Tumor necrosis factor-alpha production-inhibiting activity of phthalimide analogues on human leukemia THP-1 cells and a structure-activity relationship study

Miyachi, Hiroyuki; Ogasawara, Asuka; Azuma, Arata; Hashimoto, Yuichi

doi:10.1016/s0968-0896(97)00148-x

Cited by 58 publications

(47 citation statements)

References 27 publications

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“…Further structural development studies revealed that 5-chlorination and / or thiocarbonylation of PP-50 23 enhanced its LXR-antagonistic activity, which led us to design and prepare 5CPPSS-50 (8) (Fig. 3).…”

Section: Mode Of Tubulin Polymerization-inhibition By 5hpp-33mentioning

confidence: 99%

“…These findings suggested that thalidomide 1 is a multi-target drug, and this, in turn, implied the possible usefulness of thalidomide 1 as a template for development of various kinds of medicaments. In fact, various biologically active compounds, such as TNF-a production regulators (including bi-directional ones, pure inhibitors, and pure enhancers) [7,8], androgen antagonists [9 -11], aminopeptidase inhibitors [12 -15], a-glucosidase inhibitors [16 -18], thymidine phosphorylase inhibitors [19], cyclooxygenase (COX) inhibitors [20 -22], nitric oxide synthase (NOS) inhibitors [23,24], histone deacetylase (HDAC) inhibitors [25 -27], anti-angiogenic agents [28,29], tubulin polymerization inhibitors [30 -32], cell differentiation inducers [33], and liver X receptor (LXR) antagonists [34,35] have been developed based on the structure of thalidomide 1 ( Fig. 2 and 3).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Mode Of Tubulin Polymerization-inhibition By 5hpp-33mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hashimoto

2008

Archiv der Pharmazie

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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%

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

et al. 2007

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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...

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“…6 Some researches showed that the teratogenicity of thalidomide was caused by double carbonyls in phthalimide, 7,8 and thalidomide derivatives obviously presented the anti-angiogenesis effect because of its metabolites containing hydroxyl. 9,10 Hydroxylactams have attracted a lot of attention from biological and synthetic chemists, which were regarded as very significant structural segments in sedatives, hypnotics, and muscle relaxants such as zopiclone, pazinaclone and desmethylzopiclone.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Hydroxylactams and Esters Derived from Thalidomide and Their Antitumor Activities

Sun¹,

Liu²,

Zhou³

et al. 2014

Bulletin of the Korean Chemical Society

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A novel and convenient route for the synthesis of a series of thalidomide derivatives is described. Compound 2 was cyclized with different amines under alkaline condition to obtain 4-nitro substituted phthalimidines 3a-d. Hydroxylactams 4a-d were produced via bromination and hydroxylation. Different acyl chlorides were reacted with hydroxylactams to provide the desired esters 5a-d. All compounds were evaluated by MTT assay for their inhibitory activities against HCT-116, MG-63, MCF-7, HUVEC and HMVEC cell lines in vitro. Most of them showed no obvious cytotoxic effect on normal human cells, compounds 4a-d, 5a 2 , 5a 4 , 5a 5 , 5b 2 , 5c 2 and 5d 2 exhibited potent antitumor activities, among which compounds 5a 2 and 5b 2 were more effective than 5-FU.

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Tumor necrosis factor-alpha production-inhibiting activity of phthalimide analogues on human leukemia THP-1 cells and a structure-activity relationship study

Cited by 58 publications

References 27 publications

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

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

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

Synthesis of Hydroxylactams and Esters Derived from Thalidomide and Their Antitumor Activities

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