Background: RM-133 belongs to a new family of aminosteroid derivatives demonstrating interesting
anticancer properties, as confirmed in vivo in four mouse cancer xenograft models. However, the metabolic
stability of RM-133 needs to be improved. After investigation, the replacement of its androstane scaffold by a
more stable estrane scaffold led to the development of the mestranol derivative RM-581.
Methods: Using solid-phase strategy involving five steps, we quickly synthesized a series of RM-581 analogs
using the recently-developed diethylsilylacetylenic linker. To establish structure-activity relationships, we then
investigated their antiproliferative potency on a panel of cancer cell lines from various cancers (breast, prostate,
ovarian and pancreatic).
Results: Some of the mestranol derivatives have shown in vitro anticancer activities that are close to, or
better than, those observed for RM-581. Compound 23, a mestranol derivative having a ((3,5-dimethylbenzoyl)-
L-prolyl)piperazine side chain at position C2, was found to be active as an antiproliferative agent (IC50 = 0.38 ±
0.34 to 3.17 ± 0.10 µM) and to be twice as active as RM-581 on LNCaP, PC-3, MCF-7, PANC-1 and
OVCAR-3 cancer cells (IC50 = 0.56 ± 0.30, 0.89 ± 0.63, 1.36 ± 0.31, 2.47 ± 0.91 and 3.17 ± 0.10 µM,
Conclusion: Easily synthesized in good yields by both solid-phase organic synthesis and classic solution-phase
chemistry, promising compound 23 could be used as an antiproliferative agent on a variety of cancers, notably
pancreatic and ovarian cancers, both having very bad prognoses.