Implication of STARD5 and cholesterol homeostasis disturbance in the endoplasmic reticulum stress-related response induced by pro-apoptotic aminosteroid RM-133.

The aminosteroid derivative RM-133 is an effective anticancer molecule for which proof of concept has been achieved in several mouse xenograph models (HL-60, MCF-7, PANC-1 and OVCAR-3). To promote this new family of molecules toward a clinical phase 1 trial, the mechanism of action governing the anticancer properties of the representative candidate RM-133 needs to be characterized. In vitro experiments were first used to determine that RM-133 causes apoptosis in cancer cells.

Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models.

In the fight against androgen-sensitive prostate cancer, the enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an attractive therapeutic target considering its key role in the formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an inhibitor of 17β-HSD3, in the prostate cancer model of androgen-sensitive LAPC-4 cells xenografted in nude mice. RM-532-105 did not inhibit the tumor growth induced by 4-androstene-3,17-dione (4-dione); rather, the levels of the androgens testosterone (T) and dihydrotestosterone (DHT) increased within the tumors.

Synthesis of a dansyl-labeled inhibitor of 17β-hydroxysteroid dehydrogenase type 3 for optical imaging.

The steroidogenic enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a therapeutic target in the management of androgen-sensitive diseases such as prostate cancer and benign prostate hyperplasia. In this Letter, we designed and synthesized the first fluorescent inhibitor of this enzyme by combining a fluorogenic dansyl moiety to the chemical structure of a known inhibitor of 17β-HSD3. The synthesized compound 3 is a potent fluorogenic compound (λex=348 nm and λ em=498 nm).

Solid-phase synthesis of libraries of ethynylated aminosteroid derivatives as potential antileukemic agents.

Steroids possessing an ethynyl group at position 17α (tertiary alcohols) are well known to be more stable than their non-ethynyl analogs (secondary alcohols). To facilitate the development of new drugs with better metabolic stability, we developed a new diethylsilyl acetylenic linker allowing us to rapidly synthesize libraries of ethynylated steroid derivatives using a solid-phase strategy. To illustrate its usefulness, this linker was used to expand the molecular diversity of a lead compound having a hydroxy acetylenic pattern and to potentially find new compounds with interesting cytotoxic activity against leukemia cell lines.

The Aminosteroid Derivative RM-133 Shows In Vitro and In Vivo Antitumor Activity in Human Ovarian and Pancreatic Cancers.

Ovarian and pancreatic cancers are two of the most aggressive and lethal cancers, whose management faces only limited therapeutic options. Typically, these tumors spread insidiously accompanied first with atypical symptoms, and usually shift to a drug resistance phenotype with the current pharmaceutical armamentarium. Thus, the development of new drugs acting via a different mechanism of action represents a clear priority.

Reprint of "In vitro and in vivo evaluation of a 3β-androsterone derivative as inhibitor of 17β-hydroxysteroid dehydrogenase type 3".

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3 or HSD17B3) catalyzes the last step in the biosynthesis of the potent androgen testosterone (T), by stereoselectively reducing the C17 ketone of 4-androstene-3,17-dione (4-dione), with NADPH as cofactor. Since T plays an important role in androgen-sensitive diseases, this enzyme is thus an interesting therapeutic target. In an attempt to design compounds to lower the level of T, we synthesized androsterone derivatives substituted at position 3 as inhibitors of 17β-HSD3, and selected one of the most potent compounds for additional studies.

Design, chemical synthesis and biological evaluation of 3-spiromorpholinone/3-spirocarbamate androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3.

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a key enzyme involved in the biosynthesis of testosterone and dihydrotestosterone. These hormones are known to stimulate androgen-dependent prostate cancer. In order to generate effective inhibitors of androgen biosynthesis without androgenic effect, we synthesized a new family of 3-spiromorpholinone and 3-spirocarbamate androsterone derivatives bearing diversified hydrophobic groups.

In vitro and in vivo evaluation of a 3β-androsterone derivative as inhibitor of 17β-hydroxysteroid dehydrogenase type 3.

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3 or HSD17B3) catalyzes the last step in the biosynthesis of the potent androgen testosterone (T), by stereoselectively reducing the C17 ketone of 4-androstene-3,17-dione (4-dione), with NADPH as cofactor. Since T plays an important role in androgen-sensitive diseases, this enzyme is thus an interesting therapeutic target. In an attempt to design compounds to lower the level of T, we synthesized androsterone derivatives substituted at position 3 as inhibitors of 17β-HSD3, and selected one of the most potent compounds for additional studies.

Synthesis of 3-spiromorpholinone androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3.

Spiromorpholinone derivatives were synthesized from androsterone or cyclohexanone in 6 or 3 steps, respectively, and these scaffolds were used for the introduction of a hydrophobic group via a nucleophilic substitution. Non-steroidal spiromorpholinones are not active as inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3), but steroidal morpholinones are very potent inhibitors. In fact, those with (S) stereochemistry are more active than their (R) homologues, whereas N-benzylated compounds are more active than their non substituted precursors.

Two androsterone derivatives as inhibitors of androgen biosynthesis.

The title compounds, (3R,5S,5'R,8R,9S,10S,13S,14S)-10,13-dimethyl-5'-(2-methylpropyl)tetradecahydro-6'H-spiro[cyclopenta[a]phenanthrene-3,2'-[1,4]oxazinane]-6',17(2H)-dione, C(26)H(41)NO(3), (I), and methyl (2R)-2-[(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-2',17-dioxohexadecahydro-3'H-spiro[cyclopenta[a]phenanthrene-3,5'-[1,3]oxazolidin-3'-yl]]-4-methylpentanoate, C(28)H(43)NO(5), (II), possess the typical steroid shape (A-D rings), but they differ in their extra E ring. The azalactone E ring in (I) shows a half-chair conformation, while the carbamate E ring of (II) is planar. The orientation of the E-ring substituent is clearly established and allows a rationalization of the biological results obtained with such androsterone derivatives.