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Anthony C. Legon - One of the best experts on this subject based on the ideXlab platform.
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Rotational spectroscopy of a weak complex of Thiirane and ethyne: The identification and properties of a highly nonlinear S⋯H–C hydrogen bond
The Journal of Chemical Physics, 2003Co-Authors: R. C. Batten, Gc Cole, Anthony C. LegonAbstract:Rotational and centrifugal distortion constants were determined for eight isotopomers of a weakly bound complex of Thiirane and ethyne. The observed complex is of Cs symmetry, with ethyne lying in the symmetry (ab principal inertial) plane and with H of HCCH forming a hydrogen bond to the S atom of Thiirane. The r0 geometry is: r(S⋯H)=2.76(5) A, φ=84.0(5)°, and θ=42.9(2)°, where φ is the angle made by the S⋯H internuclear line with the local C2 axis of the Thiirane ring and θ is the angular deviation of the S⋯H–C nuclei from a linear arrangement. The nonlinearity of the hydrogen bond is attributed to a weak primary interaction S⋯H–C coupled with a secondary interaction involving the π bond of ethyne with the two equivalent H atoms of Thiirane that are closest to it. The angular geometry of (CH2)2S⋯HCCH is compared with those of other species (CH2)2S⋯HX, where X=F, Cl, Br, and CN.Rotational and centrifugal distortion constants were determined for eight isotopomers of a weakly bound complex of Thiirane and ethyne. The observed complex is of Cs symmetry, with ethyne lying in the symmetry (ab principal inertial) plane and with H of HCCH forming a hydrogen bond to the S atom of Thiirane. The r0 geometry is: r(S⋯H)=2.76(5) A, φ=84.0(5)°, and θ=42.9(2)°, where φ is the angle made by the S⋯H internuclear line with the local C2 axis of the Thiirane ring and θ is the angular deviation of the S⋯H–C nuclei from a linear arrangement. The nonlinearity of the hydrogen bond is attributed to a weak primary interaction S⋯H–C coupled with a secondary interaction involving the π bond of ethyne with the two equivalent H atoms of Thiirane that are closest to it. The angular geometry of (CH2)2S⋯HCCH is compared with those of other species (CH2)2S⋯HX, where X=F, Cl, Br, and CN.
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rotational spectroscopy of a weak complex of Thiirane and ethyne the identification and properties of a highly nonlinear s h c hydrogen bond
Journal of Chemical Physics, 2003Co-Authors: R. C. Batten, Gc Cole, Anthony C. LegonAbstract:Rotational and centrifugal distortion constants were determined for eight isotopomers of a weakly bound complex of Thiirane and ethyne. The observed complex is of Cs symmetry, with ethyne lying in the symmetry (ab principal inertial) plane and with H of HCCH forming a hydrogen bond to the S atom of Thiirane. The r0 geometry is: r(S⋯H)=2.76(5) A, φ=84.0(5)°, and θ=42.9(2)°, where φ is the angle made by the S⋯H internuclear line with the local C2 axis of the Thiirane ring and θ is the angular deviation of the S⋯H–C nuclei from a linear arrangement. The nonlinearity of the hydrogen bond is attributed to a weak primary interaction S⋯H–C coupled with a secondary interaction involving the π bond of ethyne with the two equivalent H atoms of Thiirane that are closest to it. The angular geometry of (CH2)2S⋯HCCH is compared with those of other species (CH2)2S⋯HX, where X=F, Cl, Br, and CN.Rotational and centrifugal distortion constants were determined for eight isotopomers of a weakly bound complex of Thiirane and ethyne. The observed complex is of Cs symmetry, with ethyne lying in the symmetry (ab principal inertial) plane and with H of HCCH forming a hydrogen bond to the S atom of Thiirane. The r0 geometry is: r(S⋯H)=2.76(5) A, φ=84.0(5)°, and θ=42.9(2)°, where φ is the angle made by the S⋯H internuclear line with the local C2 axis of the Thiirane ring and θ is the angular deviation of the S⋯H–C nuclei from a linear arrangement. The nonlinearity of the hydrogen bond is attributed to a weak primary interaction S⋯H–C coupled with a secondary interaction involving the π bond of ethyne with the two equivalent H atoms of Thiirane that are closest to it. The angular geometry of (CH2)2S⋯HCCH is compared with those of other species (CH2)2S⋯HX, where X=F, Cl, Br, and CN.
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The rotational spectrum of the argon—Thiirane van der Waals molecule
Chemical Physics Letters, 1992Co-Authors: Anthony C. Legon, David G. ListerAbstract:Abstract The rotational spectrum of the argon—Thiirane van der Waals molecule has been observed using pulsed-nozzle, Fourier-transform microwave spectroscopy. Transitions due to μa and μb components of the electric dipole moment have been observed and used to derive rotational and quartic centrifugal distortion constants. The molecule has Cs symmetry with a distance R = 3.79 pm from the centre of mass of Thiirane to the argon atom and an angle θ = 98° between this vector and the bisector of the CSC bond angle of the Thiirane molecule. An upper limit of 10 kHz is placed on the ground vibrational state inversion frequency in Ar…S(CH2)2.
Shahriar Mobashery - One of the best experts on this subject based on the ideXlab platform.
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chapter 10 Thiirane class of gelatinase inhibitors as a privileged template that crosses the blood brain barrier
2015Co-Authors: Major Gooyit, Shahriar Mobashery, Zhihong Peng, Mayland ChangAbstract:The gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) play important roles in the pathophysiology of several diseases, including cancer metastases, neurological diseases, and chronic wounds. MMPs also mediate beneficial repair and recovery functions. Thus, the use of selective MMP inhibitors is required to avoid side effects. The prototype gelatinase inhibitor SB-3CT displays potency and selectivity towards the gelatinases. SB-3CT contains a Thiirane ring that involves a reaction catalyzed by the gelatinases, which results in slow-binding and/or tight-binding inhibition. This unique mechanism of action is at the root of selectivity enjoyed by the Thiirane class of inhibitors. We have synthesized and evaluated >500 Thiirane derivatives. SB-3CT has shown efficacy in numerous animal models of disease, including cancer metastasis, stroke, traumatic brain injury, and diabetic wound healing. The members of the Thiirane class cross the blood–brain barrier (BBB), achieve therapeutic concentrations in the brain, and do not accumulate in the brain. These desirable attributes of the Thiiranes indicate that this class of gelatinase inhibitors holds great promise for intervention of neurological diseases and chronic wounds.
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The X-Ray Structure of Carboxypeptidase A Inhibited by a Thiirane Mechanism-Based Inhibitor
Chemical biology & drug design, 2009Co-Authors: Daniel Fernández, Sebastian A. Testero, Josep Vendrell, Francesc X. Avilés, Shahriar MobasheryAbstract:The three-dimensional X-ray crystal structure of carboxypeptidase A, a zinc-dependent hydrolase, covalently modified by a mechanism-based Thiirane inactivator, 2-benzyl-3,4-epithiobutanoic acid, has been solved to 1.38 A resolution. The interaction of the Thiirane moiety of the inhibitor with the active site zinc ion promotes its covalent modification of Glu-270 with the attendant opening of the Thiirane ring. The crystal structure determination at high resolution allowed for the clear visualization of the covalent ester bond to the glutamate side chain. The newly generated thiol from the inhibitor binds to the catalytic zinc ion in a monodentate manner, inducing a change in the zinc ion geometry and coordination, while its benzyl group fits into the S1′ specificity pocket of the enzyme. The inhibitor molecule is distorted at the position of the carbon atom that is involved in the ester bond linkage on one side and the zinc coordination on the other. This particular type of Thiirane-based metalloprotease inhibitor is for the first time analyzed in complex to the target protease at high resolution and may be used as a general model for zinc-dependent proteases.
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Active site ring-opening of a Thiirane moiety and picomolar inhibition of gelatinases.
Chemical biology & drug design, 2009Co-Authors: Christopher C. Forbes, Jed F. Fisher, Qicun Shi, Mijoon Lee, Dusan Hesek, Leticia I. Llarrull, Marta Toth, Michael Gossing, Rafael Fridman, Shahriar MobasheryAbstract:(±)-2-[(4-Phenoxyphenylsulfonyl)methyl]Thiirane 1 is a potent and selective mechanism-based inhibitor of the gelatinase sub-class of the zinc-dependent matrix metalloproteinase family. Inhibitor 1 has excellent activity in in vivo models of gelatinase-dependent disease. We demonstrate that the mechanism of inhibition is a rate-limiting gelatinase-catalyzed thiolate generation via deprotonation adjacent to the Thiirane, with concomitant Thiirane opening. A corollary to this mechanism is the prediction that thiol-containing structures, related to Thiirane-opened 1, will possess potent matrix metalloproteinase inhibitory activity. This prediction was validated by the synthesis of the product of this enzyme-catalyzed reaction on 1, which exhibited a remarkable Ki of 530 pM against matrix metalloproteinase-2. Thiirane 1 acts as a caged thiol, unmasked selectively in the active sites of gelatinases. This mechanism is unprecedented in the substantial literature on inhibition of zinc-dependent hydrolases.
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DFT Studies of the Ring-Opening Mechanism of SB-3CT, a Potent Inhibitor of Matrix Metalloproteinase 2
Organic letters, 2009Co-Authors: Peng Tao, Jed F. Fisher, Shahriar Mobashery, H. Bernhard SchlegelAbstract:SB-3CT is a 2-[(arylsulfonyl)methyl]Thiirane that achieves potent inhibition, by a Thiirane-opening mechanism, of the MMP2 and MMP9 zinc metalloproteases. The deprotonation mechanism for Thiirane opening of SB-3CT and for the opening of its oxirane analogue, both relevant to the inhibition of MMP2, was investigated computationally using the acetate anion as the Bronsted base and in methanol and acetonitrile as solvents. The activation barriers for the reaction show a significant stereoelectronic effect. The lowest energy paths have the breaking C−H bond gauche to both sulfone oxygens and with this C−H bond anti to the breaking C−S bond of the Thiirane. The calculated primary isotope effect agrees with experimental data.
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Chapter 10:Thiirane Class of Gelatinase Inhibitors as a Privileged Template that Crosses the Blood–Brain Barrier
Drug Discovery, 1Co-Authors: Major Gooyit, Shahriar Mobashery, Zhihong Peng, Mayland ChangAbstract:The gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) play important roles in the pathophysiology of several diseases, including cancer metastases, neurological diseases, and chronic wounds. MMPs also mediate beneficial repair and recovery functions. Thus, the use of selective MMP inhibitors is required to avoid side effects. The prototype gelatinase inhibitor SB-3CT displays potency and selectivity towards the gelatinases. SB-3CT contains a Thiirane ring that involves a reaction catalyzed by the gelatinases, which results in slow-binding and/or tight-binding inhibition. This unique mechanism of action is at the root of selectivity enjoyed by the Thiirane class of inhibitors. We have synthesized and evaluated >500 Thiirane derivatives. SB-3CT has shown efficacy in numerous animal models of disease, including cancer metastasis, stroke, traumatic brain injury, and diabetic wound healing. The members of the Thiirane class cross the blood–brain barrier (BBB), achieve therapeutic concentrations in the brain, and do not accumulate in the brain. These desirable attributes of the Thiiranes indicate that this class of gelatinase inhibitors holds great promise for intervention of neurological diseases and chronic wounds.
David G. Lister - One of the best experts on this subject based on the ideXlab platform.
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the rotational spectrum of the argon Thiirane van der waals molecule
Chemical Physics Letters, 1992Co-Authors: A C Legon, David G. ListerAbstract:Abstract The rotational spectrum of the argon—Thiirane van der Waals molecule has been observed using pulsed-nozzle, Fourier-transform microwave spectroscopy. Transitions due to μa and μb components of the electric dipole moment have been observed and used to derive rotational and quartic centrifugal distortion constants. The molecule has Cs symmetry with a distance R = 3.79 pm from the centre of mass of Thiirane to the argon atom and an angle θ = 98° between this vector and the bisector of the CSC bond angle of the Thiirane molecule. An upper limit of 10 kHz is placed on the ground vibrational state inversion frequency in Ar…S(CH2)2.
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The rotational spectrum of the argon—Thiirane van der Waals molecule
Chemical Physics Letters, 1992Co-Authors: Anthony C. Legon, David G. ListerAbstract:Abstract The rotational spectrum of the argon—Thiirane van der Waals molecule has been observed using pulsed-nozzle, Fourier-transform microwave spectroscopy. Transitions due to μa and μb components of the electric dipole moment have been observed and used to derive rotational and quartic centrifugal distortion constants. The molecule has Cs symmetry with a distance R = 3.79 pm from the centre of mass of Thiirane to the argon atom and an angle θ = 98° between this vector and the bisector of the CSC bond angle of the Thiirane molecule. An upper limit of 10 kHz is placed on the ground vibrational state inversion frequency in Ar…S(CH2)2.
R. C. Batten - One of the best experts on this subject based on the ideXlab platform.
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Rotational spectroscopy of a weak complex of Thiirane and ethyne: The identification and properties of a highly nonlinear S⋯H–C hydrogen bond
The Journal of Chemical Physics, 2003Co-Authors: R. C. Batten, Gc Cole, Anthony C. LegonAbstract:Rotational and centrifugal distortion constants were determined for eight isotopomers of a weakly bound complex of Thiirane and ethyne. The observed complex is of Cs symmetry, with ethyne lying in the symmetry (ab principal inertial) plane and with H of HCCH forming a hydrogen bond to the S atom of Thiirane. The r0 geometry is: r(S⋯H)=2.76(5) A, φ=84.0(5)°, and θ=42.9(2)°, where φ is the angle made by the S⋯H internuclear line with the local C2 axis of the Thiirane ring and θ is the angular deviation of the S⋯H–C nuclei from a linear arrangement. The nonlinearity of the hydrogen bond is attributed to a weak primary interaction S⋯H–C coupled with a secondary interaction involving the π bond of ethyne with the two equivalent H atoms of Thiirane that are closest to it. The angular geometry of (CH2)2S⋯HCCH is compared with those of other species (CH2)2S⋯HX, where X=F, Cl, Br, and CN.Rotational and centrifugal distortion constants were determined for eight isotopomers of a weakly bound complex of Thiirane and ethyne. The observed complex is of Cs symmetry, with ethyne lying in the symmetry (ab principal inertial) plane and with H of HCCH forming a hydrogen bond to the S atom of Thiirane. The r0 geometry is: r(S⋯H)=2.76(5) A, φ=84.0(5)°, and θ=42.9(2)°, where φ is the angle made by the S⋯H internuclear line with the local C2 axis of the Thiirane ring and θ is the angular deviation of the S⋯H–C nuclei from a linear arrangement. The nonlinearity of the hydrogen bond is attributed to a weak primary interaction S⋯H–C coupled with a secondary interaction involving the π bond of ethyne with the two equivalent H atoms of Thiirane that are closest to it. The angular geometry of (CH2)2S⋯HCCH is compared with those of other species (CH2)2S⋯HX, where X=F, Cl, Br, and CN.
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rotational spectroscopy of a weak complex of Thiirane and ethyne the identification and properties of a highly nonlinear s h c hydrogen bond
Journal of Chemical Physics, 2003Co-Authors: R. C. Batten, Gc Cole, Anthony C. LegonAbstract:Rotational and centrifugal distortion constants were determined for eight isotopomers of a weakly bound complex of Thiirane and ethyne. The observed complex is of Cs symmetry, with ethyne lying in the symmetry (ab principal inertial) plane and with H of HCCH forming a hydrogen bond to the S atom of Thiirane. The r0 geometry is: r(S⋯H)=2.76(5) A, φ=84.0(5)°, and θ=42.9(2)°, where φ is the angle made by the S⋯H internuclear line with the local C2 axis of the Thiirane ring and θ is the angular deviation of the S⋯H–C nuclei from a linear arrangement. The nonlinearity of the hydrogen bond is attributed to a weak primary interaction S⋯H–C coupled with a secondary interaction involving the π bond of ethyne with the two equivalent H atoms of Thiirane that are closest to it. The angular geometry of (CH2)2S⋯HCCH is compared with those of other species (CH2)2S⋯HX, where X=F, Cl, Br, and CN.Rotational and centrifugal distortion constants were determined for eight isotopomers of a weakly bound complex of Thiirane and ethyne. The observed complex is of Cs symmetry, with ethyne lying in the symmetry (ab principal inertial) plane and with H of HCCH forming a hydrogen bond to the S atom of Thiirane. The r0 geometry is: r(S⋯H)=2.76(5) A, φ=84.0(5)°, and θ=42.9(2)°, where φ is the angle made by the S⋯H internuclear line with the local C2 axis of the Thiirane ring and θ is the angular deviation of the S⋯H–C nuclei from a linear arrangement. The nonlinearity of the hydrogen bond is attributed to a weak primary interaction S⋯H–C coupled with a secondary interaction involving the π bond of ethyne with the two equivalent H atoms of Thiirane that are closest to it. The angular geometry of (CH2)2S⋯HCCH is compared with those of other species (CH2)2S⋯HX, where X=F, Cl, Br, and CN.
Mayland Chang - One of the best experts on this subject based on the ideXlab platform.
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chapter 10 Thiirane class of gelatinase inhibitors as a privileged template that crosses the blood brain barrier
2015Co-Authors: Major Gooyit, Shahriar Mobashery, Zhihong Peng, Mayland ChangAbstract:The gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) play important roles in the pathophysiology of several diseases, including cancer metastases, neurological diseases, and chronic wounds. MMPs also mediate beneficial repair and recovery functions. Thus, the use of selective MMP inhibitors is required to avoid side effects. The prototype gelatinase inhibitor SB-3CT displays potency and selectivity towards the gelatinases. SB-3CT contains a Thiirane ring that involves a reaction catalyzed by the gelatinases, which results in slow-binding and/or tight-binding inhibition. This unique mechanism of action is at the root of selectivity enjoyed by the Thiirane class of inhibitors. We have synthesized and evaluated >500 Thiirane derivatives. SB-3CT has shown efficacy in numerous animal models of disease, including cancer metastasis, stroke, traumatic brain injury, and diabetic wound healing. The members of the Thiirane class cross the blood–brain barrier (BBB), achieve therapeutic concentrations in the brain, and do not accumulate in the brain. These desirable attributes of the Thiiranes indicate that this class of gelatinase inhibitors holds great promise for intervention of neurological diseases and chronic wounds.
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Chapter 10:Thiirane Class of Gelatinase Inhibitors as a Privileged Template that Crosses the Blood–Brain Barrier
Drug Discovery, 1Co-Authors: Major Gooyit, Shahriar Mobashery, Zhihong Peng, Mayland ChangAbstract:The gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) play important roles in the pathophysiology of several diseases, including cancer metastases, neurological diseases, and chronic wounds. MMPs also mediate beneficial repair and recovery functions. Thus, the use of selective MMP inhibitors is required to avoid side effects. The prototype gelatinase inhibitor SB-3CT displays potency and selectivity towards the gelatinases. SB-3CT contains a Thiirane ring that involves a reaction catalyzed by the gelatinases, which results in slow-binding and/or tight-binding inhibition. This unique mechanism of action is at the root of selectivity enjoyed by the Thiirane class of inhibitors. We have synthesized and evaluated >500 Thiirane derivatives. SB-3CT has shown efficacy in numerous animal models of disease, including cancer metastasis, stroke, traumatic brain injury, and diabetic wound healing. The members of the Thiirane class cross the blood–brain barrier (BBB), achieve therapeutic concentrations in the brain, and do not accumulate in the brain. These desirable attributes of the Thiiranes indicate that this class of gelatinase inhibitors holds great promise for intervention of neurological diseases and chronic wounds.