Synthesis and Characterization of Non-Steroidal Ligands for the Glucocorticoid Receptor:  Selective Quinoline Derivatives with Prednisolone-Equivalent Functional Activity

Coghlan, Michael J.; Kym, Philip R.; Elmore, Steven W.; Wang, Alan X.; Luly, Jay R.; Wilcox, Denise; Stashko, Michael A.; Lin, Chun–Wei; Miner, Jeffrey N.; Tyree, Curtis M.; Nakane, Masaki; Jacobson, Peer B.; Lane, Benjamin C.

doi:10.1021/jm010228c

Cited by 97 publications

(72 citation statements)

References 35 publications

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“…In addition, dibenzo-α-pyrones are key intermediates in the synthesis of cannabinoids [14], and other pharmaceutically interesting compounds such as progesterone, androgen, glucocorticoid receptor agonists [15,16], as well as endothelial proliferation inhibitors [17], and antidyslipidemic agents [18]. This review mainly presents the occurrence, biosynthesis, biotransformation, and biological activities of the dibenzo-α-pyrones from bioorganisms.…”

Section: Open Accessmentioning

confidence: 99%

“…They are usually toxic to plants and animals. Typical examples include alternariol (10), alternariol 9-methyl ether (11), botrallin (16), and 2-chloro-4,6-dihydro-1,7-dihydroxy-3,9-dimethoxy-1-methyl-1H-dibenzo [b,d]pyran-4,6-dione (TMC-264, 28). The structures of the dibenzo-α-pyrones from fungi are shown in Figure 2.…”

Section: Dibenzo-α-pyrones From Fungimentioning

confidence: 99%

“…exhibited inhibitory activity on the appressorium formation of Magnaporthe grisea (M. oryzae) with IC 50 value of 51.0 μg/mL [34]. Alternariol 9-methyl ether (11), botrallin (16) and palmariol B (27) from endophytic fungus Hyalodendriella sp. Ponipodef12 showed moderate antimicrobial activity [12,43].…”

Section: Other Bioactivitiesmentioning

confidence: 99%

“…Alternariol 9-methyl ether (11), botrallin (16) and palmariol B (27) from endophytic fungus Hyalodendriella sp. Ponipodef12 also showed moderate antinematodal inhibitory activity on Caenorhabditis elegans [12].…”

Section: Other Bioactivitiesmentioning

confidence: 99%

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Natural Dibenzo-α-Pyrones and Their Bioactivities

Mao

Sun

et al. 2014

Molecules

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Natural dibenzo-α-pyrones are an important group of metabolites derived from fungi, mycobionts, plants and animal feces. They exhibit a variety of biological activities such as toxicity on human and animals, phytotoxicity as well as cytotoxic, antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory properties. Dibenzo-α-pyrones are biosynthesized via the polyketide pathway in microorganisms or metabolized from plant-derived ellagitannins and ellagic acid by intestinal bacteria. At least 53 dibenzo-α-pyrones have been reported in the past few decades. This mini-review aims to briefly summarize the occurrence, biosynthesis, biotransformation, as well as their biological activities and functions. Some considerations related to synthesis, production and applications of dibenzo-α-pyrones are also discussed.

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Section: Open Accessmentioning

confidence: 99%

Section: Dibenzo-α-pyrones From Fungimentioning

confidence: 99%

Section: Other Bioactivitiesmentioning

confidence: 99%

Section: Other Bioactivitiesmentioning

confidence: 99%

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Natural Dibenzo-α-Pyrones and Their Bioactivities

Mao

Sun

et al. 2014

Molecules

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“…In addition, this protocol would be useful for the development of non-steroidal ligands for GR. 15) If such a ligand exhibits some side effects in vivo, our protocol may indicate whether it is due to GR-mediated transactivation or due to an other mechanism derived from its novel structure.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Analysis of Glucocorticoid-Induced Reporter Gene Expression Using Gene Gun DNA Delivery.

Tanigawa

Tanaka

Nagase

et al. 2002

Biological & Pharmaceutical Bulletin

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Glucocorticoids (GCs) are the most effective treatment currently available for many allergic and inflammatory diseases. However, the severe side effects have limited their therapeutic usefulness. The development of topical or inhaled agents has been attempted to improve the therapeutic use of GCs. However, recent elucidation of the molecular mechanisms of GC action has led to a new strategy. The glucocorticoid receptor (GR) regulates gene transcription by two different mechanisms, namely, transactivation and transrepression.1-3) Transactivation depends on the binding of GR to cis-acting glucocorticoid response element (GRE) to initiate the expression of target genes, and transrepression is mediated through protein-protein interactions with other transcription factors such as AP-1 and NF-kB, thereby suppressing the transcription activities of these factors. There is increasing acceptance of the hypothesis that the side effects are mainly due to the transactivation function, whereas the antiinflammatory effects are due to the transrepression function. Therefore, the development of a novel ligand that discriminates between these two functions, so-called dissociated ligands, could lead to a beneficial agent. 4,5) The reporter gene assay is a useful method to separately evaluate these two functions in the cells. Transactivation activity can be determined as the induction of gene expression of the reporter plasmid containing GREs, and transrepression can be determined as the suppression of gene expression controlled by AP-1 or NF-kB. The application of the same protocol in vivo would be useful to examine whether the in vitro profile of the compound is sustained even in vivo.As a method for DNA transfection in vivo, ballistic particle-mediated devices have been studied to deliver genes into various tissues, and one such device is now available as the gene gun.6,7) Gene gun inoculation directly transfects cells by depositing DNA-coated gold beads within the cells and achieves high local transgene expression. Many studies have reported successful gene delivery into mouse skin by this method. 8,9) In this study, we demonstrate that gene gun inoculation into mouse skin enables the in vivo performance of a reporter gene assay for GR-mediated transactivation. MATERIALS AND METHODSMice Male ICR mice, 5 weeks old, weighing 25-33 g were obtained from CLEA Japan (Shizuoka, Japan). The animals were maintained under a 12-h light/dark cycle in a temperature-and humidity-controlled room.Plasmids and Reagents The GC inducible reporter plasmid, pMAMneoLUC, was purchased from Clontech (Palo Alto, CA, U.S.A.). To construct a human GR expression plasmid pBK-hGR, human GR cDNA was amplified by polymerase chain reaction from pRShGR (American Type Culture Collection, Rockville, MD, U.S.A.) using primers covering the entire coding region attached by restriction sites for BamHI and XbaI (sense 5Ј-CGCCATGGATGGATCCAC-CATGGACTCCAAAGAATC-3Ј and antisense 5Ј-GCTCT-AGATCACTTTTGATGAAACAGAAGT-3Ј). The amplified products were digested and ligated into...

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Anti‐Inflammatory Steroids

Avery

Woolfrey

2003

Burger's Medicinal Chemistry and Drug Discovery

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We know today that structural changes in steroids can bring about potency alterations in animal pharmacology through a number of mechanisms. The processes that are affected include pharmacokinetic parameters such as drug absorption and drug distribution, as well as drug metabolism to more or less active metabolites. There is now a large body of literature dealing with these phenomena that makes predictive thinking possible in these areas. Other mechanisms that are involved in the effect of structural changes on pharmacological activity in steroids include the effect of steroid structure on receptor affinity and the manner in which changes in the steroid agonist affect intrinsic activity through alterations in gene expression. These and other concepts relating to anti‐inflammatory steroids are discussed in this chapter.

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Synthesis and Characterization of Non-Steroidal Ligands for the Glucocorticoid Receptor: Selective Quinoline Derivatives with Prednisolone-Equivalent Functional Activity

Cited by 97 publications

References 35 publications

Natural Dibenzo-α-Pyrones and Their Bioactivities

Natural Dibenzo-α-Pyrones and Their Bioactivities

In Vivo Analysis of Glucocorticoid-Induced Reporter Gene Expression Using Gene Gun DNA Delivery.

Anti‐Inflammatory Steroids

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