Parallel Solid-Phase Synthesis using a New Diethylsilylacetylenic Linker and Leading to Mestranol Derivatives with Potent Antiproliferative Activities on Multiple Cancer Cell Lines

Author(s):

Raphaël Dutour, René Maltais, Martin Perreault, Jenny Roy and Donald Poirier*   Pages 1469 - 1481 ( 13 )

Abstract:

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. </P><P> 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). </P><P> 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 &#177; 0.34 to 3.17 &#177; 0.10 &#181;M) 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 &#177; 0.30, 0.89 &#177; 0.63, 1.36 &#177; 0.31, 2.47 &#177; 0.91 and 3.17 &#177; 0.10 &#181;M, respectively). </P><P> 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.

Keywords:

Aminosteroids, solid-phase synthesis, cancer, antiproliferative activity, acetylenic linker, mestranol derivatives.

Affiliation:

Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Quebec-Research Center (CHUL-T4), Quebec, QC, Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Quebec-Research Center (CHUL-T4), Quebec, QC, Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Quebec-Research Center (CHUL-T4), Quebec, QC, Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Quebec-Research Center (CHUL-T4), Quebec, QC, Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Quebec-Research Center (CHUL-T4), Quebec, QC

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