Prostaglandin

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Varinder K Aggarwal - One of the best experts on this subject based on the ideXlab platform.

  • stereocontrolled organocatalytic synthesis of Prostaglandin pgf2 agr in seven steps
    Nature, 2012
    Co-Authors: Graeme Coulthard, Varinder K Aggarwal
    Abstract:

    A concise new synthesis of the most complex of the Prostaglandins—diverse hormone-like chemical messengers—should make existing Prostaglandin-based drugs cheaper and also facilitate other related syntheses. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for more 40 years. In this manuscript, the authors report a concise synthesis of the most complex Prostaglandin, PGF2α. Access to this compound should not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of chemical space around the ubiquitous five-membered ring motif. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction1,2. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for over 40 years3,4. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma5,6, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex Prostaglandin, PGF2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups7. Access to this bicyclic enal will not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic Prostaglandin analogues.

  • Stereocontrolled organocatalytic synthesis of Prostaglandin PGF_2α in seven steps
    Nature, 2012
    Co-Authors: Graeme Coulthard, Varinder K Aggarwal
    Abstract:

    Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for more 40 years. In this manuscript, the authors report a concise synthesis of the most complex Prostaglandin, PGF_2α. Access to this compound should not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of chemical space around the ubiquitous five-membered ring motif. A concise new synthesis of the most complex of the Prostaglandins—diverse hormone-like chemical messengers—should make existing Prostaglandin-based drugs cheaper and also facilitate other related syntheses. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction^ 1 , 2 . Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for over 40 years^ 3 , 4 . Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma^ 5 , 6 , have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex Prostaglandin, PGF_2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups^ 7 . Access to this bicyclic enal will not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic Prostaglandin analogues.

  • stereocontrolled organocatalytic synthesis of Prostaglandin pgf2α in seven steps
    Nature, 2012
    Co-Authors: Graeme Coulthard, William Erb, Varinder K Aggarwal
    Abstract:

    A concise new synthesis of the most complex of the Prostaglandins—diverse hormone-like chemical messengers—should make existing Prostaglandin-based drugs cheaper and also facilitate other related syntheses. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for more 40 years. In this manuscript, the authors report a concise synthesis of the most complex Prostaglandin, PGF2α. Access to this compound should not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of chemical space around the ubiquitous five-membered ring motif. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction1,2. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for over 40 years3,4. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma5,6, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex Prostaglandin, PGF2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups7. Access to this bicyclic enal will not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic Prostaglandin analogues.

Graeme Coulthard - One of the best experts on this subject based on the ideXlab platform.

  • stereocontrolled organocatalytic synthesis of Prostaglandin pgf2 agr in seven steps
    Nature, 2012
    Co-Authors: Graeme Coulthard, Varinder K Aggarwal
    Abstract:

    A concise new synthesis of the most complex of the Prostaglandins—diverse hormone-like chemical messengers—should make existing Prostaglandin-based drugs cheaper and also facilitate other related syntheses. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for more 40 years. In this manuscript, the authors report a concise synthesis of the most complex Prostaglandin, PGF2α. Access to this compound should not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of chemical space around the ubiquitous five-membered ring motif. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction1,2. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for over 40 years3,4. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma5,6, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex Prostaglandin, PGF2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups7. Access to this bicyclic enal will not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic Prostaglandin analogues.

  • Stereocontrolled organocatalytic synthesis of Prostaglandin PGF_2α in seven steps
    Nature, 2012
    Co-Authors: Graeme Coulthard, Varinder K Aggarwal
    Abstract:

    Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for more 40 years. In this manuscript, the authors report a concise synthesis of the most complex Prostaglandin, PGF_2α. Access to this compound should not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of chemical space around the ubiquitous five-membered ring motif. A concise new synthesis of the most complex of the Prostaglandins—diverse hormone-like chemical messengers—should make existing Prostaglandin-based drugs cheaper and also facilitate other related syntheses. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction^ 1 , 2 . Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for over 40 years^ 3 , 4 . Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma^ 5 , 6 , have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex Prostaglandin, PGF_2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups^ 7 . Access to this bicyclic enal will not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic Prostaglandin analogues.

  • stereocontrolled organocatalytic synthesis of Prostaglandin pgf2α in seven steps
    Nature, 2012
    Co-Authors: Graeme Coulthard, William Erb, Varinder K Aggarwal
    Abstract:

    A concise new synthesis of the most complex of the Prostaglandins—diverse hormone-like chemical messengers—should make existing Prostaglandin-based drugs cheaper and also facilitate other related syntheses. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for more 40 years. In this manuscript, the authors report a concise synthesis of the most complex Prostaglandin, PGF2α. Access to this compound should not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of chemical space around the ubiquitous five-membered ring motif. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction1,2. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for over 40 years3,4. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma5,6, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex Prostaglandin, PGF2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups7. Access to this bicyclic enal will not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic Prostaglandin analogues.

Piet Borst - One of the best experts on this subject based on the ideXlab platform.

  • the human multidrug resistance protein mrp4 functions as a Prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Glen Reid, Pieter Wielinga, Noam Zelcer, Ingrid Van Der Heijden, Annemieke Kuil, Marcel De Haas, Jan Wijnholds, Piet Borst
    Abstract:

    Prostaglandins are involved in a wide variety of physiological and pathophysiological processes, but the mechanism of Prostaglandin release from cells is not completely understood. Although poorly membrane permeable, Prostaglandins are believed to exit cells by passive diffusion. We have investigated the interaction between Prostaglandins and members of the ATP-binding cassette (ABC) transporter ABCC [multidrug resistance protein (MRP)] family of membrane export pumps. In inside-out membrane vesicles derived from insect cells or HEK293 cells, MRP4 catalyzed the time- and ATP-dependent uptake of Prostaglandin E1 (PGE1) and PGE2. In contrast, MRP1, MRP2, MRP3, and MRP5 did not transport PGE1 or PGE2. The MRP4-mediated transport of PGE1 and PGE2 displayed saturation kinetics, with Km values of 2.1 and 3.4 microM, respectively. Further studies showed that PGF1alpha, PGF2alpha, PGA1, and thromboxane B2 were high-affinity inhibitors (and therefore presumably substrates) of MRP4. Furthermore, several nonsteroidal antiinflammatory drugs were potent inhibitors of MRP4 at concentrations that did not inhibit MRP1. In cells expressing the Prostaglandin transporter PGT, the steady-state accumulation of PGE1 and PGE2 was reduced proportional to MRP4 expression. Inhibition of MRP4 by an MRP4-specific RNA interference construct or by indomethacin reversed this accumulation deficit. Together, these data suggest that MRP4 can release Prostaglandins from cells, and that, in addition to inhibiting Prostaglandin synthesis, some nonsteroidal antiinflammatory drugs might also act by inhibiting this release.

William Erb - One of the best experts on this subject based on the ideXlab platform.

  • stereocontrolled organocatalytic synthesis of Prostaglandin pgf2α in seven steps
    Nature, 2012
    Co-Authors: Graeme Coulthard, William Erb, Varinder K Aggarwal
    Abstract:

    A concise new synthesis of the most complex of the Prostaglandins—diverse hormone-like chemical messengers—should make existing Prostaglandin-based drugs cheaper and also facilitate other related syntheses. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for more 40 years. In this manuscript, the authors report a concise synthesis of the most complex Prostaglandin, PGF2α. Access to this compound should not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of chemical space around the ubiquitous five-membered ring motif. Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction1,2. Their biological activities and their complex molecular architectures have made Prostaglandins popular targets for synthetic organic chemists for over 40 years3,4. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma5,6, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex Prostaglandin, PGF2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups7. Access to this bicyclic enal will not only render existing Prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic Prostaglandin analogues.

Lawrence G Raisz - One of the best experts on this subject based on the ideXlab platform.

  • the role of Prostaglandins in the regulation of bone metabolism
    Clinical Orthopaedics and Related Research, 1995
    Co-Authors: Hiroshi Kawaguchi, Carol C Pilbeam, John R Harrison, Lawrence G Raisz
    Abstract:

    Prostaglandins are likely to play an important role in the physiologic and pathologic responses of skeletal tissue. They are potent agonists that can stimulate and inhibit bone resorption and formation. In vivo, the major effect of exogenous Prostaglandins, particularly Prostaglandin E 2 , is to stimulate resorption and formation. These effects appear to involve replication and differentiation of osteoclast and osteoblast precursors, and to be mediated at least in part by cyclic 3' 5' adenosine monophosphate. Prostaglandins can inhibit the activity of isolated osteoclasts, probably also by a cyclic 3' 5' adenosine monophosphate-mediated mechanism. Inhibition of collagen synthesis can be seen in cell and organ cultures and appears to be caused by a receptor selective for Prostaglandins of the F series and to involve activation of protein kinase C. Prostaglandin production by bone cells is regulated highly by mechanical forces, cytokines, growth factors, and systemic hormones. Prostaglandins also can amplify their own production. Regulation is associated with marked changes in the newly described inducible Prostaglandin G/H synthase with less effect on the constitutive enzyme. Prostaglandins also may play a role in postmenopausal bone loss because estrogen deficiency, which increases bone turnover, can increase Prostaglandin production in bone.