Design of a Mestranol 2‐N‐Piperazino‐Substituted Derivative Showing Potent and Selective in vitro and in vivo Activities in MCF‐7 Breast Cancer Models

Abstract

Anticancer structure-activity relationship studies on aminosteroid (5α-androstane) derivatives have emerged with a promising lead candidate: RM-133 (2β-[1-(quinoline-2-carbonyl)pyrrolidine-2-carbonyl]-N-piperazine-5α-androstane-3α,17β-diol), which possesses high in vitro and in vivo activities against several cancer cells, and selectivity over normal cells. However, the relatively weak metabolic stability of RM-133 has been a drawback to its progression toward clinical trials. We investigated the replacement of the androstane backbone by a more stable mestranol moiety. The resulting compound, called RM-581 ({4-[17α-ethynyl-17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-2-yl]piperazin-1-yl}[(2S)-1-(quinolin-2-ylcarbonyl)pyrrolidin-2-yl]methanone), was synthesized efficiently in only five steps from commercially available estrone. In comparison with RM-133, RM-581 was found to be twice as metabolically stable, retains potent cytotoxic activity in breast cancer MCF-7 cell culture, and fully blocks tumor growth in a mouse xenograft model of breast cancer. Advantageously, the selectivity over normal cells has been increased with this estrane version of RM-133. In fact, RM-581 showed a better selectivity index (15.3 vs. 3.0) for breast cancer MCF-7 cells over normal breast MCF-10A cells, and was found to be nontoxic toward primary human kidney proximal tubule cells at doses reaching 50 μm.

Induction of Endoplasmic Reticulum Stress-Mediated Apoptosis by Aminosteroid RM-581 Efficiently Blocks the Growth of PC-3 Cancer Cells and Tumors Resistant or Not to Docetaxel

“…Aminosteroid derivatives (AM) are a novel class of anticancer agents showing multipotent activity in vitro and in vivo in various cancer cell lines and tumors, including breast, pancreatic, and ovarian cancers [ 20 , 21 , 22 , 23 ]. AM leads to the disturbance of cholesterol homeostasis with the concomitant induction of endoplasmic reticulum (ER) stress that ultimately triggers apoptosis [ 23 , 24 , 25 , 26 ].…”

“…AM leads to the disturbance of cholesterol homeostasis with the concomitant induction of endoplasmic reticulum (ER) stress that ultimately triggers apoptosis [ 23 , 24 , 25 , 26 ]. Among the AM family, RM-581 has emerged as the most valuable lead candidate [ 20 , 27 , 28 ]. Since ER stress inducers are a promising therapeutic approach for cancer treatment [ 29 ], including PCa [ 30 ], we assess RM-581’s potential for CRPC treatment.…”

The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

“…Aminoestrones are of particular interest thanks to their diverse biological applications [ 1 – 4 ]. There exist several aminated steroids in the literature, but the efficient generation of a C(sp 2 )–N bond on the aromatic ring A of estrone derivatives still remains a challenge.…”

2-[2-Methyl-5-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-pyrrol-3-yl]-2-oxo-N-(pyridin-4-yl) acetamide

“…An important molecular target inside the body for both the design and development of anticancer agents is tubulin protein. Recently, laboratory research and clinical investigations have focused on anti-tubulin agents to apply a series of compounds in the treatment of several types of cancer [1][2][3][4][5][6][7][8][9].…”