Silicon Analogues of the Retinoid Agonists TTNPB and 3‐Methyl‐TTNPB, Disila‐TTNPB and Disila‐3‐methyl‐TTNPB: Chemistry and Biology

Büttner, Matthias W.; Burschka, Christian; Daiß, Jürgen O.; Ivanova, Diana; Rochel, Natacha; Kammerer, Sabrina; Peluso‐Iltis, Carole; Bindler, Audrey; Gaudon, Claudine; Germain, Pierre; Moras, Dino; Gronemeyer, Hinrich; Tacke, Reinhold

doi:10.1002/cbic.200700182

Cited by 37 publications

(13 citation statements)

References 64 publications

(21 reference statements)

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“…3). Further, crystal structure comparison of silicon analogues of known protein agonists show nearly identical binding topologies 43 . Docking poses and calculated energies have also been shown to be very similar for silicon analogues 44 .…”

Section: Discussionmentioning

confidence: 99%

Development of Novel Silyl Cyanocinnamic Acid Derivatives as Metabolic Plasticity Inhibitors for Cancer Treatment

Nelson

Ronayne

Solano

et al. 2019

Sci Rep

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Novel silyl cyanocinnamic acid derivatives have been synthesized and evaluated as potential anticancer agents. In vitro studies reveal that lead derivatives 2a and 2b have enhanced cancer cell proliferation inhibition properties when compared to the parent monocarboxylate transporter (MCT) inhibitor cyano-hydroxycinnamic acid (CHC). Further, candidate compounds exhibit several-fold more potent MCT1 inhibition properties as determined by lactate-uptake studies, and these studies are supported by MCT homology modeling and computational inhibitor-docking studies. In vitro effects on glycolysis and mitochondrial metabolism also illustrate that the lead derivatives 2a and 2b lead to significant effects on both metabolic pathways. In vivo systemic toxicity and efficacy studies in colorectal cancer cell WiDr tumor xenograft demonstrate that candidate compounds are well tolerated and exhibit good single agent anticancer efficacy properties.

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Section: Discussionmentioning

confidence: 99%

Development of Novel Silyl Cyanocinnamic Acid Derivatives as Metabolic Plasticity Inhibitors for Cancer Treatment

Nelson

Ronayne

Solano

et al. 2019

Sci Rep

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“…The present study tackles this problem using RAR as a model case and testing the observations on ERα, an established functional homodimer. The rationale behind the choice of RAR lies in the observation that with the same ligand its LBD could be crystallized as a monomer and a dimer, the latter in presence of a silicon analog of the ligand and a coactivator peptide (17)(18). In contrast with other NRs we can thus have access to all different structural states, including RAR-RXR heterodimer, and correlate them to the binding of the coactivators and/or different ligands.…”

mentioning

confidence: 99%

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Ősz

Brélivet

Peluso‐Iltis

et al. 2012

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

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Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 2∶1 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.allostery | structure T he superfamily of nuclear receptors (NRs) comprises liganddependent transcription factors involved in the regulation of gene expression. They constitute key drug targets for human diseases such as cancer, osteoporosis, obesity, or type II diabetes (1-2). NRs share a common structural organization with a variable amino-terminal domain, a conserved DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) linked by a flexible hinge peptide. In addition to the ligand-binding pocket, the LBD comprises dimerization surfaces and the sites for coregulator interactions. In the classic mode of action, in absence of ligand, some NRs are associated with corepressors (NCoRs) that harbor histone-deacetylase activity to maintain the chromatin in a transcriptionally silent state (3-4). Upon ligand binding, DNA-bound receptors recruit coactivators like the steroid receptor coactivator 1 (SRC-1), a member of p160 CoA family (5), to enhance target gene expression. The receptor interaction domain (RID) of the coactivators is responsible for the interaction with NRs and contains several copies of the short consensus interaction motif LXXLL (6).The vast majority of NRs functions as dimers. RAR, like the vitamin D (VDR) and thyroid hormone (TR) receptors, heterodimerizes with rexinoid receptors (RXRs) (7). Their ability to form homodimers is also documented (8-10). RAR homodimers have been shown to be functional in yeast using a two-hybrid system, and their activity is further enhanced by the presence of SRC-2 c...

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“…However, a database search for the alcoholamine fragment, NH 2 (+)-(CH 2 ) 3 -OH, gave seven hits. Two of these, GIPHIX (Bü ttner et al, 2007) and EPANUF (Pestov et al, 2010), also involved intramolecular hydrogen bonding resulting in S 1 1 (6) graph sets, as also seen in the title compound.…”

Section: Database Surveymentioning

confidence: 83%

The crystal structure of the zwitterionic co-crystal of 2,4-dichloro-6-{[(3-hydroxypropyl)azaniumyl]methyl}phenolate and 2,4-dichlorophenol

Uprety¹,

Arderne²

2019

Acta Cryst E

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The title compound, C10H13Cl2NO2·C6H4Cl2O, was formed from the incomplete Mannich condensation reaction of 3-aminopropan-1-ol, formaldehyde and 2,4-dichlorophenol in methanol. This resulted in the formation of a co-crystal of the zwitterionic Mannich base, 2,4-dichloro-6-{[(3-hydroxypropyl)azaniumyl]methyl}phenolate and the unreacted 2,4-dichlorophenol. The compound crystallizes in the monoclinic crystal system (in space group Cc) and the asymmetric unit contains a molecule each of the 2,4-dichlorophenol and 2,4-dichloro-6-{[(3-hydroxypropyl)azaniumyl]methyl}phenolate. Examination of the crystal structure shows that the two components are clearly linked together by hydrogen bonds. The packing patterns are most interesting along the b and the c axes, where the co-crystal in the unit cell packs in a manner that shows alternating aromatic dichlorophenol fragments and polar hydrogen-bonded channels. The 2,4-dichlorophenol rings stack on top of one another, and these are held together by π–π interactions. The crystal studied was refined as an inversion twin.

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Silicon Analogues of the Retinoid Agonists TTNPB and 3‐Methyl‐TTNPB, Disila‐TTNPB and Disila‐3‐methyl‐TTNPB: Chemistry and Biology

Cited by 37 publications

References 64 publications

Development of Novel Silyl Cyanocinnamic Acid Derivatives as Metabolic Plasticity Inhibitors for Cancer Treatment

Development of Novel Silyl Cyanocinnamic Acid Derivatives as Metabolic Plasticity Inhibitors for Cancer Treatment

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

The crystal structure of the zwitterionic co-crystal of 2,4-dichloro-6-{[(3-hydroxypropyl)azaniumyl]methyl}phenolate and 2,4-dichlorophenol

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