Androstane Derivatives Research Articles

Probing the binding pocket of the active site of aromatase with 2-phenylaliphatic androsta-1,4-diene-3,17-dione steroids

A series of 2-phenylaliphatic-substituted androsta-1,4-diene-3,17-diones ( 6) as well as their androstenedione derivatives ( 5) were synthesized as aromatase inhibitors to gain insights of structure–activity relationships of varying the alkyl moiety (C 1 to C 4) of the 2-phenylaliphatic substituents as well as introducing a methyl- or trifluoromethyl function to p-position of a phenethyl moiety to the inhibitory activity. The inhibitors examined showed a competitive type inhibition. The 2-phenpropylandrosta-1,4-diene 6c was the most powerful inhibitor ( K i: 16.1 nM) among them. Compounds 6c along with the phenethyl derivative 6b caused a time-dependent inactivation of aromatase ( k inact: 0.0293 and 0.0454 min −1 for 6b and 6c, respectively). The inactivation was prevented by the substrate androstenedione, and no significant effect of l-cysteine on the inactivation was observed in each case. Molecular docking of the phenpropyl compound 6c to aromatase was conducted to demonstrate that the phenpropyl group orients to a hydrophobic binding pocket in the active site to result in the formation of thermodynamically stable enzyme–inhibitor complex.

Reactivity of 17β-hydroxy-17α-substituted androstane derivatives

The work concerns the reactivity of 17?-hydroxy-17?-substituted androstanes 1-9. Depending on the nature of the 17?-substituent, the presence of the neighboring 16-oximino group, and the reagent used, these compounds can undergo retroaddition (10-12) and fragmentation-cyclization (14-16) reactions.

Synthesis and antitumor activity of new d-seco and d-homo androstane derivatives

Starting from 3β-hydroxy-17-oxo-16,17-secoandrost-5-ene-16-nitrile ( 1), the new 16,17-secoandrostane derivatives 4– 9 were synthesized. On the other hand, 3β-hydroxy-17-oxa- d-homoandrost-5-ene-16-one ( 10) yielded the new d-homo derivatives 12, 13 and 15. In vitro antiproliferative activity of selected compounds against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER−, MDA-MB-231, prostate cancer AR−, PC-3, and normal fetal lung fibroblasts, MRC-5) was evaluated. Compounds 3 and 12 showed strong antiproliferative activity against PC-3 cells, the IC 50 values being 2 μM and 0.55 μM, respectively. Compounds 6 (10 μM) and 14 (9 μM) showed moderate activity against MDA-MB-231 cells. The synthesized compounds 1– 3, 5– 8, 10 and 12– 15 were not toxic to normal fetal lung fibroblasts cells, MRC-5.

An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors

Aromatase, an enzyme involved in the conversion of androgens into estrogens, is an important target for the endocrine treatment of breast cancer. Aromatase inhibition is usually achieved with steroids structurally related to the substrate of catalysis or, alternatively, with azole non-steroid compounds. Substituted androstenedione derivatives with Δ 1, Δ 6 and Δ 1,6 unsaturations and 6-alkyl/6-phenyl aliphatic substitutions, are among the most potent steroid aromatase inhibitors known to date. In this paper we have combined the common pharmacophoric and shape features of these molecules into a new pharmacophore model, useful for virtual screening of large compound databases. Small subsets of the best fitting anti-aromatase candidates were extracted from the NCI database and experimentally tested on an in vitro assay with human placental aromatase. New potent aromatase inhibitors were identified such as compounds 8 and 14. Considering the lack of a crystal structure for the aromatase enzyme, this ligand-based method is a valuable tool for the virtual screening of new aromatase inhibitors.

Conformation of 17-chloro-16-formylandrosta-5,16-dien-3β-yl acetate and 17-chloroandrosta-5,16-dien-3β-yl acetate

In the title compounds, C(22)H(29)ClO(3), (I), and C(21)H(29)ClO(2), (II), respectively, the B rings adopt a half-chair conformation and the D rings adopt an envelope conformation. A twist of the steroid skeleton of both compounds is observed. There is a positional disorder of the acetoxy group of (II), with the terminal atoms disordered over two positions with near equal occupancy. Quantum-mechanical ab initio calculations using a molecular orbital Hartree-Fock method were performed for the isolated molecules, thus allowing the distinction within the structural features of these two androstane derivatives of which characteristics are intrinsic to the molecules and which are due to packing effects. The skeletal twisting was found to be innate to the molecules, while the acetoxy disorder is due to packing effects.

Synthesis of 16 E-[3-methoxy-4-(2-aminoethoxy)benzylidene]androstene derivatives as potent cytotoxic agents

The synthesis and cytotoxic studies of a new series of 16 E-arylidene androstene derivatives are reported herein. The impact of incorporating bis-tertiary amino functionalities in the steroid skeleton on cytotoxicity has also been observed. The compounds have been evaluated at National cancer Institute, Bethesda, Maryland, USA for their antineoplastic activity against various tumor cell lines. The synthesized 16 E-arylidenosteroids exhibited significant cytotoxicity. Bis-tertiary amino steroid 29 possessing a diethylaminoalkoxy functionality was the most promising compound of the series with a total IP and SC score of 20 in in vivo hollow fiber assay and was selected for further detailed in vivo xenograft testing.

Brassinosteroids: Synthesis and Activity of Some Fluoro Analogues

Three types of 5alpha-androstane and ergostane analogues of brassinolide, containing a fluorine atom in either the 3alpha or the 5alpha positions or in 3alpha and 5alpha positions, were prepared using standard operations (reaction of 3beta-alcohols with (diethylamino)sulfur trifluoride, cleavage of epoxide with HF in py or BF 3.Et 2O). The 5alpha-fluorine was found to affect chemical reactivity (e.g., electrophilic addition to the Delta (2)-double bond) as well as physical properties (e.g., NMR, chromatographic behavior) of the products. Cytotoxicity of the products was studied using human normal and cancer cell lines with 28-homocastasterone as positive control and their brassinolide type activity was established using the bean second-internode test with 24-epibrassinolide as standard. The equivalence of F and OH groups was observed in some of the active compounds. The anticancer and the brassinolide-type activity do not correlate with each other: ergostane derivatives were most active in the former test while androstane derivatives were best in the latter.

Synthesis, Evaluation and QSAR Studies of 16-(4 & 3,4-Substituted) Benzylidene Androstene Derivatives as Anticancer Agents

In a systematic effort aimed at identifying new steroidal cytotoxic agents with potent antipoliferative activity against cancer cells and developing their QSAR models, series of 4-nitro, 4-isopropyl, 4-methoxy and 3,4-dimethoxy substituted benzylidene androst-5-ene derivatives were synthesized. The selected compounds were evaluated for antineoplastic activity against a panel of three human cell lines-breast, CNS and lungs at NCI, Bethesda, USA. The results presented herein reports that compounds 7, 9, 10, 15,16, 18, 20-25, 30, 32-36 and 44 have been found to be active anticancer agents. The QSAR of 20 compounds was performed separately for each cell line and best-fit QSAR models are developed. The QSAR models obtained have shown significant correlations (r(2) range: 0.9163 to 0.8164) and good predictive performance (q(2) range: 0.8499- 0.6320). The validation of models has also been performed using the test set of compounds 5, 15 and 44.

Oxidation Reactions in 9a-Halosteroids by Jones Reagent

Current investigations guided to searching androstane derivatives with potential anabolic activity, weakly androgenic one directed us to synthesize 3b,11b-dihydroxy-9a-halo-5a-androstane- 17-ones (4a-c). These compounds were oxidized by Jones' Reagent at 0 o C obtaining a selective oxidation of the equatorial 3b-hydroxyl group. This behaviour could be explained by the high steric hindrance at the 11b-position, increased by the strong inductive effect of the halogen atom at C-9a over the electronic density of the H-11a.

Analysis of intra- and intermolecular hydrogen bonding in androstane derivatives: A case study of steroids

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Analysis of intra- and intermolecular hydrogen bonding in androstane derivatives: A case study of steroids

We’ve built this digital research platform to provide academics everywhere with fast, stable and secure digital access to our library of over 110,000 scholarly books and 800,000 journal articles. We’ve tested the platform in close cooperation with leading academic institutions. If you have any questions or you notice something doesn’t quite work as it should, please visit our <a href="/publishing/faq?lang=en" class="text-primary">Help/FAQ</a> page and let us know.

Synthesis and evaluation of novel 17-indazole androstene derivatives designed as CYP17 inhibitors

A series of novel 1 H- and 2 H-indazole derivatives of the commercially available dehydroepiandrosterone acetate have been synthesized and tested for inhibition of human cytochrome 17α-hydroxylase-C 17,20-lyase (CYP17), androgen receptor (AR) binding affinity, and cytotoxic potential against three prostate cancer (PC) cell lines.

Anti-Diabetic Activity of Novel Androstane Derivatives from Syzygium cuminii Linn.

Objective: To study antidiabetic activity of two novel androstane derivatives (JB1 and JB2) isolated from the ethanolic extract of seeds of Syzygium cuminii Linn. Materials and methods: Compounds JB1 and JB2 were isolated from ethanolic extract of seeds of S. cuminii by normal phase column chromatography using toluene: ethyl acetate (80:20) as mobile phase and their structure was elucidated by spectroscopic methods. Antidiabetic activity of JB1 and JB2 and the ethanolic extract was evaluated using alloxan as diabetogenic agent. The potency of JB1 and JB2 (100 mg/kg) and the ethanolic extract (200 mg/kg), was compared with glibenclamide (5 mg/kg). The elevated blood glucose levels were monitored colorimetrically using glucose oxidase enzyme system. Results: Compound JB1 was found to be 3, 15-dihydroxy Δ 3 androstene [16, 17-C] (6' methyl, 2'- 1, 3-dihydroxy-1-propene) 4H pyran whereas JB2 to be 3-hydroxy androstane [16, 17-C] (6' methyl, 2'-1-hydroxy-isopropene-1-yl) 4, 5, 6 H pyran. Ethanolic extract of seeds of S. cuminii reduced elevated blood glucose levels in alloxan-induced diabetes in rats on single dose as well as prolonged treatment. Compound JB1 was found to be more effective than JB2 as it showed peak activity at the end of day three, which was comparable to ethanolic extract.

Catalytic alkynylation of 6-bromosteroids

An efficient method for synthesis of 6-alkynyl-substituted androstane derivatives was developed via the Pd-catalyzed Sonogashira—Hagihara coupling reaction. The use of AgCl as the cocatalyst (instead of traditionally used CuI) was shown to increase the activity of the catalytic system in several cases.

A steroid hormone that extends the lifespan of Caenorhabditis elegans

Removing the germline of Caenorhabditis elegans extends lifespan. This lifespan extension requires the nuclear receptor DAF-12 and the cytochrome P450 DAF-9, suggesting that a lipophilic hormone is involved. Here we show that C. elegans contains several hormonal steroids that are also present in humans, including pregnenolone (3beta-hydroxy-pregn-5-en-20-one; PREG) and other pregnane and androstane derivatives. We find that PREG can extend the lifespan of C. elegans. Moreover, PREG levels rise when the germline is removed in a daf-9-dependent fashion. PREG extends the lifespan of germline-defective daf-9 mutants dramatically, but has no effect on daf-12 mutants. Thus, germline removal may extend lifespan, at least in part, by stimulating the synthesis of PREG.

Physiological functions of solanaceous and tomato steroidal glycosides

Solanaceous plants are widely distributed. They are used as food and in folk medicine. Our studies focused on these plants, starting with Solanum lyratum and S. nigrum, which are used as anti-cancer and anti-herpes agents. Extensive investigations in 45 Solanum plant species revealed that a considerable amount of glycosides such as spirosolane, solanidane, spirostane and furostane is in these plants, and some of the isolated glycosides showed strong anti-proliferative activity against various cancer cell lines and anti-herpes activity. Furthermore, we have discovered a few new hypothetical biosynthetic routes in which the pathways for the biosynthesis of 16-acyl-pregnane and pregnane glycosides were the most interesting. The occurrence of these pregnane compounds indicates that they might be internally biosynthesized in the plant from furostanol glycosides by a reaction that is similar to Marker degradation. Furthermore, this may imply that the administration of steroidal glycosides may result in their metabolization into pregnane derivatives possessing various activities. In order to perform metabolic experiments using the steroidal glycosides, we recently isolated tomato glycosides from ripe tomato fruits for the first time. For this experiment, we examined the metabolites in urine obtained from persons that consumed tomatoes. We obtained androstane derivatives that were probably metabolized via pregnane derivatives from tomato glycoside. Hence, when a steroidal glycoside is administered, it may be metabolized into a type of steroidal hormone with various physiological activities.

Synthesis and Evaluation of Some 16-Benzylidene Substituted 3,17- Dioximino Androstene Derivatives as Anticancer Agents

Synthesis and Evaluation of Some 16-Benzylidene Substituted 3,17- Dioximino Androstene Derivatives as Anticancer Agents

Synthesis of 17-epi-Calcitriol from a Common Androstane Derivative, Involving the Ring B Photochemical Opening and the Intermediate Triene Ozonolysis

An efficient synthesis of 17-epi-calcitriol 2, an epimer of natural hormone, via 17-epi-cholesterol 5a is described. Synthesis of 5a includes palladium-catalyzed cyclopropanation of the common androstane derivative 7 with an alkyl diazoacetate, reductive fission of the less shielded side of cyclopropane carboxylic acid esters 6, oxidation of the products into acid 11a, and alkylation of ester 11b. Photolysis of 7,8-dedydro-17-epi-25-hydroxycholesterol 19b and consecutive thermal rearrangement gave a mixture of several products that was subjected to ozonolysis to provide, after chromatography, hydroxy ketone 3a. The silyl derivative 3b was coupled with the respective ring A building block.

1H and13C NMR spectral assignment of androstane derivatives

(1)H and (13)C NMR spectroscopic data for 5alpha-androstanes and halo-5alpha-androstanes with different substituents at positions C-3, C-9, C-11 and C-17 were examined and assigned by a combination of 1D and 2D NMR experiments. The substituent effects on the (13)C chemical shifts were compared with those of epi-androsterone, used as a reference compound. The coupling constants (n)J((19)F,(13)C) were measured for compounds 6, 8, 11 and 14.

Polychlorinated Androstanes from the Burrowing Sponge Cliona nigricans.

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