- Synthesis and biological evaluation of nitric oxide-donating analogues of sulindac for prostate cancer treatment
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A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac-NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC50 values of 6.1 ± 4.1 and 12.1 ± 3.2 μM, respectively, coupled with observed nitric oxide release.
- Nortcliffe, Andrew,Ekstrom, Alexander G.,Black, James R.,Ross, James A.,Habib, Fouad K.,Botting, Nigel P.,O'Hagan, David
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supporting information
p. 756 - 761
(2014/01/23)
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- Asymmetric oxidation of sulfides by hydrogen peroxide catalyzed by chiral manganese porphyrins in water/methanol solution
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An efficient asymmetric oxidation of sulfides catalyzed by water-soluble chiral manganese porphyrin was carried out in presence of cheap and environmentally benign oxidant H2O2 at 25 °C. Prochiral sulfides were converted to respective sulfoxides with up to 100% conversion and up to 57% enantiomeric excess. The present study demonstrated the necessity of water as solvent and imidazole as co-catalyst. Application to the preparation of the optically drug, sulindac, was demonstrated.
- Srour, Hassan,Jalkh, Joanna,Le Maux, Paul,Chevance, Soizic,Kobeissi, Marwan,Simonneaux, Gérard
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- Studies on the metabolism and biological activity of the epimers of sulindac
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Sulindac is a nonsteroidal, anti-inflammatory drug (NSAID) that has also been studied for its anticancer activity. Recent studies suggest that sulindac and its metabolites act by sensitizing cancer cells to oxidizing agents and drugs that affect mitochondrial function, resulting in the production of reactive oxygen species and death by apoptosis. In contrast, normal cells are not killed under these conditions and, in some instances, are protected against oxidative stress. Sulindac has a methyl sulfoxide moiety with a chiral center and was used in all of the previous studies as a mixture of the R- and S-epimers. Because epimers of a compound can have very different chemical and biological properties, we have separated the R- and S-epimers of sulindac, studied their individual metabolism, and performed preliminary experiments on their effect on normal and lung cancer cells exposed to oxidative stress. Previous results had indicated that the reduction of (S)-sulindac to sulindac sulfide, the active NSAID, was catalyzed by methionine sulfoxide reductase (Msr) A. In the present study, we purified an enzyme that reduces (R)-sulindac and resembles MsrB in its substrate specificity. The oxidation of both epimers to sulindac sulfone is catalyzed primarily by the microsomal cytochrome P450 (P450) system, and the individual enzymes responsible have been identified. (S)-Sulindac increases the activity of the P450 system better than (R)-sulindac, but both epimers increase primarily the enzymes that oxidize (R)-sulindac. Both epimers can protect normal lung cells against oxidative damage and enhance the killing of lung cancer cells exposed to oxidative stress. Copyright
- Brunell, David,Sagher, Daphna,Kesaraju, Shailaja,Brot, Nathan,Weissbach, Herbert
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experimental part
p. 1014 - 1021
(2012/03/10)
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- Therapeutic potential of sulindac hydroxamic acid against human pancreatic and colonic cancer cells
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The non-steroidal anti-inflammatory drug (NSAID) sulindac exhibits cyclooxygenase (COX)-dependent and COX-independent chemopreventive properties in human cancer. The present study was aimed at investigating whether the hydroxamic acid substitution for the carboxylic acid group could enhance the in vitro antitumor and antiangiogenic activities of sulindac. Characterization tools used on this study included analyses of cell viability, caspase 3/7 induction, DNA fragmentation, and gene expression. Our findings demonstrate that the newly synthesized hydroxamic acid derivative of sulindac and its sulfone and sulfide metabolites were characterized by a good anticancer activity on human pancreatic and colon cancer cells, both in terms of potency (IC 50 mean values from 6 ± 1.1 μM to 64 ± 1.1 μM) and efficacy (Emax of ～100%). Hydroxamic acid derivatives trigger a higher degree of apoptosis than carboxylic acid counterparts, increase bax/bcl-2 expression ratio and induce caspase 3/7 activation. Most notably, these compounds significantly inhibit proangiogenic growth factor-stimulated proliferation of vascular endothelial cell (HUVEC) at sub-micromolar concentrations. Our data also provide evidence that the COX-active metabolite of sulindac hydroxamic acid were the most active of the series and selective inhibition of COX-1 but not COX-2 can mimic its effects, suggesting that COX inhibition could only play a partial role in the mechanism of compound action. In conclusion, these data demonstrate that substitution of the carboxylic acid group with the hydroxamic acid moiety enhances in vitro antiproliferative, proapoptotic and antiangiogenic properties of sulindac, therefore increasing the therapeutic potential of this drug.
- Fogli, Stefano,Banti, Irene,Stefanelli, Fabio,Picchianti, Luca,Digiacomo, Maria,MacChia, Marco,Breschi, Maria Cristina,Lapucci, Annalina
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experimental part
p. 5100 - 5107
(2010/12/24)
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- Synthesis, pharmacological evaluation and docking studies of new sulindac analogues
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This paper describes the synthesis, pharmacological evaluation and docking studies of a series of new sulindac analogues. Overall, the designed compounds revealed good, in vivo, antinociceptive activity and satisfactory anti-inflammatory profile. Flexible
- Romeiro, Nelilma C.,Leite, Ramon D.F.,Lima, Lidia M.,Cardozo, Suzana V.S.,de Miranda, Ana L.P.,Fraga, Carlos A.M.,Barreiro, Eliezer J.
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experimental part
p. 1959 - 1971
(2009/09/27)
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- Process for the preparation of organic compounds containing a sulfinyl or sulfonyl group in the presence of epsilon-phthalimidoperhexanoic acid
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A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.
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