Synthesis of ponasterone A derivatives with various steroid skeleton moieties and evaluation of their binding to the ecdysone receptor of Kc cells

A series of ponasterone A (PNA) derivatives with various steroid moieties were synthesized to measure their binding activity to the ecdysone receptors of Drosophila Kc cells. The activity of compounds was evaluated by deter-mining the concentration required to give the 50% inhibition (IC50 in M) of the incorporation of [H-3]PNA to Drosophila Kc cells. Compounds with no functional groups such as OH and C=O group in the steroid skeleton moiety were inactive. By the introduction of functional groups such as the OH and the C=O group in the steroidal structure, these compounds became active. Some compounds containing the A/B-trans ring fusion, which is different from that (A/B-cis) of ecdysteroids were also active. The oxidation of CH2 at 6-position to C=O, enhanced the activity 19 times, but the activity was erased by the reduction of oxo to OH group at 6-position. The activity was enhanced about 250 times by the conversion of A/B ring configuration from trans [(20R,22R)-2 beta,3 beta,20,22-tetrahydroxy-5 alpha-cholestan-6-one: pIC(50) = 4.84] to cis [(20R,22R)-2 beta,3 beta,20,22-tetrahydroxy-5 beta-cholestan-6-one: pIC(50) = 7.23]. The latter cis-type compound which is the most potent among compounds synthesized in this study was equipotent to the natural molting hormone, 20-hydroxyecdysone, even though it is 1/50 of PNA. (C) 2008 Elsevier Inc. All rights reserved.