Synthesis, , and anti-inflammatory evaluation of 3β-cinnamoyloxy substituted pregna-4,16-diene-6,20-diones derivatives.

Pregnane derivatives have been studied mainly for their 5α-reductase activity. However, the anti-inflammatory activities of such compounds are still poorly explored. In the search for new anti-inflammatory agents, seven new pregnane derivatives -, with cinnamic acid esters at C-3 were prepared and fully characterized.

Activity of steroid 4 and derivatives 4a-4f as inhibitors of the enzyme 5α-reductase 1.

It is known that the growth of prostate metastatic bone tumor depends on androgens, and tumor formation can start from migratory malignant cells produced in that organ. These cells exhibit grater type 1 5α-reductase (5α-R1) activity than type 2 5α-reductase. Noteworthy, both isozymes convert testosterone (T) to the more active androgen dihydrotestosterone (DHT) in the target tissues.

Synthesis and cytotoxic effect of pregnenolone derivatives with one or two α,β-unsaturated carbonyls and an ester moiety at C-21 or C-3.

Four series of pregnenolone derivatives having one or two α,β-unsaturated carbonyls and an ester moiety at C-21 or C-3 were synthetized to compare their cytotoxicity effect. The final compounds were evaluated on three human cancer cell lines: PC-3 (prostate cancer), MCF-7 (breast cancer), SKLU-1 (lung cancer) and a noncancerous cell line HGF (human gingival fibroblast). Two steroids with a 4-fluorinated benzoic acid ester at C-21 were the most active against lung cancer cell line with IC of 13.

Synthesis of new derivatives of 21-imidazolyl-16-dehydropregnenolone as inhibitors of 5α-reductase 2 and with cytotoxic activity in cancer cells.

The aim of this study was to synthesize several 16-dehydropregnenolone derivatives containing an imidazole ring at C-21 and a different ester moiety at C-3 as inhibitors of 5α-reductase 1 and 2 isoenzymes. Their binding capacity to the androgen receptor (AR) was also studied. Additionally, we evaluated their pharmacological effect in a castrated hamster model and their cytotoxic activity on a panel of cancer cells (PC-3, MCF7, SK-LU-1).

Synthesis of 17β-N-arylcarbamoylandrost-4-en-3-one derivatives and their anti-proliferative effect on human androgen-sensitive LNCaP cell line.

In this study, we report the synthesis and anti-proliferative effect of a set of eight androst-4-ene-3-one derivatives with different arylcarbamoyl groups at C-17. The novel compounds were prepared from commercially available 3β-hydroxy-5-pregnen-20-one and evaluated against the androgen-sensitive human prostate adenocarcinoma LNCaP cell line. The cancerous cells were exposed to 50 μM of each compound and the proliferating agent testosterone (T) or dihydrotestosterone (DHT).

Synthesis and biological activity of two pregnane derivatives with a triazole or imidazole ring at C-21.

Pregnane derivatives are studied as agents for the treatment of different hormone-dependent diseases. The biological importance of these steroids is based on their potential use against cancer. In this study, we report the synthesis, characterization and biological activity of two pregnane derivatives with a triazole (3β-hydroxy-21-(1H-1,2,4-triazol-1-yl)pregna-5,16-dien-20-one; T-OH) or imidazole (3β-hydroxy-21-(1H-imidazol-1-yl)pregna-5,16-dien-20-one; I-OH) moieties at C-21.

Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases.

This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT.

Activity landscape analysis of novel 5α-reductase inhibitors.

Inhibitors of the enzyme 5[Formula: see text]-reductase (5aR) are promising therapeutic agents for the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. The lack of structural data of the enzyme 5aR prompts the application of ligand-based approaches to systematically explore the activity landscape of 5aR inhibitors. As part of an effort to develop inhibitors of this enzyme for the treatment of BPH, herein we discuss a chemoinformatic-based analysis of the activity landscape of a novel set of 53 novel pregnane and androstene compounds.

Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5α-reductase and on cancer cell line SK-LU-1.

Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5α-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR).

Synthesis and biological evaluation of esters of 16-formyl-17-methoxy-dehydroepiandrosterone derivatives as inhibitors of 5α-reductase type 2.

In this study, we investigated the in vitro effect of 16-formyl-17-methoxy dehydroepiandrosterone derivatives on the activity of 5α-reductase type 2 (5α-R2) obtained from human prostate. The activity of different concentrations of these derivatives was determined for the conversion of labelled testosterone to dihydrotestosterone. The results indicated that an aliphatic ester moiety at the C-3 position of these derivatives increases their in vitro potency as inhibitors of 5α-R2 activity compared to finasteride®, which is considered to be a potent inhibitor of 5α-R2.

Novel dehydroepiandrosterone benzimidazolyl derivatives as 5α-reductase isozymes inhibitors.

5α-R isozymes (types 1 and 2) play an important role in prostate gland development because they are responsible for intraprostatic dihydrotestosterone (DHT) levels when the physiological serum testosterone (T) concentration is low. In this study, we synthesized seven novel dehydroepiandrosterone derivatives with benzimidazol moiety at C-17, and determined their effect on the activity of 5α-reductase types 1 and 2. The derivatives with an aliphatic ester at C-3 of the dehydroepiandrosterone scaffold induced specific inhibition of 5α-R1 activity, whereas those with a cycloaliphatic ester (cyclopropyl, cyclobutyl, or cyclopentyl ring) or an alcohol group at C-3 inhibited the activity of both isozymes.

Synthesis and Identification of Pregnenolone Derivatives as Inhibitors of Isozymes of 5α-Reductase.

Hyperplasia of the prostate gland and prostate cancer have been associated with high levels of serum 5α-dihydrotestosterone. This steroid is formed from testosterone by the activity of the enzyme 5α-reductase (5α-R) present in the prostate. Thus, inhibition of this enzyme could be a goal for therapies to treat these diseases.

Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase.

The enzyme type 5 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives.

Effect of new hybrids based on 5,16-pregnadiene scaffold linked to an anti-inflammatory drug on the growth of a human astrocytoma cell line (U373).

In spite of the fact that anaplastic astrocytoma is an uncommon disease, very often the pathology of this disease is associated with lethal effects due to the late diagnosis and unspecific treatments. This paper reports the synthesis and the biological effect on the growth of U373 cell line (human anaplastic astrocytoma) of new hybrid compounds based on 5,16-pregnadiene scaffold linked to an anti-inflammatory drug (6a-e). Moreover, we also determined the cell growth effect of five non-steroidal anti-inflammatory drugs (naproxen, ibuprofen, ketoprofen, indomethacin and sulindac) as well as the free steroidal alcohol 5.

Effect of two antiandrogens as protectors of prostate and brain in a Huntington's animal model.

The purpose of this work is to know the effect of flutamide and a novel synthetic steroid 3β-p-Iodobenzoyloxypregnan-4,16- diene-6,20-dione (IBP) on the levels of dopamine, 5-HIAA (5-hydroxyindole acetic acid), and some oxidative stress markers in animal model with Huntington disease. Thirty male Wistar rats divided in groups of 6 animals each were subjected to the following treatment: group A, 3-nitro propionic acid (3-NPA, as inducer of Huntington); group B, flutamide; group C, 3-NPA + flutamide; group D, IBP; and group E, 3-NPA + IBP. Treatment scheme for all groups were at 4 mg/kg/day administered intraperitoneally.

Effect of dehydroepiandrosterone derivatives on the activity of 5α-reductase isoenzymes and on cancer cell line PC-3.

It is well known that testosterone (T) under the influence of 5α-reductase enzyme is converted to dihydrotestosterone (DHT), which causes androgen-dependent diseases. The aim of this study was to synthesize new dehydroepiandrosterone derivatives (3a-e, 4a-i, 6 and 7) having potential inhibitory activity against the 5α-reductase enzyme. This paper also reports the in vivo pharmacological effect of these steroidal molecules.

Synthesis and cytotoxic effect on cancer cell lines and macrophages of novel progesterone derivatives having an ester or a carbamate function at C-3 and C-17.

In this study we report the cytotoxic effect on human cancer cells of two series of novel progesterone derivatives; the first containing an aromatic ester (8a-e) or a carbamate functions both linked to C-3 (9a-e) on the pregn-4,16-diene-6,20-dione skeleton. In the second series, both functional groups (ester and carbamate) are bound to C-17 on the pregn-4,6-diene-3,20-dione scaffold (13a-e and 14a-e). The panel cancer cell lines used in this study were the following: PC-3 (human prostate cancer cell line), MCF-7 (human breast cancer cell line), HCT-15 (human colon cancer cell line) and J774 (noncancerous murine macrophages) for comparison.

Assessment of a synthetic steroid and flutamide on dopamine, GSH and H2O2 levels in rat brain in presence of fructose.

Unlabelled: Flutamide is a drug used in the treatment of androgen-dependent disorders. However, this treatment is usually accompanied by some adverse side effects. The aim of this work was to analyse the effect of flutamide and to compare this effect with that of a synthetic steroid - 3β-propionyloxy-5-androsten-17-one (PPA) - on levels of dopamine and some oxidative stress markers.

Recent advances in structure of progestins and their binding to progesterone receptors.

The role of progesterone in women's cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins.

A-ring modified steroidal azoles retaining similar potent and slowly reversible CYP17A1 inhibition as abiraterone.

Abiraterone acetate is a potent inhibitor of human cytochrome P450c17 (CYP17A1, 17α-hydroxylase/17,20-lyase) and is clinically used in combination with prednisone for the treatment of castration-resistant prostate cancer. Although many studies have documented the potency of abiraterone (Abi) in a variety of in vitro and in vivo systems for several species, the exact potency of Abi for human CYP17A1 enzyme has not yet been determined, and the structural requirements for high-potency steroidal azole inhibitors are not established. We synthesized 4 Abi analogs differing in the A-B ring substitution patterns: 3α-hydroxy-Δ(4)-Abi (13), 3-keto-Δ(4)-Abi (11), 3-keto-5α-Abi (6), and 3α-hydroxy-5α-Abi (5).

Effect of carbamates on mRNA encoding lipid enzymes in hamster flank organs.

Flank organs are an androgen-dependent pilosebaceous complex present in male and female hamsters. These organs have been used for the evaluation of antiandrogenic drugs, which could be used for the treatment of androgen-dependent afflictions. This study demonstrated the role of four different steroidal carbamates 7-10 in the expression of mRNAs coding for different enzymes involved in the lipid metabolism in flank organs.

Cytotoxic effect of novel dehydroepiandrosterone derivatives on different cancer cell lines.

The aim of this study was to determine the cytotoxic effect of human cancer cells on three series of novel dehydroepiandrosterone derivatives containing triazole or pyrazole rings at C-17 and an ester moiety at C-3 of the androstane skeleton. The panel cancer cells used in this study were the following: PC-3, MCF-7 and SKLU-1. The results from this study indicated that the steroidal derivatives 4a-4e and 4f-4k showed the highest cytotoxic potency.

Biological evaluation of androstene derivatives.

The effect of several new dihydroepiandrosterone ester derivatives A2-A6 was demonstrated using female cycling mice, which were synchronized for estrus with luteinizing hormone-releasing hormone (LHRH) and injected with the steroids. The binding to the progesterone receptor (PR), was obtained from the cytosol of uteri from adult estrogen-primed rabbits. A1 binds to the PR and inhibited the ovulation in cycling mice stimulated with LHRH.

In vivo and in vitro effect of androstene derivatives as 5α-reductase type 1 enzyme inhibitors.

The aim of these studies was to synthesize twelve ester derivatives of dehydroepiandrosterone with therapeutic potential. The effect of 1-12 was demonstrated in the flank organs of gonadectomized hamsters treated with testosterone and the synthesized steroids. In vitro studies were carried out determining the IC50 values for the inhibition of the activity of 5α-reductase type 1 and 2, which are present in rat liver and human prostate respectively.

Molecular interactions of natural and synthetic steroids in female hamsters' flank organs.

Background: The initial step of steroidal action on target cells is gene activation; therefore, the quantification of mRNA is a direct method for comparing the role of different steroids in the skin.

Objective: This study demonstrated the role of several steroids on the mRNA expression encoding for different enzymes involved in the lipid metabolism in hamsters' flank organs, which are a pilosebaceous complex.

Methods: To determine the effect of treatments with testosterone (T) progesterone (P), levonorgestrel (LNG), 17α-p-chlorobenzoyloxy-6-chloropregn-4,6-diene-3,20-dione (5) and 17α-p-chlorobenzoyloxy-4,6-pregnadiene-3,20-dione (6); T and/or LNG; T and 5 or 6; P and/or 5 or 6 on the expression of mRNA encoding for lipid enzymes, the steroids were applied to the glands; later, the mRNAs expression for the enzymes was determined by PCR.