4-o-carboxymethylascochlorin and Osteosarcoma

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.

Topics: Alkenes; Animals; Cell Differentiation; Cells, Cultured; Fibroblasts; Furans; Genes, Reporter; Genetic Vectors; Glycolates; Humans; Inhibitory Concentration 50; Ligands; Mice; Models, Molecular; Osteosarcoma; Phenols; Plasmids; Receptors, Cytoplasmic and Nuclear; Recombinant Proteins; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Transfection