Structure‐Based Design and Synthesis of Fluorene Derivatives as Novel <scp>ROR</scp><i>γ</i>t Inverse Agonists

Gabr, Moustafa T.; Abdel-Raziq, Mohammed S.

doi:10.1002/cbdv.201800244

Cited by 3 publications

(2 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fluorene and azafluorene are common scaffolds found in natural products and bioactive synthetic compounds . They are also utilized in many applications such as fluorescent probes and material chemistry .…”

Section: Introductionmentioning

confidence: 99%

Divergent Synthesis of 3-Hydroxyfluorene and 4-Azafluorene Derivatives from ortho-Alkynylarylketones

et al. 2019

View full text Add to dashboard Cite

A divergent synthesis of 3-hydroxyfluorene and 4-azafluorene derivatives has been developed. ortho-Alkynylarylketone was employed as the substrates to react with molecular iodine leading to the generation of a common intermediate, indenone precursor. This precursor could lead to the diversified products when the reaction was carried out under different conditions. The indenone intermediate was converted to the corresponding 3-hydroxyfluorene products under basic conditions while the reaction in the presence of ammonium salt provided 4-azafluorene products. This divergent method could be applied to a broad range of substrates to give the corresponding products in moderate to good yields.

show abstract

Section: Introductionmentioning

confidence: 99%

Divergent Synthesis of 3-Hydroxyfluorene and 4-Azafluorene Derivatives from ortho-Alkynylarylketones

et al. 2019

View full text Add to dashboard Cite

show abstract

“…To this end, several small molecules including digoxin and its derivatives 11,12 , diphenylpropanamide compounds 13 , benzenesulfoamide 14–17 , ursolic acid 18 and compounds containing benzhydryl amide moiety 19–21 have shown to inhibit RORγt transcriptional activity along with decreased IL-17A and IL-17F production and exhibit significant beneficial effects in animal models of Th17 mediated inflammatory diseases. Recently, small molecule RORγt inverse agonists have also been discovered and are shown to deviate RORγt away from inflammatory signaling 22–24 . However, these compounds are not RORγt specific, but rather affecting ROR family of transcription factors and whereby they will produce undesired adverse effects.…”

Section: Introductionmentioning

confidence: 99%

Silencing RORγt in Human CD4+ T cells with CD30 aptamer-RORγt shRNA Chimera

Shi

Song

Shao

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Targeting specific T cell subtypes and intervening in their function are emerging a critical strategy for treatment of autoimmune diseases. Here we report that an RNA CD30 aptamer was utilized to deliver short hairpin RNA (shRNA) to CD30 + T cells to target retinoic acid receptor-related orphan receptor gamma t (RORγt), leading to impaired expression of RORγt and suppression of IL-17A and IL-17F. A DNA template consisting of CD30 aptamer and RORγt shRNA sequences was synthesized and was transcribed CD30 aptamer-RORγt shRNA chimera (CD30-AshR-RORγt). Insertion of 2′-F-dCTP and 2′-FdUTP was incorporated during CD30-AshR-RORγt transcription to increase its resistance to RNase. CD30-AshR-RORγt was specifically up-taken by CD30 + Karpas 299 cells, but not by Jurkat cells which lack CD30. It was also up-taken by activated, CD30 expressing human CD4 + T cells, but not by resting CD4 + T cells. The RORγt shRNA moiety of CD30-AshR-RORγt chimera was cleaved and released by Dicers. Then, CD30-AshR-RORγt suppressed RORγt gene expression in Karpas 299 cells and activated human CD4 + T cells. Consistently, silence of Th17 cell differentiation and IL-17A and IL-17F synthesis with CD30-AshR-RORγt was demonstrated in activated human CD4 + T cells from healthy donors and RA patients. CD30-AshR-negative control chimera and prostate specific membrane antigen (PSMA)-AshR-RORγt had no significant impact on the expression of RORγt or IL-17A and IL-17F. These data present a novel strategy for shRNA delivery using CD30 RNA aptamers to down-regulate CD30 + Th17 cells and can be developed as a targeted therapy for treating Th17 cell mediated conditions.

show abstract

Syntheses of Acyclic and Macrocyclic Compounds Derived from 9,9‐Diethylfluorene (Part I)

Seidel

Mazik

2020

ChemistryOpen

View full text Add to dashboard Cite

A series of new 9,9-diethylfluorenes consisting of three sidearms each bearing a heterocyclic, bis(carboxymethyl)amino, bis (carbamoylmethyl)amino, bis(ethoxycarbonylmethyl)amino or an amino group were prepared on the basis of 2,4,7-tris (bromomethyl)-9,9-diethylfluorene. Imidazolyl, benzimidazolyl, pyrazolyl, pyrrolyl, 1,3-dioxoisoindolyl and pyridinium groups were taken into account as heterocyclic units, attached to the aromatic skeleton via À CH 2 À , À CH 2 NHCH 2 À or À CH 2 N=CHÀ linkers. In addition to the seventeen 2,4,7-trisubstituted 9,9diethylfluorenes, two macrocyclic compounds were prepared on the basis of 2,7-bis(aminomethyl)-9,9-diethylfluorene. The excellent yield of the macrocyclization reaction is worth a special mention. Both the acyclic and the macrocyclic fluorenebased compounds have, among other things, the potential to act as artificial receptors for different substrates in analogy to the known receptors consisting of a benzene or biphenyl core.

show abstract

Structure‐Based Design and Synthesis of Fluorene Derivatives as Novel RORγt Inverse Agonists

Cited by 3 publications

References 34 publications

Divergent Synthesis of 3-Hydroxyfluorene and 4-Azafluorene Derivatives from ortho-Alkynylarylketones

Divergent Synthesis of 3-Hydroxyfluorene and 4-Azafluorene Derivatives from ortho-Alkynylarylketones

Silencing RORγt in Human CD4+ T cells with CD30 aptamer-RORγt shRNA Chimera

Syntheses of Acyclic and Macrocyclic Compounds Derived from 9,9‐Diethylfluorene (Part I)

Contact Info

Product

Resources

About