Structure–activity relationship studies of SEN12333 analogues: Determination of the optimal requirements for binding affinities at α7 nAChRs through incorporation of known structural motifs

Despite intensive efforts, no inhibitors of the Wnt/β-catenin signaling pathway have been approved so far for the clinical treatment of cancer. We synthesized novel N-(heterocyclylphenyl)benzenesulfonamides as β-catenin inhibitors. Compounds 5−10 showed strong inhibition of the luciferase activity. Compounds 5 and 6 inhibited the MDA-MB-231, HCC1806, and HCC1937 TNBC cells. Compound 9 induced in vitro cell death in SW480 and HCT116 cells and in vivo tumorigenicity of a human colorectal cancer line HCT116. In a co-immunoprecipitation study in HCT116 cells transfected with Myc-tagged T-cell factor 4 (Tcf-4), compound 9 abrogated the association between β-catenin and Tcf-4. The crystallographic analysis of the β-catenin Armadillo repeats domain revealed that compound 9 and Tcf-4 share a common binding site within the hotspot binding region close to Lys508. To our knowledge, compound 9 is the first small molecule ligand of this region to be reported. These results highlight the potential of this novel class of β-catenin inhibitors as anticancer agents.

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“…4-(Pyridin-2-yl)aniline was synthesized as 15 starting from 20 . Yield 65%, mp 93–96 °C (mp 89–92 °C), Lit …”

Section: Methodsmentioning

confidence: 99%

“…2-(4-Nitrophenyl)pyridine was synthesized as 19 starting from 24 and (4-nitrophenyl)boronic acid ( 26 ). Yield 57%, mp 128–131 °C (mp 131–133 °C, Lit …”

Section: Methodsmentioning

confidence: 99%

Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as an Anticancer Agent

Nalli

Magno

Wang

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…Derivatives of the bicyclic nucleus of 2,5-diazabicyclo[2.2.1]heptane comprise a wide family of biochemically active compounds (Murineddu et al, 2012), including antibiotics (McGuirk et al, 1992;Remuzon et al, 1993), vasodilating (Ló pez-Ortiz et al, 2014) and antitumor agents (Hamblett et al, 2007;Shchekotikhin et al, 2014;Gerstenberger et al, 2016;Laskar et al, 2017). A broad range of these compounds have been found to exhibit potency as nicotinic acetylcholine receptor ligands (Toma et al, 2002;Artali et al, 2005;Bunnelle et al, 2007;Anderson et al, 2008;Li et al, 2010;Beinat et al, 2015;Bertrand et al, 2015). As a result of the occurrence of two chiral centers, 2,5-diazabicyclo[2.2.1]heptanes are utilized as chiral scaffolds in asymmetric catalysis (Jordis et al, 1999;Gonzá lez-Olvera et al, 2008;Castillo et al, 2013;Díaz-de-Villegas et al, 2014;Avila-Ortiz et al, 2015).…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Britvin

Rumyantsev

2017

Acta Cryst E

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The cage of 2,5-diazabicyclo[2.2.1]heptane is frequently employed in synthetic chemistry as a rigid bicyclic counterpart of the piperazine ring. The 2,5-diazabicyclo[2.2.1]heptane scaffold is incorporated into a variety of compounds having pharmacological and catalytic applications. The unsubstituted parent ring of the system, 2,5-diazabicyclo[2.2.1]heptane itself, has not been structurally characterized. We herein report on the molecular structure of the parent ring in (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide, C 5 H 12 N 2 2+ Á2Br À . The asymmetric unit contains two crystallographically independent cages of 2,5-diazabicyclo[2.2.1]heptane. Each cage is protonated at the two nitrogen sites. The overall charge balance is maintained by four crystallographically independent bromide ions. In the crystal, the components of the structure are linked via a complex three-dimensional network of N-HÁ Á ÁBr hydrogen bonds.

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“…Spectral data obtained for the compound are in good agreement with the reported data. 5 4-Methoxy-4'-methyl-1,1'-biphenyl (5). The reaction of 4nitrotoluene 1c (82 mg, 0.60 mmol) and 4-methoxyphenylboronic acid 2b (137 mg, 0.90 mmol) with optimized condition stirred for 24 h. The crude reaction mixture subjected to oxidation condition followed by purification by MPLC-Purifespoir 2 (25 g Biotage® SNAP Ultra column (25 m size), n-hexane/ethyl acetate = 100:0 to 94:6) gave the title compound (93 mg, 0.47 mmol, 78%) as a white solid.…”

Section: -([11'-biphenyl]-4-yl)morpholine (4)mentioning

confidence: 99%

Suzuki–Miyaura Coupling of Nitroarenes

2017

Synfacts

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Structure–activity relationship studies of SEN12333 analogues: Determination of the optimal requirements for binding affinities at α7 nAChRs through incorporation of known structural motifs

Cited by 12 publications

References 74 publications

Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as an Anticancer Agent

Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as an Anticancer Agent

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Suzuki–Miyaura Coupling of Nitroarenes

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