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

Abstract

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 determining the concentration required to give the 50% inhibition (IC 50 in M) of the incorporation of [ 3H]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 CH 2 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 [(20 R,22 R)-2β,3β,20,22-tetrahydroxy-5α-cholestan-6-one: pIC 50 = 4.84] to cis [(20 R,22 R)-2β,3β,20,22-tetrahydroxy-5β-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.