Human 17b-hydroxysteroid dehydrogenase type 10 (17b-HSD10) is known for its multiple functions and could be involved in the development and progression of many diseases. [1][2][3][4][5][6] 17b-HSD10 is a homotetrameric mitochondrial protein expressed in the liver and several other tissues, including brain and gonad. It plays a role in the metabolism of steroid hormones through its 17b-HSD and 3a-HSD activities (Scheme 1), as well as by its capacity to bind proteins and peptides. [1,5] This oxidative enzyme can thus inactivate estradiol (E2), the most potent steroid responsible for estrogenic activity in women, [a]

Abstract17b-Hydroxysteroid dehydrogenase type 1 (17b-HSD1) converts estrone (E1) into estradiol (E2) and is expressed in many steroidogenic tissues and breast cancer cell lines. Because the potent estrogen E2 stimulates the growth and development of hormone-dependent diseases, inhibition of the final step of E2 synthesis is considered a promising strategy for the treatment of breast cancer. On the basis of our previous study identifying 16b-(m-carbamoylbenzyl)-E2 (CC-156) as a lead compound for the inhibition of 17b-HSD1, we conducted a number of structural modifications to reduce its undesired residual estrogenic activity. The steroid derivative PBRM [3-(2-bromoethyl)-16b-(m-carbamoylbenzyl)-17b-hydroxy-1,3,5(10)-estratriene] emerged as a potent inhibitor of 17b-HSD1 with an IC 50 value of 68 nmol/L for the transformation of E1 into E2. When tested in the estrogen-sensitive breast cancer cell line T-47D and in mice, PBRM showed no estrogenic activity in the range of concentrations tested. Furthermore, with the purpose of evaluating the bioavailability of PBRM and CC-156 injected subcutaneously (2.3 mg/kg), we measured their plasmatic concentrations as a function of time, calculated the area under the curve (AUC 0-12h ) and showed a significant improvement for PBRM (772 ng à h/mL) compared with CC-156 (445 ng à h/mL). We next tested the in vivo efficiency of PBRM on the T-47D xenograft tumor model in female ovariectomized athymic nude mice. After a treatment with PBRM, tumor sizes in mice stimulated with exogenous E1 were completely reduced at the control group level (without E1 treatment). As a conclusion, PBRM is a promising nonestrogenic inhibitor of 17b-HSD1 for the treatment of estrogen-dependent diseases such as breast cancer.

No abstract

No 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.