Phenylphthalimides with Tumor Necrosis Factor Alpha Production-Enhancing Activity.

Shibata, Yoshihiro; Sasaki, K.; Hashimoto, Yuichi; Iwasaki, Shigeo

doi:10.1248/cpb.44.156

Cited by 48 publications

(50 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…16,17) Thalidomide (1) shows moderate TNF-a production-inhibitory activity in this assay system. [1][2][3][4][5]16,17) The TNF-a production-inhibitory activity of test compounds was measured as described in the experimental section as %-inhibition values, where 100% and 0% represent complete inhibition and no inhibition, respectively. Of course the %-values were variable from experiment to experiment, but the order of efficacy was reproducible.…”

Section: )mentioning

confidence: 98%

Section: )mentioning

confidence: 99%

“…16,17) THP-1 cells do not produce TNF-a under normal cell culture conditions, but do produce TNF-a in response to stimulation with 12-O-tetradecanoylphorbol 13-acetate (TPA). 16,17) Thalidomide (1) shows moderate TNF-a production-inhibitory activity in this assay system. [1][2][3][4][5]16,17) The TNF-a production-inhibitory activity of test compounds was measured as described in the experimental section as %-inhibition values, where 100% and 0% represent complete inhibition and no inhibition, respectively.…”

Section: )mentioning

confidence: 99%

“…16,17) Ring opening by hydrolysis at the phthalimide moiety (2) caused powerful enhancement of the activity (80% inhibition). On the other hand, ring opening at the glutarimide moiety (3, 4) decreased the activity (13-18%).…”

Section: )mentioning

confidence: 99%

See 3 more Smart Citations

Hydrolyzed Metabolites of Thalidomide: Synthesis and TNF-.ALPHA. Production-Inhibitory Activity

et al. 2007

Self Cite

View full text Add to dashboard Cite

Thalidomide (1) was developed in the 1950s as a nontoxic sedative/hypnotic drug, but was withdrawn from the market in the early 1960s because of its teratogenicity.1-5) However, it was subsequently identified as an effective agent for the treatment of multiple myeloma (MM), AIDS, Hansen's disease, and various cancers. [1][2][3][4][5] The US Food and Drug Administration (FDA) approved it first for the treatment of erythema nodosum in Hansen's disease in 1998, and then, in combination with dexamethasone, for the treatment of MM in 2006. Official approval for the use of thalidomide (1) to treat MM has also been applied for in Japan. Thalidomide (1) has been discovered to have various biological activities, including inhibition of tumor necrosis factor-a (TNF-a) production, and anti-inflammatory, anti-angiogenic, and cyclooxygenase (COX)-inhibitory activities. [1][2][3][4][5] Although the precise molecular mechanisms of its actions are unknown, thalidomide (1) was introduced with data linking it to inhibition of the production of TNF-a. We have already reported the TNF-a production-inhibitory activity of mono-and/or dihydroxylated metabolites of thalidomide.6) As a part of our continuing work in this area, we also investigated the TNF-a production-inhibitory activity of putative hydrolyzed metabolites of thalidomide.Thalidomide (1) is metabolically labile and many metabolites have been identified or proposed. Both enzymatic hydroxylation and spontaneous hydrolysis occur, with the latter being predominant. Thalidomide's half-life is about 5 h at the physiological pH of 7.4, and twelve hydrolyzed metabolites have been proposed to be formed through successive hydrolysis of amide bond(s) 7,8) (Fig. 1). Although thalidomide has two imide moieties, phthalimide and glutarimide, the phthalimide moiety is more hydrolytically unstable than the glutarimide moiety. 7,8) In this paper, we describe the synthesis of various candidate metabolites of thalidomide (2, 3, 4, 6, 7, 8, 10), as well as the results of chemical and physical characterization and evaluation of their TNF-a production-inhibitory activities.Chemistry The thalidomide metabolite 2, formed by hydrolysis at the phthaloyl moiety, was synthesized as shown in Chart 1. Boc-glutamine 14 was treated with 1,1Ј-carbonyldiimidazole (CDI) in the presence of a catalytic amount of 4-dimethylaminopyridine (DMAP) to afford the cyclic imide 15.9) The Boc group of 15 was removed with 30% HBr/AcOH to afford 16 as the HBr salt. The phthalic acid monobenzyl ester 17 was treated with 16 in the presence of methyl chloroformate to afford 18. The benzyl group of 18 was removed by catalytic hydrogenation with H 2 gas on 10% Pd-C to afford the hydrolyzed thalidomide metabolite 2. Putative hydrolyzed metabolites of thalidomide were prepared and characterized, and their inhibitory activity on tumor necrosis factor (TNF)-a a production in the human monocytic leukemia cell line THP-1 was evaluated. a a-(2-Carboxybenzamido)glutarimide was a more potent TNF-a a production inhibitor than thalidomi...

show abstract

Section: )mentioning

confidence: 98%

Section: )mentioning

confidence: 99%

Section: )mentioning

confidence: 99%

Section: )mentioning

confidence: 99%

See 2 more Smart Citations

Hydrolyzed Metabolites of Thalidomide: Synthesis and TNF-.ALPHA. Production-Inhibitory Activity

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 99%

Thalidomide as a Nitric Oxide Synthase Inhibitor and Its Structural Development

Shimazawa

Sano

Tanatani

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

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...

show abstract

5′-Substituted Thalidomide Analogs as Modulators of TNF-α

Teubert

Zwingenberger²,

Wnendt

et al. 1998

Arch. Pharm. Pharm. Med. Chem.

View full text Add to dashboard Cite

The synthesis of 5′‐substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide (5) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8. In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9, 10, and 11. All final compounds were tested in vitro for their inhibitory activity on the release of TNF‐α, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5’ of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL‐2 in vitro.

show abstract

Phenylphthalimides with Tumor Necrosis Factor Alpha Production-Enhancing Activity.

Cited by 48 publications

References 0 publications

Hydrolyzed Metabolites of Thalidomide: Synthesis and TNF-.ALPHA. Production-Inhibitory Activity

Hydrolyzed Metabolites of Thalidomide: Synthesis and TNF-.ALPHA. Production-Inhibitory Activity

Thalidomide as a Nitric Oxide Synthase Inhibitor and Its Structural Development

5′-Substituted Thalidomide Analogs as Modulators of TNF-α

Contact Info

Product

Resources

About