James Palmer - Academia.edu (original) (raw)
Papers by James Palmer
Biochemical Journal, 1996
Peptidyl vinyl sulphones are a novel class of extremely potent and specific cysteine protease inh... more Peptidyl vinyl sulphones are a novel class of extremely potent and specific cysteine protease inhibitors. They are highly active against the therapeutically important cathepsins O2, S and L. The highest kinact/Ki values exceed 107 M-1·s-1 for cathepsin S and 105 M-1·s-1 for cathepsins O2 and L. To study the primary specificity site of the novel human cathepsin O2 and the effectiveness of this novel class of inhibitors, a series of peptidyl vinyl sulphones with variations in the P2 residue was synthesized. Leucine in the P2 position was proven to be the most effective residue for cathepsin O2 and also for cathepsins S and L. Cathepsins O2 and S share a decreased accessibility towards P2 hydrophobic non-branched residues such as aminohexanoic acid (norleucine), methionine and oxidized methionine, but are distinguished by their different affinity towards phenylalanine in the P2 position. In contrast, cathepsin S accepts a broader range of hydrophobic residues in its S2 subsite than cat...
Bioorganic & Medicinal Chemistry Letters, Dec 1, 2013
ABSTRACT The discovery and optimisation of a new class of benzothiazole small molecules that inhi... more ABSTRACT The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
Protein Science, 2008
Cathepsin K is a cysteine protease of the papain family, which is predominantly expressed in oste... more Cathepsin K is a cysteine protease of the papain family, which is predominantly expressed in osteoclasts, and is regarded as a key protease in bone remodeling. To facilitate structural studies of the protein, the wild-type sequence of the protease has been mutated so as to replace a potential N-glycosylation site. We have expressed the mutant human cathepsin K to 190 mg/5 L using the Pichia pastoris expression system. Cathepsin K was inactivated with the mechanism-based inhibitor, APC3328, and crystallized from magnesium formate. A 2.2 8, X-ray data set has been collected on crystals belonging to space group P 2 1 2~2~. with a = 41.66 A, b = 5 1.41 A, and c = 107.72 A. There is most likely one molecule per asymmetric unit.
Bioorganic & Medicinal Chemistry, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Acta Crystallographica Section D-biological Crystallography, Dec 1, 2002
Cathepsin F is a cysteine protease believed to be involved in the antigen-presenting process of t... more Cathepsin F is a cysteine protease believed to be involved in the antigen-presenting process of the class II major histocompatibility complex (MHC-II) in macrophages. It has been expressed, puri®ed and crystallized. A complete data set to a resolution of 2.5 A Ê has been collected at room temperature. The Laue group was determined to be orthorhombic, space group P2 1 2 1 2, with unit-cell parameters a = 68.9, b = 104.8, c = 68.5 A Ê .
Protein Science, 1998
We have determined the 2.5 8, structure (Rcvyst = 20.5%, Rfree = 28.5%) of a complex between huma... more We have determined the 2.5 8, structure (Rcvyst = 20.5%, Rfree = 28.5%) of a complex between human cathepsin S and the potent, irreversible inhibitor 4-morpholinecarbonyl-Phe-hPhe-vinyl sulfone-phenyl. Noncrystallographic symmetry averaging and other density modification techniques were used to improve electron density maps which were nonoptimal due to systematically incomplete data. Methods that reduce the number of parameters were implemented for refinement. The refined structure shows cathepsin S to be similar to related cysteine proteases such as papain and cathepsins K and L. As expected, the covalently-bound inhibitor is attached to the enzyme at Cys 25, and enzyme binding subsites S3-S1' are occupied by the respective inhibitor substituents. A somewhat larger S2 pocket than what is found in similar enzymes is consistent with the broader specificity of cathepsin S at this site, while Lys 61 in the S3 site may offer opportunities for selective inhibition of this enzyme. The presence of Arg 137 in the S1' pocket, and proximal to Cys 25 may have implications not only for substrate specificity C-terminal to the scissile bond, but also for catalysis.
Journal of Clinical Investigation, 1991
Journal of Clinical Investigation, 1998
Antimicrobial Agents and Chemotherapy, 1996
We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number o... more We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development. The antimalarial effects correlated with the inhibition of falcipain. Our results suggest that vinyl sulfones or related cysteine proteinase inhibitors may have promise as antimalarial agents.
Tetrahedron Letters, 1983
... References and Notes la For a historical account of the discovery of the first polyene macrol... more ... References and Notes la For a historical account of the discovery of the first polyene macroliO see: Baldwin, RS "The Fungus Fighters", Cornell University Press, 1981, Ithaca, NY, b. For a review of the chemistry and biology of polyene macrolides see: HOltonMiller, JMT Bact. ...
Tetrahedron Letters, 2006
A chromatography-free process for the synthesis of a bis(benzimidazole)difluoromethane inhibitor ... more A chromatography-free process for the synthesis of a bis(benzimidazole)difluoromethane inhibitor of the serine protease tryptase is described. This synthesis features the introduction of the gem-difluoro moiety using the electrophilic fluorinating reagent N-fluoro-bis(phenylsulfonimide) as well as the stepwise introduction of both benzimidazole rings. A protocol for the destruction of reactive, process-related substances produced in the synthesis is also presented.
Synthetic Communications, 1986
ABSTRACT Aldol/elimination reactions of ß-ketoamides with methyl glyoxylate result in highly sele... more ABSTRACT Aldol/elimination reactions of ß-ketoamides with methyl glyoxylate result in highly selective production of Z-α,ß-unsaturated amides. An intramolecular Diels-Alder reaction of a triply activated dienophile derived from chiral dienylamine 7ZE stereospecifically affords chiral bicyclic lactam 11 at room temperature.
Synthetic Communications, 1986
Abstract The coupling of chiral dienylamine 1ZE with s-ketoesters and subsequent one-pot aldol re... more Abstract The coupling of chiral dienylamine 1ZE with s-ketoesters and subsequent one-pot aldol reaction with derivatives of glyoxylic acid, acetylation of the hydroxyester thus produced, and intramolecular Diels-Alder reaction of the diene portion of the molecule with the incipient dienophile is described. The entire sequence generates all of the requisite chiral centers in the isoindolone skeleton of cytochalasin C simultaneously, in an overall yield of approximately 85%.
Journal of Medicinal Chemistry, 1995
Journal of Medicinal Chemistry, 2006
Experimental Parasitology, 1999
proteinase inhibitors kill cultured bloodstream forms of Trypanosoma L-trans-epoxysuccinyl-leucyl... more proteinase inhibitors kill cultured bloodstream forms of Trypanosoma L-trans-epoxysuccinyl-leucylamido(4-guanidino)butane; FMK, fluorbrucei brucei. Experimental Parasitology 91, 349-355. Trypanosoma omethylketone; hPhe, homophenylalanine; IC 50 , concentration of inhibbrucei brucei is a causative agent of bovine trypanosomiasis (nagana), itor reducing growth of treated populations by 50% relative to controls; a disease of considerable economic significance in much of Africa. k ass , rate of association; Me, methyl; MeoSuc, methoxysuccinyl; MEM, Here we report investigations on the effects of various irreversible Minimal Essential Medium; Mu, morpholine urea; Pip, piperazine cysteine proteinase inhibitors, including vinyl sulfones (VS), peptidyl urea-naphthyl; ser(OBzl), benzyl ester of serine hydroxyl group; tic, chloromethylketones (CMK), diazomethylketones, and fluoromethyltetrahydroisoquinoline carboxylic acid; Tos, 4-toluenesulfonyl; ketones, on the major lysosomal cysteine proteinase (trypanopain-Tb) VamBzl; vinylogous benzylamide; VS, vinyl sulfone; VS␥AP, vinyl of T. b. brucei and on in vitro-cultured bloodstream forms of the parasite. sulfone-gamma amino phenyl; VSN, vinyl sulfone naphthylene; VS, Many of the tested inhibitors were trypanocidal at low micromolar vinyl sulfone-phenyl; Yii, diiodotyrosine. concentrations. Methylpiperazine urea-Phe-homoPhe-VS was the most effective trypanocidal agent, killing 50% of test populations at a working concentration of 0.11 M, while carbobenzoxy-Phe-Phe-CMK was the most trypanocidal of the methylketones with an IC 50 of 3.6 M.
Bioorganic Chemistry, 2002
Potent and selective cathepsin B inhibitors have previously been synthesized based upon the natur... more Potent and selective cathepsin B inhibitors have previously been synthesized based upon the natural product cysteine protease inhibitor E-64. X-ray crystal data indicates that these compounds interact through their free carboxylate with the positively charged histidine residues located on the prime-side of the active site within the occluding loop of cathepsin B. Herein, we examine the pH dependence of two primeside-binding compounds. In each case there is a dramatic decrease in k inact =K I as the pH is raised from 4 to 7.8 corresponding to a single ionization of pK a 4.4. These results suggest that targeting of the occluding loop of cathepsin B may be a poor inhibitor design strategy if the enzyme environment has a pH greater than 5.5. However, this type of inhibitor may be a useful tool to help elucidate the role and the environment of cathepsin B in invading tumors.
Bioorganic & Medicinal Chemistry Letters, 2013
A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed fr... more A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed from a lead molecule identified previously in our laboratory were synthesized and evaluated for protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Among the synthesized molecules, NM-14, a 5-Cl substituted benzothiazole analogue elicited significant PTP1B inhibition with an IC 50 of 1.88 µM against reference standard suramin (IC 50 ≥ 10 µM). Furthermore, this molecule also showed good in vivo antidiabetic activity which was comparable to that of standard antidiabetic drugs metformin and glimepiride. Overall, the results of the study clearly reveal that the reported tetrazole derivatives especially NM-14 are valuable prototypes for the development of novel non-carboxylic inhibitors of PTP1B with antidiabetic potential.
Biochemical Journal, 1996
Peptidyl vinyl sulphones are a novel class of extremely potent and specific cysteine protease inh... more Peptidyl vinyl sulphones are a novel class of extremely potent and specific cysteine protease inhibitors. They are highly active against the therapeutically important cathepsins O2, S and L. The highest kinact/Ki values exceed 107 M-1·s-1 for cathepsin S and 105 M-1·s-1 for cathepsins O2 and L. To study the primary specificity site of the novel human cathepsin O2 and the effectiveness of this novel class of inhibitors, a series of peptidyl vinyl sulphones with variations in the P2 residue was synthesized. Leucine in the P2 position was proven to be the most effective residue for cathepsin O2 and also for cathepsins S and L. Cathepsins O2 and S share a decreased accessibility towards P2 hydrophobic non-branched residues such as aminohexanoic acid (norleucine), methionine and oxidized methionine, but are distinguished by their different affinity towards phenylalanine in the P2 position. In contrast, cathepsin S accepts a broader range of hydrophobic residues in its S2 subsite than cat...
Bioorganic & Medicinal Chemistry Letters, Dec 1, 2013
ABSTRACT The discovery and optimisation of a new class of benzothiazole small molecules that inhi... more ABSTRACT The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
Protein Science, 2008
Cathepsin K is a cysteine protease of the papain family, which is predominantly expressed in oste... more Cathepsin K is a cysteine protease of the papain family, which is predominantly expressed in osteoclasts, and is regarded as a key protease in bone remodeling. To facilitate structural studies of the protein, the wild-type sequence of the protease has been mutated so as to replace a potential N-glycosylation site. We have expressed the mutant human cathepsin K to 190 mg/5 L using the Pichia pastoris expression system. Cathepsin K was inactivated with the mechanism-based inhibitor, APC3328, and crystallized from magnesium formate. A 2.2 8, X-ray data set has been collected on crystals belonging to space group P 2 1 2~2~. with a = 41.66 A, b = 5 1.41 A, and c = 107.72 A. There is most likely one molecule per asymmetric unit.
Bioorganic & Medicinal Chemistry, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Acta Crystallographica Section D-biological Crystallography, Dec 1, 2002
Cathepsin F is a cysteine protease believed to be involved in the antigen-presenting process of t... more Cathepsin F is a cysteine protease believed to be involved in the antigen-presenting process of the class II major histocompatibility complex (MHC-II) in macrophages. It has been expressed, puri®ed and crystallized. A complete data set to a resolution of 2.5 A Ê has been collected at room temperature. The Laue group was determined to be orthorhombic, space group P2 1 2 1 2, with unit-cell parameters a = 68.9, b = 104.8, c = 68.5 A Ê .
Protein Science, 1998
We have determined the 2.5 8, structure (Rcvyst = 20.5%, Rfree = 28.5%) of a complex between huma... more We have determined the 2.5 8, structure (Rcvyst = 20.5%, Rfree = 28.5%) of a complex between human cathepsin S and the potent, irreversible inhibitor 4-morpholinecarbonyl-Phe-hPhe-vinyl sulfone-phenyl. Noncrystallographic symmetry averaging and other density modification techniques were used to improve electron density maps which were nonoptimal due to systematically incomplete data. Methods that reduce the number of parameters were implemented for refinement. The refined structure shows cathepsin S to be similar to related cysteine proteases such as papain and cathepsins K and L. As expected, the covalently-bound inhibitor is attached to the enzyme at Cys 25, and enzyme binding subsites S3-S1' are occupied by the respective inhibitor substituents. A somewhat larger S2 pocket than what is found in similar enzymes is consistent with the broader specificity of cathepsin S at this site, while Lys 61 in the S3 site may offer opportunities for selective inhibition of this enzyme. The presence of Arg 137 in the S1' pocket, and proximal to Cys 25 may have implications not only for substrate specificity C-terminal to the scissile bond, but also for catalysis.
Journal of Clinical Investigation, 1991
Journal of Clinical Investigation, 1998
Antimicrobial Agents and Chemotherapy, 1996
We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number o... more We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development. The antimalarial effects correlated with the inhibition of falcipain. Our results suggest that vinyl sulfones or related cysteine proteinase inhibitors may have promise as antimalarial agents.
Tetrahedron Letters, 1983
... References and Notes la For a historical account of the discovery of the first polyene macrol... more ... References and Notes la For a historical account of the discovery of the first polyene macroliO see: Baldwin, RS "The Fungus Fighters", Cornell University Press, 1981, Ithaca, NY, b. For a review of the chemistry and biology of polyene macrolides see: HOltonMiller, JMT Bact. ...
Tetrahedron Letters, 2006
A chromatography-free process for the synthesis of a bis(benzimidazole)difluoromethane inhibitor ... more A chromatography-free process for the synthesis of a bis(benzimidazole)difluoromethane inhibitor of the serine protease tryptase is described. This synthesis features the introduction of the gem-difluoro moiety using the electrophilic fluorinating reagent N-fluoro-bis(phenylsulfonimide) as well as the stepwise introduction of both benzimidazole rings. A protocol for the destruction of reactive, process-related substances produced in the synthesis is also presented.
Synthetic Communications, 1986
ABSTRACT Aldol/elimination reactions of ß-ketoamides with methyl glyoxylate result in highly sele... more ABSTRACT Aldol/elimination reactions of ß-ketoamides with methyl glyoxylate result in highly selective production of Z-α,ß-unsaturated amides. An intramolecular Diels-Alder reaction of a triply activated dienophile derived from chiral dienylamine 7ZE stereospecifically affords chiral bicyclic lactam 11 at room temperature.
Synthetic Communications, 1986
Abstract The coupling of chiral dienylamine 1ZE with s-ketoesters and subsequent one-pot aldol re... more Abstract The coupling of chiral dienylamine 1ZE with s-ketoesters and subsequent one-pot aldol reaction with derivatives of glyoxylic acid, acetylation of the hydroxyester thus produced, and intramolecular Diels-Alder reaction of the diene portion of the molecule with the incipient dienophile is described. The entire sequence generates all of the requisite chiral centers in the isoindolone skeleton of cytochalasin C simultaneously, in an overall yield of approximately 85%.
Journal of Medicinal Chemistry, 1995
Journal of Medicinal Chemistry, 2006
Experimental Parasitology, 1999
proteinase inhibitors kill cultured bloodstream forms of Trypanosoma L-trans-epoxysuccinyl-leucyl... more proteinase inhibitors kill cultured bloodstream forms of Trypanosoma L-trans-epoxysuccinyl-leucylamido(4-guanidino)butane; FMK, fluorbrucei brucei. Experimental Parasitology 91, 349-355. Trypanosoma omethylketone; hPhe, homophenylalanine; IC 50 , concentration of inhibbrucei brucei is a causative agent of bovine trypanosomiasis (nagana), itor reducing growth of treated populations by 50% relative to controls; a disease of considerable economic significance in much of Africa. k ass , rate of association; Me, methyl; MeoSuc, methoxysuccinyl; MEM, Here we report investigations on the effects of various irreversible Minimal Essential Medium; Mu, morpholine urea; Pip, piperazine cysteine proteinase inhibitors, including vinyl sulfones (VS), peptidyl urea-naphthyl; ser(OBzl), benzyl ester of serine hydroxyl group; tic, chloromethylketones (CMK), diazomethylketones, and fluoromethyltetrahydroisoquinoline carboxylic acid; Tos, 4-toluenesulfonyl; ketones, on the major lysosomal cysteine proteinase (trypanopain-Tb) VamBzl; vinylogous benzylamide; VS, vinyl sulfone; VS␥AP, vinyl of T. b. brucei and on in vitro-cultured bloodstream forms of the parasite. sulfone-gamma amino phenyl; VSN, vinyl sulfone naphthylene; VS, Many of the tested inhibitors were trypanocidal at low micromolar vinyl sulfone-phenyl; Yii, diiodotyrosine. concentrations. Methylpiperazine urea-Phe-homoPhe-VS was the most effective trypanocidal agent, killing 50% of test populations at a working concentration of 0.11 M, while carbobenzoxy-Phe-Phe-CMK was the most trypanocidal of the methylketones with an IC 50 of 3.6 M.
Bioorganic Chemistry, 2002
Potent and selective cathepsin B inhibitors have previously been synthesized based upon the natur... more Potent and selective cathepsin B inhibitors have previously been synthesized based upon the natural product cysteine protease inhibitor E-64. X-ray crystal data indicates that these compounds interact through their free carboxylate with the positively charged histidine residues located on the prime-side of the active site within the occluding loop of cathepsin B. Herein, we examine the pH dependence of two primeside-binding compounds. In each case there is a dramatic decrease in k inact =K I as the pH is raised from 4 to 7.8 corresponding to a single ionization of pK a 4.4. These results suggest that targeting of the occluding loop of cathepsin B may be a poor inhibitor design strategy if the enzyme environment has a pH greater than 5.5. However, this type of inhibitor may be a useful tool to help elucidate the role and the environment of cathepsin B in invading tumors.
Bioorganic & Medicinal Chemistry Letters, 2013
A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed fr... more A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed from a lead molecule identified previously in our laboratory were synthesized and evaluated for protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Among the synthesized molecules, NM-14, a 5-Cl substituted benzothiazole analogue elicited significant PTP1B inhibition with an IC 50 of 1.88 µM against reference standard suramin (IC 50 ≥ 10 µM). Furthermore, this molecule also showed good in vivo antidiabetic activity which was comparable to that of standard antidiabetic drugs metformin and glimepiride. Overall, the results of the study clearly reveal that the reported tetrazole derivatives especially NM-14 are valuable prototypes for the development of novel non-carboxylic inhibitors of PTP1B with antidiabetic potential.