Thalidomide and its analogues as cyclooxygenase inhibitors

Noguchi, Takao; Shimazawa, Rumiko; Nagasawa, Kazuo; Hashimoto, Yuichi

doi:10.1016/s0960-894x(02)00084-7

Cited by 70 publications

(46 citation statements)

References 25 publications

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“…Notably, the threshold for bitter compounds generally appears to be lower than that of sweet compounds [7]. The absence of a sweet taste may be due to the flat sp 2 hybridization of the nitrogen in the urea moiety of 9 as well as inability for the sp 3 nitrogen to exhibit dynamic chirality preventing recognition by the receptors for sweetness.…”

Section: Discussionmentioning

confidence: 99%

“…Substitution of a chiral carbon by nitrogen can thus create a dynamic chiral center in a molecule possessing properties of both enantiomers of its carbon counterpart. For example, replacement of the chiral carbon center by nitrogen in the drug thalidomide (1, Figure 1) gave aza-thalidomide 2 possessing activity comparable to its racemic mixture in which the inhibitory effects of the R-enantiomer on cyclooxygenase were tempered by the inactive S-isomer [2]. Alternatively, potential to adopt receptor requirements for recognition can give an aza-analog with potency similar to that of the more potent enantiomer.…”

Section: Introductionmentioning

confidence: 99%

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Examination of the Potential for Adaptive Chirality of the Nitrogen Chiral Center in Aza-Aspartame

Bouayad‐Gervais

Lubell

2013

Molecules

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Abstract:The potential for dynamic chirality of an azapeptide nitrogen was examined by substitution of nitrogen for the α-carbon of the aspartate residue in the sweetener S,S-aspartame. Considering that S,S-and R,S-aspartame possess sweet and bitter tastes, respectively, a bitter-sweet taste of aza-aspartame 9 could be indicative of a low isomerization barrier for nitrogen chirality inter-conversion. Aza-aspartame 9 was synthesized by a combination of hydrazine and peptide chemistry. Crystallization of 9 indicated a R,S-configuration in the solid state; however, the aza-residue chiral center was considerably flattened relative to its natural amino acid counterpart. On tasting, the authors considered aza-aspartame 9 to be slightly bitter or tasteless. The lack of bitter sweet taste of aza-aspartame 9 may be due to flattening from sp 2 hybridization in the urea as well as a high barrier for sp 3 nitrogen inter-conversion, both of which may interfere with recognition by taste receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Examination of the Potential for Adaptive Chirality of the Nitrogen Chiral Center in Aza-Aspartame

Bouayad‐Gervais

Lubell

2013

Molecules

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“…3, i.e. TNF-a productionregulating activity [36,37], COX-inhibiting activity [20], NOS-inhibiting activity [23], and anti-angiogenic activity [29]. In addition, thalidomide 1 is a labile compound both metabolically and chemically.…”

Section: Introductionmentioning

confidence: 99%

Thalidomide as a Multi‐Template for Development of Biologically Active Compounds

Hashimoto

2008

Archiv der Pharmazie

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Thalidomide is a teratogenic/hypnotic/sedative agent which elicits a wide range of pharmaceutical/biological activities. The diversity of its biological activities suggested that the drug might be useful as a multi-template for development of various kinds of biologically active compounds. We adopted two strategies for the structural development of thalidomide. The first was to develop the structure of the drug based on the target molecules to which thalidomide itself and/ or its metabolites directly bind, or the assay systems in which thalidomide itself and/or its metabolites exhibit activity. Based on this strategy, tumor necrosis factor-a production-regulating agents, cyclooxygenase inhibitors, nitric oxide synthase inhibitors, histone deacetylase inhibitors, anti-angiogenic agents, and tubulin polymerization inhibitors have been created. The second was to develop the structure of thalidomide based on hypothetical target molecule(s)/biological response(s) which might be relevant to the pharmacological effects elicited by thalidomide. Based on this strategy, androgen antagonists, progesterone antagonists, cell differentiation inducers, aminopeptidase inhibitors, thymidine phosphorylase inhibitors, l-calpain inhibitors, a-glucosidase inhibitors and nuclear liver X receptors (LXRs) antagonists have been created. Our structural development studies on thalidomide are reviewed focusing on recent development of tubulin polymerization inhibitors, a-glucosidase inhibitors, and nuclear liver X receptors antagonists.

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“…Our studies resulted in the creation of TNF-a production regulators (including bi-directional ones, as well as pure inhibitors and enhancers), 3,4,[6][7][8] androgen antagonists, 3,4,9,10) peptidase inhibitors, 4,[11][12][13][14][15] glucosidase inhibitors, 16,17) thymidine phosphorylase inhibitors 18) and cyclooxygenase inhibitors. 19,20) Nevertheless, not all of the beneficial pharmacological effects elicited by thalidomide can be fully interpreted in terms of the above activities, indicating the existence of other target molecules/phenomena. We suspected that nitric oxide synthase (NOS) might be another target molecule of thalidomide, because the drug is effective against diabetes and has hypoglycemic effect, whereas NO acts as disease-progressing factor.…”

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confidence: 99%

“…So we chose N-phenyl(homo)phthalimide or N-phenylquinazolinedione derivatives as lead compounds, based on our previous studies on peptidase inhibitors and COX inhibitors derived from thalidomide. 4,[12][13][14][15][16]19,20) Substituted phthalimide and homophthalimide compounds were prepared by routine organic synthetic methods, i.e., condensation of appropriate amines with phthalic (3) or homophthalic anhydride (4)(5)(6)(7)(8)(9)(10)(11). Quinazolinedione derivatives (12)(13)(14) were prepared by the condensation of 2,6-dialkylanilines and methyl anthranilate in the presence of triphosgene.…”

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confidence: 99%

Thalidomide as a Nitric Oxide Synthase Inhibitor and Its Structural Development

Shimazawa

Sano

Tanatani

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Thalidomide has been found to exhibit weak nitric oxide synthase (NOS)-inhibitory activity. Structural development studies of thalidomide showed that some N-2,6-dimethylphenylhomophthalimide analogs possess NOS-inhibiting activity.Key words thalidomide; nitric oxide synthase (NOS); inhibitor; structural development Thalidomide (1) is a hypnotic/sedative drug that was withdrawn from the market because of its severe teratogenicity. [2][3][4] In spite of this, research into thalidomide was not halted, and the drug has since been established to be effective for the treatment of various diseases, including leprosy, myeloma and AIDS. [3][4][5] Although thalidomide affects production of various cytokines, the prevailing hypothesis was that the effectiveness of thalidomide in these diseases is elicited entirely through regulation of tumor necrosis factor (TNF)-a production.We have been engaged in structural development studies of thalidomide, and have demonstrated that thalidomide is in fact a multi-target drug. Our studies resulted in the creation of TNF-a production regulators (including bi-directional ones, as well as pure inhibitors and enhancers), 3,4,[6][7][8] androgen antagonists, 3,4,9,10) peptidase inhibitors, 4,[11][12][13][14][15] glucosidase inhibitors, 16,17) thymidine phosphorylase inhibitors 18) and cyclooxygenase inhibitors. 19,20) Nevertheless, not all of the beneficial pharmacological effects elicited by thalidomide can be fully interpreted in terms of the above activities, indicating the existence of other target molecules/phenomena. We suspected that nitric oxide synthase (NOS) might be another target molecule of thalidomide, because the drug is effective against diabetes and has hypoglycemic effect, whereas NO acts as disease-progressing factor.The family of nitric oxide synthases (NOS), which includes neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS), 21) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO), an important cellular messenger molecule which has been implicated in both physiological and pathophysiological functions. In this paper, we describe evaluation of the NOS-inhibitory activity of thalidomide and its analogs.First we investigated NOS-inhibitory activity of thalidomide (1). Inhibitory activity was assayed by monitoring nitrite/nitrate production using Ichimori's protocol with a little modifications. 22,23) Although the quantitative values differed from experiment to experiment, the results were basically reproducible, and average inhibition rate are presented in Table 1. In the assay system, the IC 50 value of N G -nitro-L-arginine methyl ester (NNA, 2), which is a well-known analog of the endogenous NOS substrate, L-arginine, was determined to be 10 mM. The assay was performed in triplicate, and repeated at least three times. The result showed that thalidomide at 1 mM inhibits NOS by about 23% (Table 1). Although the NOS-inhibitory activity of thalidomide was weak, one or more of the thalidomide metabolites or decomposition products mig...

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Thalidomide and its analogues as cyclooxygenase inhibitors

Cited by 70 publications

References 25 publications

Examination of the Potential for Adaptive Chirality of the Nitrogen Chiral Center in Aza-Aspartame

Examination of the Potential for Adaptive Chirality of the Nitrogen Chiral Center in Aza-Aspartame

Thalidomide as a Multi‐Template for Development of Biologically Active Compounds

Thalidomide as a Nitric Oxide Synthase Inhibitor and Its Structural Development

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