Enantioselective inhibition of TNF-? release by thalidomide and thalidomide-analogues

Wnendt, Stephan; Finkam, Michael; Winter, Werner; Ossig, Joachim; Raabe, G; Zwingenberger, K.

doi:10.1002/(sici)1520-636x(1996)8:5<390::aid-chir6>3.0.co;2-i

Cited by 87 publications

(30 citation statements)

References 17 publications

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“…Inhibition of endothelial IL-1␤ activity or availability was achieved by addition of neutralizing anti-rat-IL-1␤ antibodies [150 g/ml with a half-maximal neutralizing dose (ND 50 ) of 20 g/ml in the presence of ϳ1000 U/ml rat IL-1␤] or neutralizing anti-human-IL-1␤ antibodies (100 g/ml with an ND 50 of 0.2 g/ml in the presence of ϳ500 U/ml recombinant human IL-1␤), respectively. Endogenous endothelial TNF-␣ production was inhibited by thalidomide (20 g/ml) (Wnendt et al, 1996;Sastry, 1999) or TNF-␣ activity was neutralized by addition of antirat-TNF-␣ antibodies (150 g/ml with an ND 50 of 25 g/ml in the presence of 500 U/ml rat TNF-␣) or anti-human-TNF-␣ antibodies (25 g/ml with an ND 50 of 0.01 g/ml in the presence of 100 U/ml recombinant human TNF-␣), respectively. Specificity, as well as the…”

Section: Methodsmentioning

confidence: 99%

Revisiting an Old Antimicrobial Drug: Amphotericin B Induces Interleukin-1–Converting Enzyme as the Main Factor for Inducible Nitric-Oxide Synthase Expression in Activated Endothelia

Suschek

Bonmann²,

Kapsokefalou³

et al. 2002

Mol Pharmacol

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We have investigated the impact of the widely used antifungal agent Amphotericin B (AmB) on cytokine activated aortic endothelial cells (AEC) and their inflammatory response as monitored by cytokine and inducible nitric-oxide synthase (iNOS) expression as well as high-output nitric oxide synthesis. Because both blood-borne infections and systemically administered drugs will first encounter vessel lining endothelial cells, this cell type represents an important participant in innate immune reactions against xenobiotics. Culturing cytokine-activated AEC in the presence of 1.25 g/ml AmB, a concentration equivalent to serum levels during patient treatment, we find increases in iNOS promoter activity up to 120%, in iNOS mRNA or protein expressions by factors of up to 3.5 Ϯ 1.1, and in iNOS activity of up to 180% compared with cells with cytokines only. In parallel, a strong increase in endothelial interleukin (IL)-1␤-converting enzyme (ICE) and IL-1␤ expression and activity was observed. Specific inhibition of ICE activity or IL-1␤ functionality significantly reduces expression and activity of the iNOS to control values. Because ICE activity is essential for the endogenous synthesis of active IL-1␤, ICE overexpression represents the key signal in the AmB-induced and IL-1␤-mediated effects on iNOS activity. In summary, in endothelial cells, AmB strongly augments cytokine-induced iNOS expression and activity by increasing the expression and activity of the ICE. This adjuvant activity for augmented endogenous cytokine processing adds to the efficacy of the antimycotic activity of AmB. Furthermore, our data underline the relevance of the endothelial iNOS as a potent effector of the innate immune system.

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Section: Methodsmentioning

confidence: 99%

Revisiting an Old Antimicrobial Drug: Amphotericin B Induces Interleukin-1–Converting Enzyme as the Main Factor for Inducible Nitric-Oxide Synthase Expression in Activated Endothelia

Suschek

Bonmann²,

Kapsokefalou³

et al. 2002

Mol Pharmacol

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“…The strongly acidic hydrogen atom at the asymmetric center of 1 rapidly epimerizes under physiological conditions, rendering bioassay of the enantiomers difficult. [10][11][12] Therefore, elucidation of the difference of biological activities between thalidomide enantiomers previously reported is said to be difficult. Therefore, the development of non-racemizable, chiral analogues of thalidomide has attracted much attention.…”

mentioning

confidence: 99%

Synthesis and Configurational Stability of (S)- and (R)-Deuteriothalidomides

Yamamoto

Tokunaga

Nakamura

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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A fundamental question is whether thalidomide (1) is stereospecifically teratogenic. The revival of 1 in the clinical field in the 21st century has re-activated an investigation of the molecular mechanism of the teratogenicity of 1. [1][2][3][4][5][6][7][8] Thalidomide (1) was popular especially for pregnant women as an effective antiemetic for morning sickness in the 1950-60s. The teratogenic side effects, leading to birth defects such as limb reduction, produced one of the most notorious medical disasters of modern medical history, and 1 was consequently withdrawn from the market in 1962. Thalidomide (1) possesses an asymmetric center in the glutarimide ring. Since 1 was marketed as a racemate, it was conceivable that sedative effects of 1 might be associated with one enantiomer and the unexpected teratogenic side effects might be ascribed to the other enantiomer. Twenty years after the thalidomide disaster, only (S)-thalidomide (1) was proved to be teratogenic.9) It was then concluded that the disaster could have been avoided if only the (R)-isomer of 1 had been marketed. However, it is presently unclear whether any of the actions of racemic 1 can be separated out using a pure enantiomer. According to the reports, considerable chiral inversion took place after incubation of enantiomerically pure 1. The strongly acidic hydrogen atom at the asymmetric center of 1 rapidly epimerizes under physiological conditions, rendering bioassay of the enantiomers difficult.10-12) Therefore, elucidation of the difference of biological activities between thalidomide enantiomers previously reported is said to be difficult. Therefore, the development of non-racemizable, chiral analogues of thalidomide has attracted much attention.13-16) 3Ј-Fluorothalidimide (2) was developed for this purpose several years ago by a member of our group and by others.17,18) Although the fluorine atom at the asymmetric center of 2 effectively obstructs racemization, the fluorine atom also introduces substantial electronic alterations into the molecule due to its highest electron negativity of 4.0, alterations that could be expected to significantly modulate biological activity. 19) Incidentally, deuterated drugs have been noted as a new strategy for drug discovery. [20][21][22][23][24][25] They have basically the same properties as hydrogenated compounds, but are resistant to metabolism due to the higher stability of the carbon-deuterium (C-D) bond than that of the carbon-hydrogen (C-H) bond. As a result of our research designed to produce an analogue of thalidomide that is resistant to racemization and is also a close structural mimic, [26][27][28][29] we describe herein the design and synthesis of 3Ј-deuteriothalidomide (3), the most closed isostere of thalidomide (Fig. 1). Deuterium at the 3Ј-position of 3 is expected to effectively block the racemization of thalidomide due to its isotopic effect without major alterations of biological activities. Results and DiscussionOptically pure 3Ј-deuteriothalidomide (3) was synthesized in four steps from ...

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“…The determination of absolute configuration of the enantiomers of deuterated compound 2 was not possible, because there is no prior data available on the enantiomers, and we did not obtain crystals of the enantiomers. However, based on available data for other thalidomide analogs (22,37,38) and the TNF-α inhibition data that we obtained for the enantiomers of deuterated compound 2, it is likely that the most efficacious enantiomer, (−)-D-2, is (S)-D-2. The same tentative stereochemistry assignment can be made from the reported crystal structure of thalidomide, lenalidomide, and pomalidomide with target protein complex DDB1-CRBN, where the (S)-enantiomer was systematically shown to be preferentially bound through the constant and required 3-aminopiperidine-2,6-dione moiety (40).…”

Section: Discussionmentioning

confidence: 95%

“…In actuality, each enantiomer may have unique pharmacological and safety profiles. Although there is limited data available and the enantiomers interconvert during the time course of the studies, a few groups have shown that the teratogenicity, in vitro antiinflammatory activity, and in vivo efficacy of protonated thalidomide analogs are caused, in large part, by the (S)-enantiomer (22,(36)(37)(38). (S)-pomalidomide was originally advanced into clinical trials as ENMD 0995 (39) but soon abandoned because of the rapid racemization of the exchangeable chiral center (28,29).…”

mentioning

confidence: 99%

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Jacques¹,

Czarnik²,

Judge³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using “deuterium-enabled chiral switching” (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (−)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics.

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Enantioselective inhibition of TNF-? release by thalidomide and thalidomide-analogues

Cited by 87 publications

References 17 publications

Revisiting an Old Antimicrobial Drug: Amphotericin B Induces Interleukin-1–Converting Enzyme as the Main Factor for Inducible Nitric-Oxide Synthase Expression in Activated Endothelia

Revisiting an Old Antimicrobial Drug: Amphotericin B Induces Interleukin-1–Converting Enzyme as the Main Factor for Inducible Nitric-Oxide Synthase Expression in Activated Endothelia

Synthesis and Configurational Stability of (S)- and (R)-Deuteriothalidomides

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

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