3,5-Disubstituted-indole-7-carboxamides: The discovery of a novel series of potent, selective inhibitors of IKK-β

Miller, David D.; Bamborough, Paul; Christopher, John; Baldwin, Ian R.; Champigny, Aurélie C.; Cutler, Geoffrey J.; Kerns, Jeffrey K.; Longstaff, Timothy; Mellor, Geoffrey W.; Morey, J. V.; Morse, Mary A.; Nie, Hong; Rumsey, William L.; Taggart, John J.

doi:10.1016/j.bmcl.2011.02.107

Cited by 18 publications

(9 citation statements)

References 17 publications

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“…IKK- β , which is a key subunit of IKK [ 17 ], is involved in the phosphorylation of I κ B α as part of the signaling pathway responsible for the transcription of NF- κ B [ 25 ]. The IKK-mediated phosphorylation of the Ser32 and Ser36 residues of cytoplasmic I κ B α leads to the poly-ubiquitination and subsequent proteasomal degradation of I κ B α , which results in the release of NF- κ B and its subsequent translocation to the nucleus [ 17 , 18 ].…”

Section: Resultsmentioning

confidence: 99%

Inhibition of IKK-β by epidioxysterols from the flowers of Calotropis gigantea (Niu jiao gua)

Parhira

Zhu

et al. 2016

Chin Med

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BackgroundCalotropis gigantea (Asclepiadaceae) (Niu jiao gua) has been used as a poultice in Chinese medicine for treating inflammatory skin diseases, e.g., neurodermatitis. This study aims to isolate the epidioxysterols from the flowers of C. gigantea, elucidate their structures and evaluate their possible inhibitory effects on the NF-κB pathway.MethodsThe two epidioxysterols 9,11-dehydroergosterol peroxide (1) and ergosterol peroxide (2) were isolated from the powdered flowers of C. gigantea by ultrasonic-assisted extraction, followed by the purification of the crude extract by column chromatography (i.e., silica gel and MCI-gel CHP 20P open columns). The chemical structures of these compounds were identified through a comparison of their HRMS, 1H and 13C NMR data with those in the literature. The in vitro IKK-β inhibitory activities of compounds 1 and 2 (1–100 µM) were evaluated using an IKK α and β Assay/Inhibitor Screening Kit, which is a single-site, semi-quantitative immunoassay. Berberine was used as a positive control. The IKK-β inhibitory activities between compounds 1 and 2 were compared by a two-tailed Student’s t test to summarize the structure activity relationship.ResultsCompounds 1 and 2 exhibited a dose-dependent inhibitory activity towards IKK-β in a similar manner to that of berberine. The IKK-β inhibitory activities of these two epidioxysterols were significantly stronger (P = 0.001 for compound 1 and P = 0.028 for compound 2) than that of berberine at the concentration of 100 µM. Furthermore, at the same concentration the suppressive effect of compound 1 towards IKK-β was greater than that of compound 2 (P = 0.041), while their activities at 10 and 50 µM were comparable. The difference in the results at 100 µM therefore suggested that the double bond between C-9 and C-11 in compound 1 could be responsible for its higher inhibitory activity towards IKK-β at this concentration.Conclusions9,11-dehydroergosterol peroxide (1) and ergosterol peroxide (2) were isolated from the flowers of C. gigantea and exhibited in vitro inhibitory activities towards IKK-β.Electronic supplementary materialThe online version of this article (doi:10.1186/s13020-016-0081-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Inhibition of IKK-β by epidioxysterols from the flowers of Calotropis gigantea (Niu jiao gua)

Parhira

Zhu

et al. 2016

Chin Med

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“…In this context, an indirect method to access these compounds involved the reduction of indoles to the indolines and then orthoselective esterification, followed by oxidation (Fig. 1D, top) (47)(48)(49)(50). Here, we develop a P(III)directed C7selective C-H esterification of indoles by palladium catalysis in which the CO and alcohols are used as the carbonylative sources (Fig.…”

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confidence: 99%

External oxidant-compatible phosphorus(III)-directed site-selective C–H carbonylation

Dong

Qian

et al. 2020

Sci. Adv.

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The first development of an external oxidant-compatible system involving a phosphorus(III)-directed C–H functionalization has been uncovered. An efficient C–H esterification of indoles with CO and alcohols has been reported in which the high reactivity and the exclusive C7-selectivity derives from the selection of a P(III)–directing group and the utilization of benzoquinone as an external oxidant with palladium catalysis. This strategy shows many advantages, involving an easily accessible and removable directing group, the use of cheap carbonylation sources, a broad substrate scope, and excellent positional selectivity. Two cyclopalladated intermediates were confirmed by x-ray analysis, uncovering key mechanistic features of this P(III)-directed C–H metalation event.

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“…To assess in vivo activity, we compared compound 6 to the previously reported 2 10 in an LPS induced neutrophilia model in rat. Both compounds were given orally.…”

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“…Comparison of potency, ligand efficiency (LE), solubility, and parallel artificial membrane permeability (PAMPA) of early lead compounds10 …”

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3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent

Kerns

Busch-Petersen

et al. 2018

ACS Med. Chem. Lett.

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IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity.

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3,5-Disubstituted-indole-7-carboxamides: The discovery of a novel series of potent, selective inhibitors of IKK-β

Cited by 18 publications

References 17 publications

Inhibition of IKK-β by epidioxysterols from the flowers of Calotropis gigantea (Niu jiao gua)

Inhibition of IKK-β by epidioxysterols from the flowers of Calotropis gigantea (Niu jiao gua)

External oxidant-compatible phosphorus(III)-directed site-selective C–H carbonylation

3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent

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