Facile functionalization of FK506 for biological studies by the thiol–ene ‘click’ reaction

Guo, Zhi-Fo; Zhang, Roushu; Liang, Fu‐Sen

doi:10.1039/c3ra47867j

Cited by 11 publications

(19 citation statements)

References 33 publications

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“…1 H NMR (400 Hz, CDCl 3 ): δ H : 7.81 (2H, d, J = 8.4Hz), 7.37 (2H, d, J = 8.0Hz), 4.63 (1H, bs), 4.10 (2H, t, J = 6.0Hz), 3.18 (2H, t, J = 6.4Hz), 2.47 (3H, s), 1.86 (2H, q, J = 6.4Hz), 1.44 (9H, s). The proton NMR signals are consistent with data previously published for this compound [ 23 ].…”

Section: Methodssupporting

confidence: 90%

Synthesis of [18F]2B-SRF101: A Sulfonamide Derivative of the Fluorescent Dye Sulforhodamine 101

Kreimerman

Porcal

Olivera

et al. 2017

CRP

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Background: The red fluorescent dye Sulforhodamine 101 (SR101) has been used in neuroscience research as a useful tool for staining of astrocytes, since it has been reported as a marker of astroglia in the neocortex of rodents in vivo. The aim of this work is to label SR101 with positron emission radionuclides, in order to provide a radiotracer to study its biological behavior. This is the first attempt to label SR101 by [18F], using a chem-ical derivatization via a sulfonamide-linker and a commercially available platform.Methods: The synthesis of SR101 N-(3-Bromopropyl) sulfonamide and SR101 N-(3-Fluoropropyl) sulfonamide (2B-SRF101) was carried out. The radiosynthesis of SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]2B-SRF101) was performed in a TRACERlab® FX-FN. Different labeling conditions were tested. Three pilot batches were produced and quality control was performed. Lipophilicity, plasma protein binding and radiochemical sta-bility of [18F]2B-SRF101 in final formulation and in plasma were determined.Results: SR101 N-(3-Bromopropyl) sulfonamide was synthetized as a precursor for radio-labeling with [18F]. 2B-SRF101 was prepared for analytical purpose. [18F]2B-SRF101 was obtained with radiochemical purity of (97.0 ± 0.6%). The yield of the whole synthesis was (11.9 ± 1.7%), non-decay corrected. [18F]2B-SRF101 was found to be stable in final for-mulation and in plasma. The octanol-water partition coefficient was (Log POCT = 1.88 ± 0.14). The product showed a high percentage of plasma protein binding.Conclusions: The derivatization of SR101 via sulfonamide-linker and the first radiosyn-thesis of [18F]2B-SRF101 were performed. It was obtained in accordance with quality con-trol specifications. In vitro stability studies verified that [18F]2B-SRF101 was suitable for preclinical evaluations.

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Section: Methodssupporting

confidence: 90%

Synthesis of [18F]2B-SRF101: A Sulfonamide Derivative of the Fluorescent Dye Sulforhodamine 101

Kreimerman

Porcal

Olivera

et al. 2017

CRP

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“…Additionally, a symmetric bivalent dimerizer of FK506 (FK1012) was synthesized, which abolished binding to calcineurin (Spencer et al, 1993). Recently, Guo et al simplified the synthesis of this dimerizer by a one-step thiol-ene reaction (Guo et al, 2014).…”

Section: Chemical Tools/chemically Induced Dimerization Utilizing Fkbpsmentioning

confidence: 99%

FKBP Ligands—Where We Are and Where to Go?

et al. 2018

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In recent years, many members of the FK506-binding protein (FKBP) family were increasingly linked to various diseases. The binding domain of FKBPs differs only in a few amino acid residues, but their biological roles are versatile. High-affinity ligands with selectivity between close homologs are scarce. This review will give an overview of the most prominent ligands developed for FKBPs and highlight a perspective for future developments. More precisely, human FKBPs and correlated diseases will be discussed as well as microbial FKBPs in the context of anti-bacterial and anti-fungal therapeutics. The last section gives insights into high-affinity ligands as chemical tools and dimerizers.

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“…This was ideal for development of the CEM system because FK506, a natural product that forms a high affinity interaction with FKBP, can serve as the transcription factor ligand. 28 Our control cell line expresses the unmodified Gal4 protein, removing the ability to bind and recruit FK506.…”

Section: Resultsmentioning

confidence: 99%

Targeted Gene Repression Using Novel Bifunctional Molecules to Harness Endogenous Histone Deacetylation Activity

et al. 2017

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Epigenome editing is a powerful method for life science research and could give rise to new therapies for diseases initiated or maintained by epigenetic dysregulation, including several types of cancers and autoimmune disorders. In addition, much is still unknown about the mechanisms by which histone-modifying proteins work in concert to properly regulate gene expression. To investigate and manipulate complex epigenetic interactions in live cells, we have developed a small molecule platform for specifically inducing gene repression and histone deacetylation at a reporter gene. We synthesized bifunctional ligands, or chemical epigenetic modifiers (CEMs), that contain two functional groups: a FK506 derivative capable of binding to a FKBP-Gal4 fusion transcription factor, and a histone deacetylase (HDAC) inhibitor that recruits HDAC-containing corepressor complexes. In our reporter cell line, which contains a GFP reporter allele upstream of a Gal4 DNA binding array in the murine Oct4 locus, our lead CEM repressed GFP expression by 50%. We also show that CEM recruitment of deacetylation activity causes marked deacetylation along our target loci. This system allowed us to detail the direct results of deacetylation to chromatin and measure the resulting gene expression in a chemically dependent and reversible manner. The CEMs system provides new insights into epigenetic gene regulation and has the potential to control disease-relevant gene regulation. The CEMs are derived from FDA-approved epigenetic modulator drugs, and use their pharmacology in a gene-specific way that avoids the toxicities and off-target effects caused by whole-cell application of these drugs.

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Facile functionalization of FK506 for biological studies by the thiol–ene ‘click’ reaction

Cited by 11 publications

References 33 publications

Synthesis of [18F]2B-SRF101: A Sulfonamide Derivative of the Fluorescent Dye Sulforhodamine 101

Synthesis of [18F]2B-SRF101: A Sulfonamide Derivative of the Fluorescent Dye Sulforhodamine 101

FKBP Ligands—Where We Are and Where to Go?

Targeted Gene Repression Using Novel Bifunctional Molecules to Harness Endogenous Histone Deacetylation Activity

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