Ascochlorin derivatives as ligands for nuclear hormone receptors.
Nuclear receptor family proteins are structurally related transcription factors activated by specific lipophilic compounds. Because they are activated by a variety of hormonal molecules, including retinoic acid, vitamin D, and steroid hormones, they are assumed to be promising targets for clinical drugs. We previously found that one ascochlorin (1) derivative, 4-O-carboxymethyl-ascochlorin (2), is a potent agonist of peroxisome proliferator activated receptor gamma (PPARgamma). Here, we synthesized derivatives of 1, designated as a lead compound, to create new modulators of nuclear hormone receptors. Two derivatives, 4-O-carboxymethyl-2-O-methylascochlorin (9) and 4-O-isonicotinoyl-2-O-methylascochlorin (10), showed improved agonistic activity for PPARgamma and induced differentiation of a progenitor cell line, C3H10T1/2. We also found that 1, dehydroascofuranon (29), and a 2,4-O-diacetyl-1-carboxylic acid derivative of 1 (5) specifically activated estrogen receptors, PPARalpha, and an androgen receptor. All of the derivatives (1-29) activated the pregnane X receptor. These results suggest that the chemical structure of 1 is useful in designing novel modulators of nuclear receptors.
Togashi
Marie
M
Department of Biotechnology, Institute of Research and Innovation, 1201 Takada, Kashiwa 277-0861, Japan.
Ozawa
Satoshi
S
Abe
Shoko
S
Nishimura
Tomoyuki
T
Tsuruga
Mie
M
Ando
Kunio
K
Tamura
Gakuzo
G
Kuwahara
Shigefumi
S
Ubukata
Makoto
M
Magae
Junji
J
D000475:Alkenes / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D005822:Genetic Vectors; D006016:Glycolates / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D012516:Osteosarcoma / Q000378:metabolism; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000235:genetics; D000077154:Rosiglitazone; D013844:Thiazoles / Q000737:chemistry; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D014162:Transfection
D000475:Alkenes; D005663:Furans; D006016:Glycolates; D008024:Ligands; D010636:Phenols; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C043832:4-O-carboxymethylascochlorin; C415745:ascochlorin