Sulindac sulfide

FIGURE 4.28 Oxidation of sulindac sulfide to sulindac sulfoxide by FMO and oxidation of clindamycin to clindamycin sulfoxide by CYP3A4. 

While N-oxidation is essentially driven by FMO, it is not true of S-oxidation. As indicated earlier, P450 can contribute significantly to S-oxidation and, in some cases, it is the dominant or even only enzyme catalyzing the reaction. Sulindac sulfide, a metabolite of the nonsteroidal anti-inflammatory agent, sulindac, is reoxidized by FMO (71) with a high degree of stereoselectivity toward the (7 )-enantiomer back to enantiomerically... 

Conversion of haloperidol to reduced haloperidol (a secondary alcohol) Glutathine dependent reduction of disulfiram to deithyldithiocarbamate Thioredoxin dependent of sulindac to sulindac sulfide DT diaphorase reduction of menadione to hydroquinone Conversion of pentabromoethane to tetra bromoethane (releasing free bromide ion)... 

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

Goldberg Y, Nassif II, Pittas A, et al. The anti-proliferative effect of sulindac and sulindac sulfide on HT-29 colon cancer cells alterations in tumor suppressor and cell cycle-regulatory proteins. Oncogene 1996 12 893-901. 

Piazza GA, Rahm AL, Krutzsch M, et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995 55 3110-3116. 

Sulindac shows no relevant inhibition of cyclooxygenase (Warner et al., 1999), whereas the active metabolite sulindac sulfide shows inhibition of both isoenzymes with a preference for COX-1 in a whole blood assay (see also Brideau et al., 1996 ratio COX-1/COX-2 = 0.1). Sulindac is one of the NSAIDs, extensively studied in cancer reseach (Haanen, 2001). The metabolite sulindac sulfone induces apoptosis in tumor cells. 

Sulindac is absorbed from the gastrointestinal tract and reversibly metabolised to sulindac sulfide and irreversibly metabolised to sulindac sulfone. Peak plasma... 

Structures of the metabolites sulindac sulfide and sulindac sulfone... 

Evaluation of the scavenging activity for H2O2 by NSAIDs, namely indole derivatives (indomethacin, acemetacin, etodolac), pyrrole derivatives (tol-metin, ketorolac), oxazole derivative (oxaprozin), indene derivative (sulin-dac) and its metabolites (sulindac sulfide and sulindac sulfone) was performed by Costa et al. [ 103]. The obtained results against endogenous antioxidants melatonin and GSH demonstrated that all the studied NSAIDs display... 

Fig. 5.7 Thermal scans of DPPC multil-amellar dispersions with various mole ratios of sulindac sulfide, sulindac, and sulindac sulfone (50 mM phosphate buffer, pH 7.0). (Reprinted from Fig. 6 of ref. 28 with permission from the American Chemical Society.)...

Sulindac 90 93 (and high for metabolites) 7-8 (16.4 sulfide) <1% of sulindac dose appears as active sulfide metabolite Yes sulindac and sulfone undergo extensive enterohepatic circulation relative to sulfide Extensive in liver - oxidation to sulfone, reduction to sulfide and glucuronidation Sulindac sulfide (parent is prodrug)... 

Sulindac is an inactive prodrug which needs to be converted in the liver to its active metabolite, sulindac sulfide. The metabolic pathway for sulindac is complicated, even in healthy subjects, by the reversibility of this process, the possibility of conversion to an inactive sulfone metabolite, and the extensive enterohepatic circulation of all three species [25, 26]. 

Figure 2 Importance of the 2 -methyl group for inhibition of COX by indomethacin and sulindac sulfide, (a) Indomethacin bound in the active site of COX-2. The 2 -methyl group of indomethacin, shown with its Van der Waals surface, sits in a hydrophobic pocket that consists of Val-349, Ala-527, Ser-530, and Leu-531. Hydrogens are included on the residues of the hydrophobic pocket and the 2 -methyl group of indomethacin. (b) Structures and inhibitory activities of indomethacin, sulindac sulfide, and their des-methyl analogs.

Sulindac sulfide, the bioactive metabolite of sulindac, is struchirally very similar to INDO and is a slow, tight-binding inhibitor of COX (Fig. 2b) (12, 13). As with INDO, removal of the methyl group from sulindac sulfide results in loss of COX-1 and COX-2 inhibition (14). However, it should be noted that the benzylidine double bond of rfei-methyl sulindac sulfide (DM-SS) exists in the F-conformation, whereas sulindac sulfide exists in the Z-conformer. 

Takahashi Y, Hayashi I, Tominari Y, Rikimaru K, Morohashi Y, Kan T, Natsugari H, Fukuyama T, Tomita T, Iwatsubo T. Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. J. Biol. Chem. 2003 278 18664-18670. 

Celecoxib and rofecoxib have also been studied in AD. Randomized double blind, placebo controlled trials failed to demonstrate a therapeutic benefit (Sainetti et al., 2000 Aisen et al., 2003). The rofecoxib trial used naproxen as a control the results were consistent with other studies in which nonselective NSAIDs such as diclofenac, have been ineffective in AD (Scharf et al., 1999). Other NSAIDs including ibuprofen, indomethacin and sulindac sulfide have demonstrated potential efficacy in AD (Rogers et al., 1993 t Veld et al., 2001), but definitive trials have not yet been conducted. 

Sulindac Sulfide metabolite of sulindac Sulfoxide reduction... 

All compounds of the test dataset are nonsteroidal anti-inflammatory drugs (NSAIDs) and are thus relatively similar in terms of their pharmacological properties (Fig. 18). The compounds are 1, acetylsalicylic acid 2, diclofenac 3, flufe-namic acid 4, flubiprofen 5, ibuprofen 6, indometacin 7, ketoprofen 8, meclofe-namic acid 9, mefenamic acid 10, naproxen 11, piroxicam 12, sulindac sulfide (active metabolite of sulindac) 13, tenoxicam 14, meloxicam 15, cgp 28238 16, DuP-697 17, L-745-337 18, 6-methoxy-2-naphthylacetic acid (active metabolite of nabumeton) 19, NS-389 20, SC 58125. 

Fig. 16. Chemical structures for Ras inhibitors, (a) GTP analogs with modified bases bind to Ras with up to a Kiel (IC50 of Analog divided by the IC50 of GDP) of 3.30. (b) Sulindac sulfide ((3Z)-3-(4-(methylthio)benzylidene)-6-fluoro-3,3a-dihydro-2-methyl-2H-indene-1 -carboxylic acid) disrupts this interaction with an IC50 of approximately 210 pM. (c) An optimized sulindac analog ((3Z)-6-fluoro-3-((furan-3-yl)methylene)-3,3a-dihydro-2-methyl-2H-indene-1 -carboxylic acid) has an IC50 of approximately 30 pM. The molecular basis of the compound s mechanism of action is unknown, but both (b) and (c) are hypothesized to operate by disrupting Ras-Raf interactions.

Etienne, F., Resnick, L., Sagher, D., Brot, N., and Weissbach, H. (2003) Reduction of sulindac to its active metabolite, sulindac sulfide assay and role of the methionine sulfoxide reductase system. Biochem. Biophys. Res. Commun. 312, 1005-1010. 

Shirin, El. et al.. Antiproliferative effects ofS-allylmercaptocysteine on colon cancer cells when tested alone or in combination with sulindac sulfide. Cancer Res., 61, 725,2001. 

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