Discovery of Novel and Potent Retinoic Acid Receptor α Agonists:  Syntheses and Evaluation of Benzofuranyl-pyrrole and Benzothiophenyl-pyrrole Derivatives

Yoshimura, Hidetoshi; Kikuchi, K.; Hibi, Shigeki; Tagami, Katsuya; Satoh, Takashi; Yamauchi, Toshihiko; Ishibahi, Akira; Tai, Kenji; Hida, Takayuki; Tokuhara, Naoki; Nagai, Mitsuo

doi:10.1021/jm000098s

Cited by 30 publications

(18 citation statements)

References 30 publications

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“…However, the extent of HB-EGF upregulation was distinct among those agents. All four RARa-specific synthetic retinoids, Am80, Am580, ER-38925, and TAC-101, showed relatively low promotion of HB-EGF mRNA compared with all three isotypes of retinoic acid, whereas they demonstrated a higher affinity to RARa and higher activity in other actions such as growth suppression of neoplasm than did atRA (13)(14)(15)(16). The reason for the variation in promotion of HB-EGF mRNA among retinoids remains unknown, but it may be partly due to differential binding affinity to RARg.…”

Section: Discussionmentioning

confidence: 99%

“…All six retinoids were generous gifts from Dr Kagechika (University of Tokyo, Tokyo) (Am80, Am580, Ch55 and Re80), Taiho Pharmaceuticals Co, Ltd (Tokyo, Japan) (TAC101) and Eisai Co, Ltd. (Tokyo, Japan) (ER‐38925). Am80, Am580, TAC‐101, and ER‐38925 are RARα‐selective agonists (13–16), while Ch55 and Re80 are panagonists for all three RAR subtypes (12,17).…”

Section: Methodsmentioning

confidence: 99%

“…The synthetic retinoids were Am80 (Tokyo, Japan) (ER-38925). Am80, Am580, TAC-101, and ER-38925 are RARa-selective agonists (13)(14)(15)(16), while Ch55 and Re80 are panagonists for all three RAR subtypes (12,17).…”

Section: Reagentsmentioning

confidence: 99%

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Differential expression of heparin‐binding EGF‐like growth factor (HB‐EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids

Yoshimura

Uchida

Okazaki

et al. 2003

Experimental Dermatology

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It was recently revealed that epidermal growth following topical treatment with all-trans retinoic acid (atRA) was at least partly induced by heparin-binding epidermal growth factor-like growth factor (HB-EGF) released from suprabasal keratinocytes. Since proliferation of keratinocytes appears to be one of the critical roles of atRA in depigmentation treatment and promotion of wound healing, HB-EGF is considered suitable for assessing the therapeutic value of topical retinoids. In this study, HB-EGF mRNA expression in normal human keratinocytes after atRA treatment was examined, and the effects of a variety of natural and synthetic retinoids were compared. The results of reverse transcription polymerase chain reaction (RT-PCR) suggested that induction of differentiation increased HB-EGF mRNA expression in cultured keratinocytes. Real-time PCR analyses revealed that HB-EGF mRNA expression was elevated dose-dependently with atRA, peaking at 12 h. This elevation was more prominent in confluent keratinocytes than in subconfluent cells, suggesting that differentiated keratinocytes are more subject to stimulation of HB-EGF expression by atRA than proliferating keratinocytes. HB-EGF mRNA was upregulated in differentiation-induced keratinocytes by all retinoids used in this study at 1 micromol/l, and marked upregulation was seen when treated with three isotypes of retinoic acid (atRA, and 9-cis and 13-cis retinoic acid). RARalpha-selective agonists (Am80, Am580, ER-38925, and TAC-101) and a panagonist of RARs (Re80) caused relatively low elevation of HB-EGF transcripts, as did all-trans retinol (Rol) and all-trans retinal (Ral). Although another panagonist (Ch55) showed the highest elevation of HB-EGF mRNA, it was relatively cytotoxic at the concentration employed. Ral and Rol were found to upregulate HB-EGF when used at 100 micromol/l to 1 mmol/l, to a similar extent of atRA at 1-10 micromol/l. The capacity of retinoids to upregulate HB-EGF may be an important index for investigation and development of an ideal synthetic retinoid, which has maximum benefits and minimum side-effects

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Differential expression of heparin‐binding EGF‐like growth factor (HB‐EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids

Yoshimura

Uchida

Okazaki

et al. 2003

Experimental Dermatology

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“…The structure of various bioisosteric retinoic acid receptor agonists highlights the dominantly geometric parameter of this bioisostery (Figure 8.60) [208]. …”

Section: A Structural Parametersmentioning

confidence: 99%

Molecular Variations Based on Isosteric Replacements

Ciapetti¹,

Giethlen

2008

The Practice of Medicinal Chemistry

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“…Pyrrole is one of the most significant N-containing heterocycles, and is the component of numerous biologically active molecules [1][2][3], natural products [4][5][6] and functional materials [7][8][9]. For example, atorvastatin A [10,11], which is one of the world's best-selling drugs, was first introduced to the market in 1997 by Pfizer as an effective HMG-CoA reductase inhibitor for lowering blood cholesterol.…”

Section: Introductionmentioning

confidence: 99%

Practical Pd(TFA)2-Catalyzed Aerobic [4+1] Annulation for the Synthesis of Pyrroles via “One-Pot” Cascade Reactions

Mang

Yang

et al. 2016

Catalysts

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Abstract:The Pd(TFA) 2 -catalyzed [4+1] annulation of chained or cyclic α-alkenyl-dicarbonyl compounds and unprotected primary amines for "one-pot" synthesis of pyrroles is reported here. Enamination and amino-alkene were involved in this practical and efficient tandem reaction. The annulation products were isolated in moderate to excellent yields with O 2 as the terminal oxidant under mild conditions. In addition, this method was applied to synthesize highly regioselective aminomethylated and di(1H-pyrrol-3-yl)methane products.

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Discovery of Novel and Potent Retinoic Acid Receptor α Agonists: Syntheses and Evaluation of Benzofuranyl-pyrrole and Benzothiophenyl-pyrrole Derivatives

Cited by 30 publications

References 30 publications

Differential expression of heparin‐binding EGF‐like growth factor (HB‐EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids

Differential expression of heparin‐binding EGF‐like growth factor (HB‐EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids

Molecular Variations Based on Isosteric Replacements

Practical Pd(TFA)2-Catalyzed Aerobic [4+1] Annulation for the Synthesis of Pyrroles via “One-Pot” Cascade Reactions

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