Abstract:
17β-HSD10 is a mitochondrial enzyme that catalyzes the conversion of a hydroxy group to a keto group on a
steroid skeleton and thus it is involved in the maintenance of steroid homeostasis. The druggability of 17β-HSD10 is related
to potential treatment for neurodegenerative diseases including Alzheimer's disease or certain types of cancer. Here, a series
of steroidal derivatives with an acidic hemiester substituent at position C-3 on the skeleton were designed, synthesized, and
evaluated using pure recombinant 17β-HSD10 converting estradiol to estrone. Compounds 22 (IC50 = 6.95 ± 0.35 μM) and 23
(IC50 = 5.59 ± 0.25 μM) were identified as the most potent inhibitors from the series. Compound 23 inhibited 17β-HSD10
activity regardless of the substrate and was found not cytotoxic towards the HEK-293 cell line. Together, these findings support
steroidal compounds as promising candidates for further development as 17β-HSD10 inhibitors.
