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http://ir.nhri.org.tw/handle/3990099045/10227
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| Title: | Phenyl benzenesulfonylhydrazides: Selective indoleamine 2,3-dioxygenase inhibitors with potent in vivo pharmacodynamic activity and antitumor efficacy |
| Authors: | Ueng, SH;Yeh, TK;Song, JS;Wu, SY;Kuo, CC;Shih, C;Pan, SL;Hung, MS |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research |
| Abstract: | Background: Indoleamine 2,3-dioxygenase has been identified to play a key role in local tryptophan metabolism along the kynurenine pathway, and has emerged as a therapeutic target for cancer immunotherapy. Several pharmaceutical companies have discovered indoleamine 2,3-dioxygenase inhibitors that utilized as anti-tumor agents in recent years. Our prior study identified a phenyl benzenesulfonyl hydrazide indoleamine 2,3-dioxygenase inhibitor that had potent in vitro activity but was inactive in vivo. Lead optimization to improve the physicochemical properties of compounds and resulted in several in vivo active compounds. Material and Methods: Chemistry: All commercial solvents and chemicals were of reagent grade and used without further purification unless otherwise stated. All reactions were carried out under an atmosphere of dry nitrogen or Argon. IDO enzyme activity assay: The IDO activity of test compounds was measured in the assay buffer (pH 6.5) containing, ascorbic acid, methylene blue, catalase, L-tryptophan, purified IDO enzyme and the test compounds in 96-well black plates. The reactions were further incubated with NaOH to hydrolyze N-formylkynurenine to kynurenine. The amount of kynurenine produced was determined by the emission of fluorescence [l(ex) = 355 nm, l(em) = 460 nm]. IDO cellular assay: Human IFN-g and compounds in a culture medium containing L-tryptophan were added to the HeLa cells seeded in 96well culture plates. After incubation for 24 hours, the supernatant was mixed with 6.1 N of trichloroacetic acid. The reaction mixture was then centrifuged to remove sediments. The supernatant was mixed with 2% (w/v) p-dimethylaminobenzaldehyde in acetic acid and measured at OD480 nm. In vivo pharmacodynamic assay: Compounds at a dose of 50 mg/kg were administered by oral gavage to C57BL/6 male mice (n = 4 animals/group). The levels of kynurenine (kyn) and tryptophan (trp) were measured and the kyn/trp ratios were calculated. In vivo tumor growth inhibition: The murine CT-26 colorectal syngeneic mouse model was used to evaluate the in vivo tumor growth inhibition for test compounds. Results: The resulting N’-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5sulfonyl hydrazide, which exhibited IDO IC50 = 36 nM and EC50 =68nM, demonstrated 59% of oral bioavailability with favorable oral exposure (7205 ng/mL×h) and 73% of tumor growth delay in a murine CT26 syngeneic model, after oral administration of 400 mg/kg, without apparent body weight loss. Conclusion: Phenyl benzenesulfonylhydrazides have been identified as selective IDO inhibitors with potent enzymatic and cellular activities. Lead optimization resulted in the N’-(4-bromophenyl)-2-oxo-2,3-dihydro1H-indole-5-sulfonyl hydrazide as a potent in vivo active IDO inhibitor. Accordingly, this compound is proposed as a drug lead for advanced preclinical evaluation. |
| Date: | 2016-12 |
| Relation: | European Journal of Cancer. 2016 Dec;68(Suppl. 1):S83-S84. |
| Link to: | http://www.ejcancer.com/article/S0959-8049(16)32844-1/pdf |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0959-8049&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000390503500239 |
| Appears in Collections: | [洪明秀] 會議論文/會議摘要
[石全(2014-2017)] 會議論文/會議摘要
[郭靜娟] 會議論文/會議摘要
[伍素瑩] 會議論文/會議摘要
[葉燈光] 會議論文/會議摘要
[翁紹華] 會議論文/會議摘要
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| ISI000390503500239.pdf | 60Kb | Adobe PDF | 499 | View/Open |
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