Cyclic analogue of S-benzylisothiourea that suppresses kynurenine production without inhibiting indoleamine 2,3-dioxygenase activity

Fukuda, Miwa; Sasaki, Tomomi; Hashimoto, Tomoko; Miyachi, Hiroyuki; Waki, Minoru; Asai, Akira; Takikawa, Osamu; Ohno, Osamu; Matsuno, Kenji

doi:10.1016/j.bmcl.2018.07.034

Cited by 6 publications

(3 citation statements)

References 19 publications

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“…An examination of the literature reveals several examples of related Heck reactions giving mixtures of isomers [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. In several cases, the ratios of isomers were not given and generally, the origin of the selectivities observed was not discussed.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Bio-Inspired 1,3-Diarylpropene Derivatives via Heck Cross-Coupling and Cytotoxic Evaluation on Breast Cancer Cells

et al. 2022

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The Heck cross-coupling reaction is a well-established chemical tool for the synthesis of unsaturated compounds by formation of a new C-C bond. In this study, 1,3-diarylpropene derivatives, designed as structural analogues of stilbenoids and dihydrostilbenoids, were synthesised by the palladium-catalysed reactions of 2-amidoiodobenzene derivatives with either estragole or eugenol. The products were obtained with high (E) stereoselectivity but as two regioisomers. The ratios of isomers were found to be dependent on the nature of the allylbenzene partner and were rationalised by electronic effects exercising a determining influence in the β-hydride elimination step. In addition, the cytotoxic effects of all the Heck reaction products were evaluated against MCF-7 and MDA-MB-231 human breast cancer cells, with unpromising results. Among all, compound 7d exhibited weak cytotoxic activity towards MCF-7 cell lines with IC50 values of 47.92 µM in comparison with tamoxifen and was considered to have general toxicity (SI value < 2).

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Section: Resultsmentioning

confidence: 99%

Synthesis of Bio-Inspired 1,3-Diarylpropene Derivatives via Heck Cross-Coupling and Cytotoxic Evaluation on Breast Cancer Cells

et al. 2022

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“…Column chromatography was performed using 200–300 mesh silica gel eluted with the solvents as indicated. ( E )- o -arylvinylbenzaldehydes 6a–6m , ( E )- o -alkylvinylbenzaldehydes 6n–6o , , ( Z )- o -styrylbenzaldehyde 6p , ( E )-1-styryl-2-naphthaldehyde 9 , and ( E )-2-styrylnicotinaldehyde 10 were prepared based on the literature methods.…”

Section: Methodsmentioning

confidence: 99%

Experimental and Theoretical Study on the Regioselective Radical Cyclization Reactions of 1-(o-Alkenylaryl)-2-amido-1-ketones for the Construction of Indeno[2,1-d][1,3]oxazin-9-ones

et al. 2022

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A simple and efficient two-step method for the construction of novel 2,4,9a-trisubstituted-4a,9a-dihydroindeno[2,1-d][1,3]oxazin-9-ones has been developed. The NHC-catalyzed aza-benzoin reaction of o-alkenyl benzaldehydes with N-acylarylimines afforded 1-(o-alkenylaryl)-2-amido-2-aryl-1-ethanones, which underwent regioselective 5-exo-trig radical cyclization to furnish the three-ring-fused heterocyclic products, generally in good yields. The synthetic method displayed good tolerance toward the nature of substituents, substitution pattern, and steric hindrance of o-alkenyl benzaldehydes. Based on this method, the synthesis of unprecedented dihydrobenzo[6,7]indeno[2,1-d][1,3]oxazin-7-ones and dihydropyrido[2′,3′:3,4]cyclopenta[1,2-d][1,3]oxazin-9-ones has been achieved by employing o-alkenylnaphthaldehyde and o-alkenylnicotinaldehyde as substrates. The regioselectivity between 5-exo-trig and 6-endo-trig radical cyclization reactions of different 1-(o-alkenylaryl)-2-amido-2-aryl-1-ethanones were elucidated with DFT calculations.

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“…27 We previously reported IDO1 inhibitors that suppress cellular kynurenine production, namely, a derivative of the antihypertensive agent candesartan 1 28 and S-benzylisothiourea 2. 29 In addition, our efforts to convert the isothiourea moiety of S-benzylisothiourea 2 to drug-like heterocycles 30 provided oxazoline derivative 3a, which exhibits weak recombinant human IDO1 (rhIDO1) inhibition (40% @100 μM). During the course of this derivatization, we attempted alkaline hydrolysis of the 4-COOMe moiety of compound 3a.…”

mentioning

confidence: 99%

Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors

Kumazawa

Tejima

Fukuda

et al. 2021

ACS Med. Chem. Lett.

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A structure−activity relationship study unexpectedly showed that carbonothioates 4a and 4b, obtained by a unique alkaline hydrolysis of 2-alkylthio-oxazolines 3a and 3b, respectively, are a novel scaffold for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Derivatization of the carbonothioates enhanced inhibitory activity against IDO1 and cellular kynurenine production without cytotoxicity and led to the discovery of the related scaffolds carbonodithioates 5 and cyanocarbonimidodithioates 6 as IDO1 inhibitors. Incorporation of an OH group provided the most potent analogue 5i. UV−visible absorption spectroscopy of the Soret band, as well as docking and peptide mapping studies, suggested that these molecules bind to the heme in the active site of IDO1.Our unique IDO1 inhibitors are potential leads for future development.

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Cyclic analogue of S-benzylisothiourea that suppresses kynurenine production without inhibiting indoleamine 2,3-dioxygenase activity

Cited by 6 publications

References 19 publications

Synthesis of Bio-Inspired 1,3-Diarylpropene Derivatives via Heck Cross-Coupling and Cytotoxic Evaluation on Breast Cancer Cells

Synthesis of Bio-Inspired 1,3-Diarylpropene Derivatives via Heck Cross-Coupling and Cytotoxic Evaluation on Breast Cancer Cells

Experimental and Theoretical Study on the Regioselective Radical Cyclization Reactions of 1-(o-Alkenylaryl)-2-amido-1-ketones for the Construction of Indeno[2,1-d][1,3]oxazin-9-ones

Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors

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