Kirby Sample - Academia.edu (original) (raw)

Papers by Kirby Sample

Inorg Chem, 1996

Superoxide radical anion has been demonstrated to be a mediator of many disease states, including... more Superoxide radical anion has been demonstrated to be a mediator of many disease states, including inflammatory, autoimmune, and cancerous diseases. As a consequence, we have developed a program to design, synthesize, and test synthetic low-molecular weight superoxide dismutase (SOD) mimics as potential pharmaceutical agents. A critical feature of the design of metal-based drugs is not only high activity as an enzyme mimic but also chemical stability. In this report we describe the synthesis and characterization of a series of C-substituted 1,4,7,-10,13-pentaazacyclopentadecane, [15]aneN 5 , ligands, 1, and their corresponding Mn(II) complexes, 2 and 3, as their dichloro complexes, [Mn([15]aneN 5)Cl 2 ]. The purpose of the work is to probe the role that substituent (methyl and fused cycloalkyl) groups exert on the catalytic activity and stability of the complexes. All of the 18 new complexes described here are catalysts for the dismutation of superoxide, and substantial substituent effects are observed with k cat values at pH) 7.4 varying in the range (1.4-9.1) × 10 7 M-1 s-1. The kinetic and thermodynamic stabilities of these new complexes were studied by a Cu(II) ion competition spectrophotometric assay and by potentiometric titrations, respectively. It is observed that increasing the number of carbon substituents increases the kinetic stability of the complexes, while the thermodynamic stability increases, but less dramatically. The crystal structure for one of these new complexes, [Mn(2,2,3,3-Me 4 [15]aneN 5)Cl 2 ], 2i, was determined, and reveals that the Mn(II) ion is coordinated by a pentagonal bipyramid array of five macrocyclic derived nitrogen atoms in a plane with the Mn(II) center and capped by trans-dichloro ligands. Crystal data for MnC 14 H 33 N 5-Cl 2 ‚CH 3 CH 2 OH: triclinic, P1 h-C i 1 (#2), a) 9.941(2) Å, b) 11.190(2) Å, c) 11.613(2) Å, V) 1125.4(4) Å 3 , Z) 2, T) 20 (1°C, for 3357 independent absorption-corrected reflections having 2θ(Cu KR) < 120.0°and I > 3σ(Ι), with R int) 0.027.

Bioorganic Chemistry, Feb 1, 2022

Liver X Receptors (LXRs) are members of the nuclear receptor family, and they play significant ro... more Liver X Receptors (LXRs) are members of the nuclear receptor family, and they play significant role in lipid and cholesterol metabolism. Moreover, they are key regulators of several inflammatory pathways. Pharmacological modulation of LXRs holds great potential in treatment of metabolic diseases, neurodegenerative diseases, and cancer. We were the first group to identify LXR inverse agonists SR9238 (6) and SR9243 (7) and demonstrate their potential utility in treating liver diseases and cancer. Here, we present the results of structure-activity relationship (SAR) studies, based around SR9238 (6) and SR9243 (7). This study led to identification of 16, 17, 19, and 38, which were more potent inverse agonists than SR9238 (6) and SR9243 (7) and inhibited expression of the fatty acid synthase gene in DU145 cells. We previously demonstrated that inhibition of FASN is correlated to the anticancer activity of SR9243 (7) and this suggests that new inverse agonists have great potential as anticancer agents. We identified compounds with distinct selectivity toward both LXR isoforms, which can be excellent tools to study the pharmacology of both isoforms. We employed molecular dynamic (MD) simulations to better understand the molecular mechanism underlying inverse agonist activity and to guide our future design.

Tetrahedron Letters, May 1, 1994

ABSTRACT A general synthetic method for the preparation of carbon-functionalized polyazamacrocycl... more ABSTRACT A general synthetic method for the preparation of carbon-functionalized polyazamacrocycles from the corresponding cyclic peptides is described.

The Journal of Organic Chemistry, 1991

Refolding of Synthetic Enzymes. Each synthetic enzyme obtained from the previoua step was dissolv... more Refolding of Synthetic Enzymes. Each synthetic enzyme obtained from the previoua step was dissolved in 25% acetic acid and passed through a Sephadex G-25 column (0.7 X 18 cm) to remove reeidual low molecular weight impurities remaining from the deprotection. The protein peak was colleded and lyophilized. The deprotected peptide was dissolved in the reduction-denaturation buffer of Pace and CreightonM (0.2 M Tris-HC1,2 mM EDTA, 0.1 M D'M', 6 M guanidine chloride, pH 8.7). The tube was purged with nitrogen, sealed, and allowed to stand for 3 h. The sample was then applied to a column of Sephadex G-25 (0.7 X 9 cm) equilibrated with 0.1 M NaCl and eluted with the same solution. The protein peak eluted first and was collected into a plastic microtube. The protein solution was kept for several hours at room temperature to allow oxidation to take place before being concentrated in a Speed-Vac apparatus to 0.1 mL and applied to a Sephadex G-25 column (0.7 x 9 cm) eluting with water. The desalted protein was collected and stored at 4 OC. Concentrations of synthetic enzymes were calculated based on the UV absorbance (cne =: 1.91 mL/mg.cm)." The mutant enzyme was assumed to have the same absorbance. Assays were as described." Acknowledgment. The mass spectrometric measurements were made by the Rockefeller Mass Spectrometric Biotechnology Resource supported by the Divison of Research Resources, NIH (Grant RR-00862-15). We thank Drs. Meng F. Ho and Berkley Lynch for carrying out some preliminary experiments including the synthesis of several (47) Takahaahi, K.

Bioorganic & Medicinal Chemistry Letters, 2005

We describe the structure-based design, synthesis, and enzymatic activity of a series of substitu... more We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P 1 amidine designed to explore additional interactions with the VIIa residues in the so-called ÔS 1 side pocketÕ. A crystal structure of the designed inhibitors demonstrates the ability of the P 1 side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.

Tetrahedron Letters, 1994

Thiophene derivatives R 0090 Asymmetric Synthesis of Highly Functionalized Tetrahydrothiophenes b... more Thiophene derivatives R 0090 Asymmetric Synthesis of Highly Functionalized Tetrahydrothiophenes by Organocatalytic Domino Reactions.-By use of optically active pyrrolidine PYR as organocatalyst for the Michael-aldol reaction of α,β-unsaturated aldehydes (I) and thiol (II), two types of tetrahydrothiophenes (III) or (IV) are obtained as single diastereomers with high enantioselectivities. The regioselectivity of the reaction leading to either carbaldehydes (III) or ketones (IV) can be controlled by the type of additive, benzoic acid or sodium bicarbonate. The high stability of both product types is explained by strong intra-and intermolecular hydrogen bondings.-(BRANDAU, S.; MAERTEN, E.;

Organic Letters, 2003

A general demonstration of orthogonal selectivity of the Liebeskind−Srogl cross-coupling protocol... more A general demonstration of orthogonal selectivity of the Liebeskind−Srogl cross-coupling protocol compared to the Suzuki−Miyaura and Stille variants is reported.

Inorganic Chemistry, 1996

Superoxide radical anion has been demonstrated to be a mediator of many disease states, including... more Superoxide radical anion has been demonstrated to be a mediator of many disease states, including inflammatory, autoimmune, and cancerous diseases. As a consequence, we have developed a program to design, synthesize, and test synthetic low-molecular weight superoxide dismutase (SOD) mimics as potential pharmaceutical agents. A critical feature of the design of metal-based drugs is not only high activity as an enzyme mimic but also chemical stability. In this report we describe the synthesis and characterization of a series of C-substituted 1,4,7,-10,13-pentaazacyclopentadecane, [15]aneN 5 , ligands, 1, and their corresponding Mn(II) complexes, 2 and 3, as their dichloro complexes, [Mn([15]aneN 5)Cl 2 ]. The purpose of the work is to probe the role that substituent (methyl and fused cycloalkyl) groups exert on the catalytic activity and stability of the complexes. All of the 18 new complexes described here are catalysts for the dismutation of superoxide, and substantial substituent effects are observed with k cat values at pH) 7.4 varying in the range (1.4-9.1) × 10 7 M-1 s-1. The kinetic and thermodynamic stabilities of these new complexes were studied by a Cu(II) ion competition spectrophotometric assay and by potentiometric titrations, respectively. It is observed that increasing the number of carbon substituents increases the kinetic stability of the complexes, while the thermodynamic stability increases, but less dramatically. The crystal structure for one of these new complexes, [Mn(2,2,3,3-Me 4 [15]aneN 5)Cl 2 ], 2i, was determined, and reveals that the Mn(II) ion is coordinated by a pentagonal bipyramid array of five macrocyclic derived nitrogen atoms in a plane with the Mn(II) center and capped by trans-dichloro ligands. Crystal data for MnC 14 H 33 N 5-Cl 2 ‚CH 3 CH 2 OH: triclinic, P1 h-C i 1 (#2), a) 9.941(2) Å, b) 11.190(2) Å, c) 11.613(2) Å, V) 1125.4(4) Å 3 , Z) 2, T) 20 (1°C, for 3357 independent absorption-corrected reflections having 2θ(Cu KR) < 120.0°and I > 3σ(Ι), with R int) 0.027.

Cheminform, May 27, 2010

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.

Tetrahedron Letters, 1999

The asymmetric synthesis of the highly functionalized (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoic a... more The asymmetric synthesis of the highly functionalized (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoic acid, the key amino acid fragment of sperabillins B and D, was achieved by an asymmetric Michael addition of lithium (R)-(et-methylbenzyl)allylamide 10 to (E,E)-2,5-heptadienoate establishing the C-3 stereogenic centre, the information from which was propagated to the C-5 and C-6 centres by a highly stereoselective iodocyclocarbamation reaction.

Inorg Chem, 1996

Superoxide radical anion has been demonstrated to be a mediator of many disease states, including... more Superoxide radical anion has been demonstrated to be a mediator of many disease states, including inflammatory, autoimmune, and cancerous diseases. As a consequence, we have developed a program to design, synthesize, and test synthetic low-molecular weight superoxide dismutase (SOD) mimics as potential pharmaceutical agents. A critical feature of the design of metal-based drugs is not only high activity as an enzyme mimic but also chemical stability. In this report we describe the synthesis and characterization of a series of C-substituted 1,4,7,-10,13-pentaazacyclopentadecane, [15]aneN 5 , ligands, 1, and their corresponding Mn(II) complexes, 2 and 3, as their dichloro complexes, [Mn([15]aneN 5)Cl 2 ]. The purpose of the work is to probe the role that substituent (methyl and fused cycloalkyl) groups exert on the catalytic activity and stability of the complexes. All of the 18 new complexes described here are catalysts for the dismutation of superoxide, and substantial substituent effects are observed with k cat values at pH) 7.4 varying in the range (1.4-9.1) × 10 7 M-1 s-1. The kinetic and thermodynamic stabilities of these new complexes were studied by a Cu(II) ion competition spectrophotometric assay and by potentiometric titrations, respectively. It is observed that increasing the number of carbon substituents increases the kinetic stability of the complexes, while the thermodynamic stability increases, but less dramatically. The crystal structure for one of these new complexes, [Mn(2,2,3,3-Me 4 [15]aneN 5)Cl 2 ], 2i, was determined, and reveals that the Mn(II) ion is coordinated by a pentagonal bipyramid array of five macrocyclic derived nitrogen atoms in a plane with the Mn(II) center and capped by trans-dichloro ligands. Crystal data for MnC 14 H 33 N 5-Cl 2 ‚CH 3 CH 2 OH: triclinic, P1 h-C i 1 (#2), a) 9.941(2) Å, b) 11.190(2) Å, c) 11.613(2) Å, V) 1125.4(4) Å 3 , Z) 2, T) 20 (1°C, for 3357 independent absorption-corrected reflections having 2θ(Cu KR) < 120.0°and I > 3σ(Ι), with R int) 0.027.

Bioorganic Chemistry, Feb 1, 2022

Liver X Receptors (LXRs) are members of the nuclear receptor family, and they play significant ro... more Liver X Receptors (LXRs) are members of the nuclear receptor family, and they play significant role in lipid and cholesterol metabolism. Moreover, they are key regulators of several inflammatory pathways. Pharmacological modulation of LXRs holds great potential in treatment of metabolic diseases, neurodegenerative diseases, and cancer. We were the first group to identify LXR inverse agonists SR9238 (6) and SR9243 (7) and demonstrate their potential utility in treating liver diseases and cancer. Here, we present the results of structure-activity relationship (SAR) studies, based around SR9238 (6) and SR9243 (7). This study led to identification of 16, 17, 19, and 38, which were more potent inverse agonists than SR9238 (6) and SR9243 (7) and inhibited expression of the fatty acid synthase gene in DU145 cells. We previously demonstrated that inhibition of FASN is correlated to the anticancer activity of SR9243 (7) and this suggests that new inverse agonists have great potential as anticancer agents. We identified compounds with distinct selectivity toward both LXR isoforms, which can be excellent tools to study the pharmacology of both isoforms. We employed molecular dynamic (MD) simulations to better understand the molecular mechanism underlying inverse agonist activity and to guide our future design.

Tetrahedron Letters, May 1, 1994

ABSTRACT A general synthetic method for the preparation of carbon-functionalized polyazamacrocycl... more ABSTRACT A general synthetic method for the preparation of carbon-functionalized polyazamacrocycles from the corresponding cyclic peptides is described.

The Journal of Organic Chemistry, 1991

Refolding of Synthetic Enzymes. Each synthetic enzyme obtained from the previoua step was dissolv... more Refolding of Synthetic Enzymes. Each synthetic enzyme obtained from the previoua step was dissolved in 25% acetic acid and passed through a Sephadex G-25 column (0.7 X 18 cm) to remove reeidual low molecular weight impurities remaining from the deprotection. The protein peak was colleded and lyophilized. The deprotected peptide was dissolved in the reduction-denaturation buffer of Pace and CreightonM (0.2 M Tris-HC1,2 mM EDTA, 0.1 M D'M', 6 M guanidine chloride, pH 8.7). The tube was purged with nitrogen, sealed, and allowed to stand for 3 h. The sample was then applied to a column of Sephadex G-25 (0.7 X 9 cm) equilibrated with 0.1 M NaCl and eluted with the same solution. The protein peak eluted first and was collected into a plastic microtube. The protein solution was kept for several hours at room temperature to allow oxidation to take place before being concentrated in a Speed-Vac apparatus to 0.1 mL and applied to a Sephadex G-25 column (0.7 x 9 cm) eluting with water. The desalted protein was collected and stored at 4 OC. Concentrations of synthetic enzymes were calculated based on the UV absorbance (cne =: 1.91 mL/mg.cm)." The mutant enzyme was assumed to have the same absorbance. Assays were as described." Acknowledgment. The mass spectrometric measurements were made by the Rockefeller Mass Spectrometric Biotechnology Resource supported by the Divison of Research Resources, NIH (Grant RR-00862-15). We thank Drs. Meng F. Ho and Berkley Lynch for carrying out some preliminary experiments including the synthesis of several (47) Takahaahi, K.

Bioorganic & Medicinal Chemistry Letters, 2005

We describe the structure-based design, synthesis, and enzymatic activity of a series of substitu... more We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P 1 amidine designed to explore additional interactions with the VIIa residues in the so-called ÔS 1 side pocketÕ. A crystal structure of the designed inhibitors demonstrates the ability of the P 1 side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.

Tetrahedron Letters, 1994

Thiophene derivatives R 0090 Asymmetric Synthesis of Highly Functionalized Tetrahydrothiophenes b... more Thiophene derivatives R 0090 Asymmetric Synthesis of Highly Functionalized Tetrahydrothiophenes by Organocatalytic Domino Reactions.-By use of optically active pyrrolidine PYR as organocatalyst for the Michael-aldol reaction of α,β-unsaturated aldehydes (I) and thiol (II), two types of tetrahydrothiophenes (III) or (IV) are obtained as single diastereomers with high enantioselectivities. The regioselectivity of the reaction leading to either carbaldehydes (III) or ketones (IV) can be controlled by the type of additive, benzoic acid or sodium bicarbonate. The high stability of both product types is explained by strong intra-and intermolecular hydrogen bondings.-(BRANDAU, S.; MAERTEN, E.;

Organic Letters, 2003

A general demonstration of orthogonal selectivity of the Liebeskind−Srogl cross-coupling protocol... more A general demonstration of orthogonal selectivity of the Liebeskind−Srogl cross-coupling protocol compared to the Suzuki−Miyaura and Stille variants is reported.

Inorganic Chemistry, 1996

Superoxide radical anion has been demonstrated to be a mediator of many disease states, including... more Superoxide radical anion has been demonstrated to be a mediator of many disease states, including inflammatory, autoimmune, and cancerous diseases. As a consequence, we have developed a program to design, synthesize, and test synthetic low-molecular weight superoxide dismutase (SOD) mimics as potential pharmaceutical agents. A critical feature of the design of metal-based drugs is not only high activity as an enzyme mimic but also chemical stability. In this report we describe the synthesis and characterization of a series of C-substituted 1,4,7,-10,13-pentaazacyclopentadecane, [15]aneN 5 , ligands, 1, and their corresponding Mn(II) complexes, 2 and 3, as their dichloro complexes, [Mn([15]aneN 5)Cl 2 ]. The purpose of the work is to probe the role that substituent (methyl and fused cycloalkyl) groups exert on the catalytic activity and stability of the complexes. All of the 18 new complexes described here are catalysts for the dismutation of superoxide, and substantial substituent effects are observed with k cat values at pH) 7.4 varying in the range (1.4-9.1) × 10 7 M-1 s-1. The kinetic and thermodynamic stabilities of these new complexes were studied by a Cu(II) ion competition spectrophotometric assay and by potentiometric titrations, respectively. It is observed that increasing the number of carbon substituents increases the kinetic stability of the complexes, while the thermodynamic stability increases, but less dramatically. The crystal structure for one of these new complexes, [Mn(2,2,3,3-Me 4 [15]aneN 5)Cl 2 ], 2i, was determined, and reveals that the Mn(II) ion is coordinated by a pentagonal bipyramid array of five macrocyclic derived nitrogen atoms in a plane with the Mn(II) center and capped by trans-dichloro ligands. Crystal data for MnC 14 H 33 N 5-Cl 2 ‚CH 3 CH 2 OH: triclinic, P1 h-C i 1 (#2), a) 9.941(2) Å, b) 11.190(2) Å, c) 11.613(2) Å, V) 1125.4(4) Å 3 , Z) 2, T) 20 (1°C, for 3357 independent absorption-corrected reflections having 2θ(Cu KR) < 120.0°and I > 3σ(Ι), with R int) 0.027.

Cheminform, May 27, 2010

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.

Tetrahedron Letters, 1999

The asymmetric synthesis of the highly functionalized (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoic a... more The asymmetric synthesis of the highly functionalized (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoic acid, the key amino acid fragment of sperabillins B and D, was achieved by an asymmetric Michael addition of lithium (R)-(et-methylbenzyl)allylamide 10 to (E,E)-2,5-heptadienoate establishing the C-3 stereogenic centre, the information from which was propagated to the C-5 and C-6 centres by a highly stereoselective iodocyclocarbamation reaction.