Cyclooxygenase 2 inhibitors: discovery, selectivity and the future

Marnett, Lawrence J.; Kalgutkar, Amit S.

doi:10.1016/s0165-6147(99)01385-1

Cited by 195 publications

(128 citation statements)

References 45 publications

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“…PGHS-1 is constitutively expressed and generates prostaglandins in response to hormone stimulation, whereas PGHS-2 is an inducible enzyme that is expressed in response to growth factors, tumor promotors, or cytokines (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Both isoforms are quite similar structurally (12)(13)(14)(15) and mechanistically (1,2,16), with only subtle kinetic differences in substrate (17,18) and inhibitor (19,20) specificities, and hydroperoxide activator requirements (21)(22)(23).…”

Section: Prostaglandin Endoperoxide H Synthase (Pghs)mentioning

confidence: 99%

Structure of Eicosapentaenoic and Linoleic Acids in the Cyclooxygenase Site of Prostaglandin Endoperoxide H Synthase-1

Malkowski

Thuresson

Lakkides

et al. 2001

Journal of Biological Chemistry

115

101

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Prostaglandin endoperoxide H synthases-1 and -2 (PGHSs) can oxygenate 18 -22 carbon polyunsaturated fatty acids, albeit with varying efficiencies. Here we report the crystal structures of eicosapentaenoic acid (EPA, 20:5 n-3) and linoleic acid (LA, 18:2 n-6) bound in the cyclooxygenase active site of Co 3؉ protoporphyrin IX-reconstituted ovine PGHS-1 (Co 3؉ -oPGHS-1) and compare the effects of active site substitutions on the rates of oxygenation of EPA, LA, and arachidonic acid (AA). Both EPA and LA bind in the active site with orientations similar to those seen previously with AA and dihomo-␥-linolenic acid (DHLA). For EPA, the presence of an additional double bond (C-17/C-18) causes this substrate to bind in a "strained" conformation in which C-13 is misaligned with respect to Tyr-385, the residue that abstracts hydrogen from substrate fatty acids. Presumably, this misalignment is responsible for the low rate of EPA oxygenation. Prostaglandin endoperoxide H synthase (PGHS)1 converts arachidonic acid (AA) to prostaglandin H 2 in the committed step of prostaglandin and thromboxane biosynthesis (1, 2). Two isoforms of PGHS exist in mammalian tissues. PGHS-1 is constitutively expressed and generates prostaglandins in response to hormone stimulation, whereas PGHS-2 is an inducible enzyme that is expressed in response to growth factors, tumor promotors, or cytokines (1-11). Both isoforms are quite similar structurally (12-15) and mechanistically (1, 2, 16), with only subtle kinetic differences in substrate (17, 18) and inhibitor (19, 20) specificities, and hydroperoxide activator requirements (21-23).Both PGHS-1 and -2 catalyze two different reactions: a cyclooxygenase reaction and a peroxidase reaction. Structural studies indicate that the active sites are spatially distinct from each other and separated by a heme group (12-15). The cyclooxygenase reaction occurs within a hydrophobic channel that extends from the membrane binding domain of the enzyme into the core of the globular domain. The fatty acid substrate is positioned within this site in an extended L-shaped conformation (15,24). Cyclooxygenase catalysis begins with abstraction of the 13-pro-S hydrogen from AA by a tyrosyl radical centered on Tyr-385 in the rate-determining step to generate an arachidonyl radical (25-27). Two molecules of O 2 are then sequentially added to the arachidonyl radical to form the bicyclic hydroperoxide prostaglandin G 2 (PGG 2 ). This intermediate diffuses to the peroxidase active site where the 15-hydroperoxyl group undergoes a two-electron reduction to the alcohol prostaglandin H 2 . Although the peroxidase activity can function independently of the cyclooxygenase activity (28), activation of the cyclooxygenase requires a functional peroxidase (1,2,23).AA is the preferred substrate for PGHS-1 and PGHS-2 (17). Both isoforms will, however, oxygenate a variety of n-3 and n-6 18 -22 carbon fatty acids albeit with reduced catalytic efficiencies (17, 29 -36). Most of these alternative fatty acid substrates have somewhat higher K m...

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Section: Prostaglandin Endoperoxide H Synthase (Pghs)mentioning

confidence: 99%

Structure of Eicosapentaenoic and Linoleic Acids in the Cyclooxygenase Site of Prostaglandin Endoperoxide H Synthase-1

Malkowski

Thuresson

Lakkides

et al. 2001

Journal of Biological Chemistry

115

101

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“…Due to their more selective function, these latter drugs, referred to as coxibs, promise to offer the therapeutic benefit of traditional NSAIDs with less of the associated side effects. [4][5][6][7][8] Celecoxib is widely prescribed under the trade name Celebrex ® for relief of symptoms of osteoarthritis and rheumatoid arthritis, and was recently approved as an adjunct to standard care for patients with familial adenomatous polyposis (FAP)…”

Section: Introductionmentioning

confidence: 99%

Dimethyl-Celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-Inhibitory function, potently mimics the anti-tumor effects of celecoxib on burkitt’s lymphoma in vitro and in vivo

Kardosh

Wang

Uddin

et al. 2005

Cancer Biology & Therapy

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“…The pharmacological effects of NSAIDs stem from their inhibition of cyclooxygenase (prostaglandin endoperoxide synthase or COX) enzymes (32). COX exists in the human body as three isozymes: COX-1, COX-2, and COX-3.…”

mentioning

confidence: 99%

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Julius

Farha²,

Chiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

110

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Carboranes represent a potentially rich but underutilized class of inorganic and catabolism-inert pharmacophores. The regioselectivity and ease of derivatization of carboranes allows for facile syntheses of a wide variety of novel structures. The steric bulk, rigidity, and ease of B-and C-derivatization and lack ofinteractions associated with hydrophobic carboranes may be exploited to enhance the selectivity of previously identified bioactive molecules. Transthyretin (TTR) is a thyroxine-transport protein found in the blood that has been implicated in a variety of amyloid related diseases. Previous investigations have identified a variety of nonsteroidal antiinflammatory drugs (NSAIDs) and structurally related derivatives that imbue kinetic stabilization to TTR, thus inhibiting its dissociative fragmentation and subsequent aggregation to form putative toxic amyloid fibrils. However, the cyclooxygenase (COX) activity associated with these pharmaceuticals may limit their potential as long-term therapeutic agents for TTR amyloid diseases. Here, we report the synthesis and evaluation of carborane-containing analogs of the promising NSAID pharmaceuticals previously identified. The replacement of a phenyl ring in the NSAIDs with a carborane moiety greatly decreases their COX activity with the retention of similar efficacy as an inhibitor of TTR dissociation. The most promising of these compounds, 1-carboxylic acid-7-[3-fluorophenyl]-1,7-dicarba-closo-dodecaborane, showed effectively no COX-1 or COX-2 inhibition at a concentration more than an order of magnitude larger than the concentration at which TTR dissociation is nearly completely inhibited. This specificity is indicative of the potential for the exploitation of the unique properties of carboranes as potent and selective pharmacophores.amyloid ͉ cyclooxygenase ͉ nonsteroidal antiinflammatory drug ͉ fibril T he dicarba-closo-dodecaboranes (carboranes) are icosahedral carbon-containing boron clusters with extraordinary characteristic properties (such as resistance to catabolism, kinetic inertness to reagents, strong hydrophobicity, and wellestablished chemistry) that afford the opportunity for their exploitation as novel hydrophobic pharmacophores. The three isomeric dicarbon carboranes, closo-1,2-C 2 B 10 H 12 , closo-1,7-C 2 B 10 H 12 , and closo-1,12-C 2 B 10 H 12 , commonly known as ortho-, meta-, and para-carborane, respectively, share approximately the same volume as a rotated phenyl ring. This, as well as their structural integrity, ease of substitution, and delocalized bonding, suggests their description as three-dimensional analogs of aromatic hydrocarbons (1), allowing their facile substitution for phenyl rings as rigid scaffolding in pharmacological agents. This rigid scaffolding can be easily and selectively derivatized through deprotonation of the slightly acidic C-H vertices by a strong base (alkyllithium reagents, Grignard reagents, etc.) affording a strongly nucleophilic carboranyl anion capable of reaction with a wide range of electrophiles, inclu...

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Cyclooxygenase 2 inhibitors: discovery, selectivity and the future

Cited by 195 publications

References 45 publications

Structure of Eicosapentaenoic and Linoleic Acids in the Cyclooxygenase Site of Prostaglandin Endoperoxide H Synthase-1

Structure of Eicosapentaenoic and Linoleic Acids in the Cyclooxygenase Site of Prostaglandin Endoperoxide H Synthase-1

Dimethyl-Celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-Inhibitory function, potently mimics the anti-tumor effects of celecoxib on burkitt’s lymphoma in vitro and in vivo

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

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