Carlo Gallina - Academia.edu (original) (raw)

Papers by Carlo Gallina

Research paper thumbnail of Synthesis and evaluation of new tripeptide phosphonate inhibitors of MMP-8 and MMP-2

European Journal of Medicinal Chemistry, 2005

The phosphotryptophan derivative L-Pro-L-Leu-L-(P)Trp(OH) 2 (2b) was reported as the first exampl... more The phosphotryptophan derivative L-Pro-L-Leu-L-(P)Trp(OH) 2 (2b) was reported as the first example of left-hand-side 1 phosphonate inhibitor of MMP-8. Its uncommon mode of binding to MMP-8 was mainly ascribed to the presence of the proline residue in P 3. Ten new analogues of 2b were obtained by replacement of the aminoterminal L-Pro with aminoacid residues bearing small side chains. Most of the new analogues show an increase of affinity for MMP-2 and MMP-8, and different profiles of selectivity. Computer simulations were performed to explain the effects of substitutions on the preferred mode of binding. They reveal that most of the new analogues are probably accommodated in the right, rather than left-hand side of MMP-8 active site.

Research paper thumbnail of α-Biphenylsulfonylamino 2-methylpropyl phosphonates: Enantioselective synthesis and selective inhibition of MMPs

Bioorganic & Medicinal Chemistry, 2007

Biphenylsulfonylamino 2-methylpropyl phosphonates attain nM potency against several MMPs and are ... more Biphenylsulfonylamino 2-methylpropyl phosphonates attain nM potency against several MMPs and are the most effective inhibitors based on phosphonate as zinc binding group. Since their preparation by direct N-acylation of expensive, enantiopure, a-aminophosphonic acids proceeds in low yields, we devised and evaluated a stereoselective and straightforward method of synthesis that avoids the unfavourable step of N-acylation. The key intermediate (R)-4-bromophenylsulfonylamino 2-methylpropyl phosphonate 9 was obtained by highly stereoselective addition of dibenzylphosphite to the enantiopure (S)-N-isobutylidene-pbromobenzenesulfinamide 3, followed by oxidation with m-CPBA. Suzuki coupling of 9 with the desired arylboronic acids, gave the expected biphenylsulfonylamino derivatives in satisfactory yields. Liberation of the phosphonic group by hydrogenolysis led to the desired (R)-a-biphenylsulfonylamino 2-methylpropyl phosphonates 14a-i. Screening of the new compounds on MMP-1,-2,-3,-7,-8,-9,-13 and-14 showed IC 50 in the range of nM in most cases.

Research paper thumbnail of AMBER force field implementation of the boronate function to simulate the inhibition of β-lactamases by alkyl and aryl boronic acids

European Journal of Medicinal Chemistry, 2005

Boronic acids are a very appealing class of serine proteases inhibitors whose rational design suf... more Boronic acids are a very appealing class of serine proteases inhibitors whose rational design suffers, in spite of their therapeutic potential, from the lack of boron-related parameters in force fields commonly used for proteins. We introduced bonded, non-bonded and point charges in the MacroModel/Amber force field, as well as GB/SA solvation parameters, to model boronic acids as tetrahedral adducts formed after protease's serine Oc coordination. With the aim to check the implemented force field, flexible docking studies were performed on three crystallographic complexes of b-lactamases with boronic acids that output the crystallographic conformation of the complexes as the global minimum energy structure. Although the used approach was basic, nevertheless the resultant force field seems to be efficient and suitable for the structure-based design of new boronic inhibitors of b-lactamases.

Research paper thumbnail of Human Alpha-Thrombin Inhibition by CBZ-Pro-Azalys-Onp

Research paper thumbnail of Iodo and diiodotyrosine epoxysuccinyl derivatives as selective inhibitors of cathepsin B

European Journal of Medicinal Chemistry, 1993

Research paper thumbnail of New Matrix Metalloproteinase Inhibitors Based on N-hydroxyurea as zinc-binding group: synthesis, biological evaluation and computational studies

Research paper thumbnail of Synthesis and biological evaluation of new matrix metalloproteinases inhibitors

Research paper thumbnail of Mode of binding of R- and S- sunlphonamide phosphonate inhibitors in the active site of MMP-8

Research paper thumbnail of Peptidyl and azapeptidyl methylketones as substrate analog inhibitors of papain and cathepsin B

European Journal of Medicinal Chemistry, 1995

-Peptldyl methylketones containing Phe, Tyr, Tyr(I), Tyr(I2), Leu and lie in P2 were synthesized ... more -Peptldyl methylketones containing Phe, Tyr, Tyr(I), Tyr(I2), Leu and lie in P2 were synthesized and tested as substrate analog reversible inhibitors of papaln and bovine spleen cathepsm B. The most effective cathepsm B inhibitor contained Tyr(I2) and displayed an inhibition constant of 4.7 [aM at pH 6.8 and 25°C, while Leu or Ile gave practically inert analogs. Replacement of the amino acids in P~ with the analogous ~-azaamino acids, as well as the glycine in P~ with ~-azaglycine, led to complete loss of inhibiting activity. Introducing alkoxy substituents at the methyl adJacent to the ketone group generally resulted in more effective mhibitors, with inhibition constants m the micromolar range for both papain and cathepsin B. enzyme inhibiting activity cysteine protease / slow binding / peptidyl methylketone / azapeptidyl methylketone / papain / cathepsin B

Research paper thumbnail of Inhibitors of Metalloproteinases, Their Therapeutic Use, and Process for the Production of the Starting Compound in Their Synthesis

Research paper thumbnail of ChemInform Abstract: Conformationally Constrained Analogues of Endogenous Tripeptide Inhibitors of Zinc Metalloproteinases

Research paper thumbnail of Synthesis of derivatives of 2-aminoproline and 5-aminoproline

Research paper thumbnail of Hydroxyurea as zinc binding group in matrix metalloproteinase inhibition: Mode of binding in a complex with MMP-8

Bioorg Medicinal Chem Letter, 2006

The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of ... more The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of a matrix metalloproteinase is reported. The ligand and three other analogues were prepared and studied as inhibitors of MMP-2, MMP-3, and MMP-8. The crystal structure of the complex with MMP-8 shows that the N-hydroxyurea, contrary to the analogous hydroxamate, binds the catalytic zinc ion in a monodentate rather than bidentate mode and with high out-of-plane distortion of the amide bonds.The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of MMP-8 is reported. The hydroxyurea moiety, contrary to the analogous hydroxamate, binds the catalytic zinc ion as a monodentate rather than a bidentate ligand.

Research paper thumbnail of ChemInform Abstract: Palladium-Catalyzed Vinylation of Allylic Alcohols with Enol Triflates. A Convenient Synthesis of Conjugated Dienols

Research paper thumbnail of ChemInform Abstract: Conformationally Constrained DNA Mimics: Synthesis of a Novel Cyclopropyl-Amide Linked Dimer

ChemInform, 1996

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance th... more AbstractChemInform 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.

Research paper thumbnail of Synthesis of derivatives of 2-aminoproline and 5-aminoproline

The Journal of Organic Chemistry, 1970

Research paper thumbnail of Structural Insight into the Stereoselective Inhibition of MMP-8 by Enantiomeric Sulfonamide Phosphonates

Journal of Medicinal Chemistry, 2006

Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases t... more Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases that can degrade all the components of the extracellular matrix, could be useful for treatment of diseases such as cancer and arthritis. The most potent MMP inhibitors are based on hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino phosphonates incorporate a particularly favorable combination of phosphonate as ZBG and arylsulfonylamino backbone so that their affinity exceptionally attains the nanomolar strength frequently observed for hydroxamate analogues. The detailed mode of binding of [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has been clarified by the crystal structures of the complexes that the R- and S-enantiomers respectively form with MMP-8. The reasons for the preferential MMP-8 inhibition by the R-phosphonate are underlined and the differences in the mode of binding of analogous alpha-arylsulfonylamino hydroxamates and carboxylates are discussed.

Research paper thumbnail of Functional residues at the active site of horse liver phosphopantothenoylcysteine decarboxylase

FEBS Letters, 1988

Horse liver phosphopantothenoylcysteine decarboxylase (EC 4.1.1.36) is rapidly inactivated by N-a... more Horse liver phosphopantothenoylcysteine decarboxylase (EC 4.1.1.36) is rapidly inactivated by N-acetoacetylation with diketene following a pseudo-first-order kinetics: the presence of substrate quantitatively protects against this inactivation. Histidine photo-oxidation with methylene blue or rose bengal brings about the total loss of activity. These results indicate the presence of functional lysyl and histidyl groups at the active site of the enzyme. The substrate sulphydryl group is essential for enzyme activity. Enzymatic decarboxylation is proposed to result from a combined action of the keto group of the enzyme-bound pyruvate protonated by an essential histidine and a protonated amino group of a lysine.

Research paper thumbnail of Synthesis and inhibiting activities of 1-peptidyl-2-haloacetyl hydrazines toward cathepsin B and calpains

European Journal of Medicinal Chemistry, 1993

ABSTRACT Twenty-four 1-peptidyl-2-haloacetyl hydrazines which can be considered azapeptide halome... more ABSTRACT Twenty-four 1-peptidyl-2-haloacetyl hydrazines which can be considered azapeptide halomethanes were synthesized and tested as models of cathepsin B, calpain I and calpain II inhibitors. Reagents designed for cathepsin B inactivation include Z-Tyr, Z-Tyr(I) and Z-Leu-Leu attached to an α-azaglycine or α-azaalanine unit in P1. By use of kinetic analysis, they proved to irreversibly inactivate cathepsin B via a reversible enzyme-inhibitor intermediate. Second-order rate constants in the range 725-306 000 M−1s−1 were found for cathepsin B inactivation, with no more than 7 500 M−1s−1 for calpain II. K1 for the reversible EI adducts ranged from 11 to 0.06 μM for cathepsin B. Structure of the possible reversible EI complex is proposed and used to discuss the effects of structural variation of the inhibitors on the kinetic parameters of inactivation. 1-Peptidyl-2-haloacetyl hydrazines designed for calpain inactivation include Boc-Val-(Nϵ-carbomethoxy)Lys-Leu, Boc-Val-Lys(Nϵ-Z)-Leu, Boc-Val-Lys(Nϵ-Tos)-Leu and Z-Leu-Leu attached to an α-azatyrosine unit in P1. They gave poor results. Title compounds proved to be selective for cysteine proteases, since no inhibiting activity could be detected toward trypsin, chymotrypsin and porcine pancreatic elastase at 0.1 mM concentration. Relatively low aspecific alkylating properties were also demonstrated in tests using glutathione as the nucleophile.

Research paper thumbnail of N-Hydroxyurea as zinc binding group in matrix metalloproteinase inhibition: Mode of binding in a complex with MMP-8

Bioorganic & Medicinal Chemistry Letters, 2006

The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of ... more The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of a matrix metalloproteinase is reported. The ligand and three other analogues were prepared and studied as inhibitors of MMP-2, MMP-3, and MMP-8. The crystal structure of the complex with MMP-8 shows that the N-hydroxyurea, contrary to the analogous hydroxamate, binds the catalytic zinc ion in a monodentate rather than bidentate mode and with high out-of-plane distortion of the amide bonds.

Research paper thumbnail of Synthesis and evaluation of new tripeptide phosphonate inhibitors of MMP-8 and MMP-2

European Journal of Medicinal Chemistry, 2005

The phosphotryptophan derivative L-Pro-L-Leu-L-(P)Trp(OH) 2 (2b) was reported as the first exampl... more The phosphotryptophan derivative L-Pro-L-Leu-L-(P)Trp(OH) 2 (2b) was reported as the first example of left-hand-side 1 phosphonate inhibitor of MMP-8. Its uncommon mode of binding to MMP-8 was mainly ascribed to the presence of the proline residue in P 3. Ten new analogues of 2b were obtained by replacement of the aminoterminal L-Pro with aminoacid residues bearing small side chains. Most of the new analogues show an increase of affinity for MMP-2 and MMP-8, and different profiles of selectivity. Computer simulations were performed to explain the effects of substitutions on the preferred mode of binding. They reveal that most of the new analogues are probably accommodated in the right, rather than left-hand side of MMP-8 active site.

Research paper thumbnail of α-Biphenylsulfonylamino 2-methylpropyl phosphonates: Enantioselective synthesis and selective inhibition of MMPs

Bioorganic & Medicinal Chemistry, 2007

Biphenylsulfonylamino 2-methylpropyl phosphonates attain nM potency against several MMPs and are ... more Biphenylsulfonylamino 2-methylpropyl phosphonates attain nM potency against several MMPs and are the most effective inhibitors based on phosphonate as zinc binding group. Since their preparation by direct N-acylation of expensive, enantiopure, a-aminophosphonic acids proceeds in low yields, we devised and evaluated a stereoselective and straightforward method of synthesis that avoids the unfavourable step of N-acylation. The key intermediate (R)-4-bromophenylsulfonylamino 2-methylpropyl phosphonate 9 was obtained by highly stereoselective addition of dibenzylphosphite to the enantiopure (S)-N-isobutylidene-pbromobenzenesulfinamide 3, followed by oxidation with m-CPBA. Suzuki coupling of 9 with the desired arylboronic acids, gave the expected biphenylsulfonylamino derivatives in satisfactory yields. Liberation of the phosphonic group by hydrogenolysis led to the desired (R)-a-biphenylsulfonylamino 2-methylpropyl phosphonates 14a-i. Screening of the new compounds on MMP-1,-2,-3,-7,-8,-9,-13 and-14 showed IC 50 in the range of nM in most cases.

Research paper thumbnail of AMBER force field implementation of the boronate function to simulate the inhibition of β-lactamases by alkyl and aryl boronic acids

European Journal of Medicinal Chemistry, 2005

Boronic acids are a very appealing class of serine proteases inhibitors whose rational design suf... more Boronic acids are a very appealing class of serine proteases inhibitors whose rational design suffers, in spite of their therapeutic potential, from the lack of boron-related parameters in force fields commonly used for proteins. We introduced bonded, non-bonded and point charges in the MacroModel/Amber force field, as well as GB/SA solvation parameters, to model boronic acids as tetrahedral adducts formed after protease's serine Oc coordination. With the aim to check the implemented force field, flexible docking studies were performed on three crystallographic complexes of b-lactamases with boronic acids that output the crystallographic conformation of the complexes as the global minimum energy structure. Although the used approach was basic, nevertheless the resultant force field seems to be efficient and suitable for the structure-based design of new boronic inhibitors of b-lactamases.

Research paper thumbnail of Human Alpha-Thrombin Inhibition by CBZ-Pro-Azalys-Onp

Research paper thumbnail of Iodo and diiodotyrosine epoxysuccinyl derivatives as selective inhibitors of cathepsin B

European Journal of Medicinal Chemistry, 1993

Research paper thumbnail of New Matrix Metalloproteinase Inhibitors Based on N-hydroxyurea as zinc-binding group: synthesis, biological evaluation and computational studies

Research paper thumbnail of Synthesis and biological evaluation of new matrix metalloproteinases inhibitors

Research paper thumbnail of Mode of binding of R- and S- sunlphonamide phosphonate inhibitors in the active site of MMP-8

Research paper thumbnail of Peptidyl and azapeptidyl methylketones as substrate analog inhibitors of papain and cathepsin B

European Journal of Medicinal Chemistry, 1995

-Peptldyl methylketones containing Phe, Tyr, Tyr(I), Tyr(I2), Leu and lie in P2 were synthesized ... more -Peptldyl methylketones containing Phe, Tyr, Tyr(I), Tyr(I2), Leu and lie in P2 were synthesized and tested as substrate analog reversible inhibitors of papaln and bovine spleen cathepsm B. The most effective cathepsm B inhibitor contained Tyr(I2) and displayed an inhibition constant of 4.7 [aM at pH 6.8 and 25°C, while Leu or Ile gave practically inert analogs. Replacement of the amino acids in P~ with the analogous ~-azaamino acids, as well as the glycine in P~ with ~-azaglycine, led to complete loss of inhibiting activity. Introducing alkoxy substituents at the methyl adJacent to the ketone group generally resulted in more effective mhibitors, with inhibition constants m the micromolar range for both papain and cathepsin B. enzyme inhibiting activity cysteine protease / slow binding / peptidyl methylketone / azapeptidyl methylketone / papain / cathepsin B

Research paper thumbnail of Inhibitors of Metalloproteinases, Their Therapeutic Use, and Process for the Production of the Starting Compound in Their Synthesis

Research paper thumbnail of ChemInform Abstract: Conformationally Constrained Analogues of Endogenous Tripeptide Inhibitors of Zinc Metalloproteinases

Research paper thumbnail of Synthesis of derivatives of 2-aminoproline and 5-aminoproline

Research paper thumbnail of Hydroxyurea as zinc binding group in matrix metalloproteinase inhibition: Mode of binding in a complex with MMP-8

Bioorg Medicinal Chem Letter, 2006

The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of ... more The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of a matrix metalloproteinase is reported. The ligand and three other analogues were prepared and studied as inhibitors of MMP-2, MMP-3, and MMP-8. The crystal structure of the complex with MMP-8 shows that the N-hydroxyurea, contrary to the analogous hydroxamate, binds the catalytic zinc ion in a monodentate rather than bidentate mode and with high out-of-plane distortion of the amide bonds.The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of MMP-8 is reported. The hydroxyurea moiety, contrary to the analogous hydroxamate, binds the catalytic zinc ion as a monodentate rather than a bidentate ligand.

Research paper thumbnail of ChemInform Abstract: Palladium-Catalyzed Vinylation of Allylic Alcohols with Enol Triflates. A Convenient Synthesis of Conjugated Dienols

Research paper thumbnail of ChemInform Abstract: Conformationally Constrained DNA Mimics: Synthesis of a Novel Cyclopropyl-Amide Linked Dimer

ChemInform, 1996

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance th... more AbstractChemInform 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.

Research paper thumbnail of Synthesis of derivatives of 2-aminoproline and 5-aminoproline

The Journal of Organic Chemistry, 1970

Research paper thumbnail of Structural Insight into the Stereoselective Inhibition of MMP-8 by Enantiomeric Sulfonamide Phosphonates

Journal of Medicinal Chemistry, 2006

Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases t... more Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases that can degrade all the components of the extracellular matrix, could be useful for treatment of diseases such as cancer and arthritis. The most potent MMP inhibitors are based on hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino phosphonates incorporate a particularly favorable combination of phosphonate as ZBG and arylsulfonylamino backbone so that their affinity exceptionally attains the nanomolar strength frequently observed for hydroxamate analogues. The detailed mode of binding of [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has been clarified by the crystal structures of the complexes that the R- and S-enantiomers respectively form with MMP-8. The reasons for the preferential MMP-8 inhibition by the R-phosphonate are underlined and the differences in the mode of binding of analogous alpha-arylsulfonylamino hydroxamates and carboxylates are discussed.

Research paper thumbnail of Functional residues at the active site of horse liver phosphopantothenoylcysteine decarboxylase

FEBS Letters, 1988

Horse liver phosphopantothenoylcysteine decarboxylase (EC 4.1.1.36) is rapidly inactivated by N-a... more Horse liver phosphopantothenoylcysteine decarboxylase (EC 4.1.1.36) is rapidly inactivated by N-acetoacetylation with diketene following a pseudo-first-order kinetics: the presence of substrate quantitatively protects against this inactivation. Histidine photo-oxidation with methylene blue or rose bengal brings about the total loss of activity. These results indicate the presence of functional lysyl and histidyl groups at the active site of the enzyme. The substrate sulphydryl group is essential for enzyme activity. Enzymatic decarboxylation is proposed to result from a combined action of the keto group of the enzyme-bound pyruvate protonated by an essential histidine and a protonated amino group of a lysine.

Research paper thumbnail of Synthesis and inhibiting activities of 1-peptidyl-2-haloacetyl hydrazines toward cathepsin B and calpains

European Journal of Medicinal Chemistry, 1993

ABSTRACT Twenty-four 1-peptidyl-2-haloacetyl hydrazines which can be considered azapeptide halome... more ABSTRACT Twenty-four 1-peptidyl-2-haloacetyl hydrazines which can be considered azapeptide halomethanes were synthesized and tested as models of cathepsin B, calpain I and calpain II inhibitors. Reagents designed for cathepsin B inactivation include Z-Tyr, Z-Tyr(I) and Z-Leu-Leu attached to an α-azaglycine or α-azaalanine unit in P1. By use of kinetic analysis, they proved to irreversibly inactivate cathepsin B via a reversible enzyme-inhibitor intermediate. Second-order rate constants in the range 725-306 000 M−1s−1 were found for cathepsin B inactivation, with no more than 7 500 M−1s−1 for calpain II. K1 for the reversible EI adducts ranged from 11 to 0.06 μM for cathepsin B. Structure of the possible reversible EI complex is proposed and used to discuss the effects of structural variation of the inhibitors on the kinetic parameters of inactivation. 1-Peptidyl-2-haloacetyl hydrazines designed for calpain inactivation include Boc-Val-(Nϵ-carbomethoxy)Lys-Leu, Boc-Val-Lys(Nϵ-Z)-Leu, Boc-Val-Lys(Nϵ-Tos)-Leu and Z-Leu-Leu attached to an α-azatyrosine unit in P1. They gave poor results. Title compounds proved to be selective for cysteine proteases, since no inhibiting activity could be detected toward trypsin, chymotrypsin and porcine pancreatic elastase at 0.1 mM concentration. Relatively low aspecific alkylating properties were also demonstrated in tests using glutathione as the nucleophile.

Research paper thumbnail of N-Hydroxyurea as zinc binding group in matrix metalloproteinase inhibition: Mode of binding in a complex with MMP-8

Bioorganic & Medicinal Chemistry Letters, 2006

The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of ... more The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of a matrix metalloproteinase is reported. The ligand and three other analogues were prepared and studied as inhibitors of MMP-2, MMP-3, and MMP-8. The crystal structure of the complex with MMP-8 shows that the N-hydroxyurea, contrary to the analogous hydroxamate, binds the catalytic zinc ion in a monodentate rather than bidentate mode and with high out-of-plane distortion of the amide bonds.