neurotransmitter and it has been found that selective dopamine D2 or D1 and mixed D1/D2 agonists are useful in the treatment of Parkinson disease. As D2 (but not D1) agonists have shown undesirable dyskinetic effects it is of highest interest to understand the reasons behind D1/D2 agonist selectivity. This thesis is focused on the identification of structural features that determine the selectivity of D1 and D2 receptor agonists for their respective receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor, and excluded volumes where no heavy atoms are permitted. The sets of D1 and D2 ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. 3D receptor models in their agonist bound state were also generated for dopamine D1 and D2, in order to get improved insight into agonist binding. The constructed D1 and D2 agonist pharmacophore models were superimposed into their corresponding receptor model. The arrangement of pharmacophoric features were in agreement with the position of the agonist key interacting amino acids in the binding site, with exception of one hydrogen bond accepting/donating feature in the D2 model and the positioning of the excluded volumes in both models. Both pharmacophore models were refined to better reflect the shape of the binding pocket and had similar pharmacophore hit rate when screening the test sets of dopamine ligands. Several key factors for D1/D2 agonist selectivity were identified. In addition, a semi-empirical method to model transmembrane proteins with focus on the ligand binding site has been developed. The method was evaluated by generating a β1-adrenergic receptor model which had an RMSD of 1.6 Å for all heavy atoms in the binding site relative the crystal structure. A D2 receptor model with an agonist present was constructed, but this model was unable to discriminate actives from inactives in a docking study.

ChemMedChem, Feb 1, 2010

The inside cover picture shows apomorphine docked into the dopamine D2 receptor pharmacophore mod... more The inside cover picture shows apomorphine docked into the dopamine D2 receptor pharmacophore model. The solid spheres represent excluded volumes (grey), H bond acceptors/donors (cyan), functionalities interacting with the protonated amino group (Asp-TM3) (red), and projected features of the p-system normals (orange). The mesh spheres represent a cation feature (blue) and an aromatic centroid feature (orange). For more details, see the Full Paper by P. Svensson, et al. on p. 232 ff.

Journal of Organic Chemistry, Jun 17, 2021

This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoa... more This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoates. The reaction is a BBr 3-promoted cyclization of 1,6-ketoesters (1) to five-membered diketo compounds (2). The synthesis is interesting as it constitutes one of the few examples of modular stereoselective synthesis of structures with a cis-oriented vicinal diphenylethylene. The core structure of 2 can be smoothly derivatized, which makes it a promising synthetic building block for further stereoselective synthetic applications.

Journal of Computer-aided Molecular Design, Mar 1, 2013

Prediction of 3D structures of membrane proteins, and of G-protein coupled receptors (GPCRs) in p... more Prediction of 3D structures of membrane proteins, and of G-protein coupled receptors (GPCRs) in particular, is motivated by their importance in biological systems and the difficulties associated with experimental structure determination. In the present study, a novel method for the prediction of 3D structures of the membrane-embedded region of helical membrane proteins is presented. A large pool of candidate models are produced by repacking of the helices of a homology model using Monte Carlo sampling in torsion space, followed by ranking based on their geometric and ligand-binding properties. The trajectory is directed by weak initial

The Journal of Organic Chemistry, 2021

This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoa... more This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoates. The reaction is a BBr 3-promoted cyclization of 1,6-ketoesters (1) to five-membered diketo compounds (2). The synthesis is interesting as it constitutes one of the few examples of modular stereoselective synthesis of structures with a cis-oriented vicinal diphenylethylene. The core structure of 2 can be smoothly derivatized, which makes it a promising synthetic building block for further stereoselective synthetic applications.

ACS Chemical Neuroscience, 2019

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associat... more Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N-desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M 1 receptor (M 1) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M 1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesised to establish a structureactivity relationship (SAR) at the M 1 receptor as an indication of potential pro-cognitive properties. In vitro evaluation revealed a narrow SAR in which M 1 agonist activity was established by functionalisation in the 4-and 8-positions in the tricyclic core. In vivo behavioural response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M 1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M 1 agonist activity. Co-treatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f, in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential pro-cognitive activity.

Bioorganic & Medicinal Chemistry, 2019

Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD +-dependent protein deacylases... more Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD +-dependent protein deacylases regulating the acylation state of ε-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.

Journal of Medicinal Chemistry, 2016

Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-s... more Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.

European Journal of Medicinal Chemistry, 2016

A scaffold approach has been used to develop somatostatin β-turn mimetics based on chroman-4-one ... more A scaffold approach has been used to develop somatostatin β-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II´ β-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2-and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have K i-values in the low µM range when evaluated for their affinity for the sst2 and sst4 receptors.

ACS chemical neuroscience, May 17, 2016

Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack ... more Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose-response. Apomorphine increased the distance of each swim...

Journal of Medicinal Chemistry, 2016

The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR−Nurr1) and is a pr... more The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR−Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC 50 of 8.2) and RXR−Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.

Journal of medicinal chemistry, Jan 11, 2014

Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N(ε)-acetyl lysines on various pr... more Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N(ε)-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 th...