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Description. Mestanolone is an oral analogue of dihydrotestosterone.
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Description

Mestanolone

Description

Mestanolone, also known as methylandrostanolone and sold under the brand names Androstalone and Ermalone among others, is an androgen and anabolic steroid medication which is mostly no longer used. It is still available for use in Japan however. It is taken by mouth. Wikipedia

FormulaC20H32O2
ChEMBL Id261514
Trade nameAndrostalone, Ermalone, others
Drug classAndrogen; Anabolic steroid
PubChem CID10633
Mestanolone is an oral analogue of dihydrotestosterone. This steroid is a 17-alpha methylated form of this potent endogenous androgen, being essentially (in structure) to dihydrotestosterone what methyltestosterone is to testosterone. Overall, mestanolone has an activity profile not very dissimilar from the hormone it is derived from. Like dihydrotestosterone, mestanolone is primarily androgenic in nature, displaying a low level of anabolic activity. Both dihydrotestosterone and mestanolone are also devoid of estrogenic activity. Dihydrotestosterone was synthesized in 1935. After that 17-alpha-methylated version also appeared. This steroid was not frequently used in clinical medicine. It was produced under the name of ermalon for short period of time. Most studies involving mestanolone were carried out in the 1950s and 1960s. In the 1970s and 1980s it was used as part of the East German doping machine. Mestanolone was evaluated not for its anabolic ability but for its androgenic essence. It improved the functioning of the CNS and neuromuscular interaction. Athletes claimed that it did not make them huge, but gave them speed, strength, aggression, stamina and resistance to stress. Mestanolone is still valued as an oral androgen.

Mestanolone, also known as methylandrostanolone and sold under the brand names Androstalone and Ermalone among others, is an androgen and anabolic steroid (AAS) medication which is mostly no longer used.[1][2][3][4] It is still available for use in Japan however.[2][3] It is taken by mouth.[4]

Side effects of mestanolone include symptoms of masculinization like acneincreased hair growthvoice changes, and increased sexual desire.[4] It can also cause liver damage.[4] The drug is a synthetic androgen and anabolic steroid and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).[4][5] It has strong androgenic effects and weak anabolic effects, which make it useful for producing masculine psychological and behavioral effects.[4] The drug has no estrogenic effects.[4]

Mestanolone was discovered in 1935 and was introduced for medical use in the 1950s.[6][7][8][4] In addition to its medical use, mestanolone has been used to improve physique and performance.[4] It was used in East Germany in Olympic athletes as part of a state-sponsored doping program in the 1970s and 1980s.[4] The drug is a controlled substance in many countries and so non-medical use is generally illicit.[4]

Mestanolone Medical uses[edit]

Available forms[edit]

Mestanolone was available in the form of 25 mg sublingual tablets (brand name Ermalone).[9]

Pharmacology[edit]

Pharmacodynamics[edit]

Mestanolone is an AAS, with both androgenic and anabolic effects.[4] It is very similar in its effects to androstanolone (dihydrotestosterone; DHT), and can be thought of as an orally active version of this AAS.[4] Due to inactivation by 3α-hydroxysteroid dehydrogenase (3α-HSD) in skeletal muscle, mestanolone is described as a very poor anabolic agent, similarly to androstanolone and mesterolone.[4] As mestanolone is 5α-reduced, it cannot be aromatized and hence has no propensity for estrogenic side effects such as gynecomastia.[4] The drug also has no progestogenic activity.[4] Like other 17α-alkylated AAS, mestanolone is hepatotoxic.[4]

Pharmacokinetics[edit]

Due to its C17α methyl group, unlike androstanolone, mestanolone is orally active.[4]

Chemistry[edit]

Mestanolone, also known as 17α-methyl-4,5α-dihydrotestosterone (17α-methyl-DHT) or as 17α-methyl-5α-androstan-17β-ol-3-one, is a synthetic androstane steroid and a 17α-alkylated derivative of dihydrotestosterone (DHT).[1][4] It differs from DHT only by the presence of the methyl group at the C17α position.[1][4] Close synthetic relatives of mestanolone include oxandrolone (2-oxa-17α-methyl-DHT), oxymetholone (2-hydroxymethylene-17α-methyl-DHT), and stanozolol (a derivative of 17α-methyl-DHT (mestanolone) with a pyrazole ring fused to the A ring).[1][4]

Side effects[edit]

Side effects of mestanolone include virilization and hepatotoxicity among others.[4]

History[edit]

Mestanolone was first synthesized in 1935 along with methyltestosterone and methandriol.[6][7] It was developed by Roussel in the 1950s and was introduced for medical use, under the brand names Androstalone and Ermalone, by at least 1960.[4][10][8] It was marketed in Germany.[4] The drug was originally thought to be a potent anabolic agent, but subsequent research showed that it actually has relatively weak anabolic effects and is mostly an androgen.[4] Mestanolone was used as a doping agent in athletes competing in the Olympics from East Germany due to a state-sponsored doping program in the 1970s and 1980s.[4] Its value is said to have been less as a muscle-builder and more as an androgen in the central nervous system and neuromuscular interaction, improving speed, strength, aggressionfocusendurance, and stress resilience.[4] Today, mestanolone has mostly been discontinued in medicine, though it is still available in Japan.[2][3][4]

Society and culture[edit]

Generic names[edit]

Mestanolone is the generic name of the drug and its INNBAN, and JAN.[1][11]

Brand names[edit]

Mestanolone was marketed under the brand names Andoron, Androstalone, Ermalone, Mesanolon, and Notandron among many others.[4][2][12][3]

Availability[edit]

Mestanolone has mostly been discontinued but remains available in Japan.[2][3][4]

The microbial transformation of anabolic androgenic steroid mestanolone (1) with Macrophomina phaseolina and Cunninghamella blakesleeana has afforded seven metabolites. The structures of these metabolites were characterized as 17β-hydroxy-17α-methyl-5α-androsta-1-ene-3,11-dione (2), 14α,17β-dihydroxy-17α-methyl-5α-androstan-3,11-dione (3), 17β-hydroxy-17α-methyl-5α-androstan-1,14-diene-3,11-dione (4), 17β-hydroxy-17α-methyl-5α-androstan-3,11-dione (5), 11β,17β-dihydroxy-17α-methyl-5α-androstan-1-ene-3-one (6), 9α,11β,17β-trihydroxy-17α-methyl-5α-androstan-3-one (7), and 1β,11α,17β-trihydroxy-17α-methyl-5α-androstan-3-one (8). All the metabolites, except 5 and 6, were identified as new compounds. Substrate 1 (IC50 = 27.6 ± 1.1 μM), and its metabolites 2 (IC50 = 19.2 ± 2.9 μM) and 6 (IC50 = 12.8 ± 0.6 μM) exhibited moderate cytotoxicity against the HeLa cancer cell line (human cervical carcinoma). All metabolites were noncytotoxic to 3T3 (mouse fibroblast) and H460 (human lung carcinoma) cell lines. The metabolites were also evaluated for immunomodulatory activity, and all were found to be inactive.


Introduction

Biotransformation has been widely used in organic chemistry for stereoslective synthesis.1–6 Biotransformation reactions can be achieved by a variety of agents, such as enzymes, animals and plant cell cultures, and microorganisms; however, microorganisms are most effectively used for this purpose. Microbial enzyme systems can be used for reduction, oxidation, hydroxylation, and Michael addition. Regio- and stereo-selective oxidation and hydroxylation of steroids have been extensively achieved through microbial transformation. The cytochrome P450 monooxygenase system, present in microorganisms – particularly in fungi – is responsible for the stereoselective hydroxylation at various sites of the steroidal skeleton.7–9

Mestanolone (1) (C20H18O2) is a member of the anabolic-androgenic class of steroids. It is weakly anabolic and strongly androgenic. Mestanolone was first synthesized by the oxidation of 17β-methylandrostan-3β,17β-diol. It is used as a starting material for the synthesis of other anabolic steroids, such as 17-methyl-1-testosterone, and oxandrolone.10,11 Compound 1 was earlier subjected to microbial transformation, and several new analogues were obtained.12

In continuation of our research on biotransformation of bioactive compounds, and drug molecules,13–15 mestanolone (1) was incubated with Macrophomina phaseolina, and Cunninghamella blakesleeana, which yielded metabolites 2–8 (Fig. 1 and 2).

image file: c8ra01309h-f1.tif
Fig. 1 Biotransformation of mestonolone (1) with M. phaseolina.

image file: c8ra01309h-f2.tif
Fig. 2 Biotransformation of mestonolone (1) with C. blakesleeana.

Experimental

General

Mestanolone (1) was acquired from Hangzhu Dayangchem (Cat no. 541-11-9, China). Sabouraud dextrose agar (SDA) was purchased from Merck KGaA (Cat no. 146392, Germany). Silica gel precoated TLC plates (PF254, Merck KGaA, Germany) were used for thin layer chromatography; phosphomolybdic acid solution was used as a staining reagent for UV inactive compounds. Silica gel (70–230 mesh, Merck, Germany) was used for column chromatography. Final purification of the compounds was carried out by using recycling preparative HPLC-LC-908 (Japan), equipped with JAIGEL-ODS-L-80 column, with MeOH–H2O as the mobile phase. Melting points were recorded on Buchi M-560 (Buchi, Switzerland) apparatus. Optical rotations were measured on JASCO P-2000 (JASCO, Japan) polarimeter. UV Spectra were recorded on Hitachi U-3200 (Hitachi, Tokyo, Japan) spectrophotometer. IR Spectra were recorded as KBr discs on Bruker Vector 22 FT-IR (Bruker) spectrometer. Electron ionization (EI-MS) and high resolution electron ionization mass spectra (HREI-MS) were recorded on JEOL JMS600H mass spectrometer (JEOL, Japan). 1H-, 13C- and 2D-NMR spectra were recorded on Bruker Avance spectrometers (Bruker, Switzerland) in CD3OD. X-Ray diffraction data of the compound 6 was recorded on Bruker SMART APEX II single-crystal X-ray diffractometer (Germany).

Microbial cultures and media preparation

Macrophomina phaseolina (KUCC730), and Cunninghamella blakesleeana (ATCC8688A) were acquired from the Karachi University Culture Collection (KUCC) and American Type Culture Collection (ATCC). Cultures were grown, and stored on Sabouraud dextrose agar (SDA) slant at 4 °C. Liquid media (5.0 L) was prepared to grow M. phaseolina (KUCC 730) in distilled H2O by using the following ingredients; glucose (50.0 g), glycerol (50.0 mL), peptone (25.0 g), yeast extract (25.0 g), KH2PO4 (25.0 g), and NaCl (25.0 g). Similarly media for C. blakesleeana was prepared by mixing peptone (20.0 g), glucose (40.0 g), yeast extract (20.0 g), KH2PO4 (20.0 g), NaCl (20.0 g), and glycerol (40.0 mL) in 4 L distilled water.

General fermentation and extraction protocol

The media was prepared by using the aforementioned ingredients. The media was transferred to flasks and autoclaved at 120 °C. Seed flasks were prepared under sterilized conditions by transferring the spores of M. phaseolina from slants into the flasks, and then incubated at 25 ± 2 °C for 3 days on a rotary shaker (128 rpm). Similarly, seed flasks of C. blakesleeana were also prepared. The remaining flasks were inoculated by transferring the mycelia from the seed flasks and incubated on rotary shaker at 25 ± 2 °C. After appropriate fungal growth, compound 1 was dissolved in methanol and distributed evenly in all flasks. Fermentation was continued and the degree of transformation was analyzed by performing time course studies after different time intervals. In order to assess the fungal metabolites, and degradation of compound 1 in the aqueous media, two parallel control experiments were also conducted in order to assess the fungal metabolites a negative control (fungi + liquid media without compound) and, for degradation of compound 1 in the aqueous media, a positive control (liquid media + compound without fungi). After 12 days, the reaction was stopped by adding dichloromethane (CH2Cl2), and the broth was filtered to remove the mycelia. The broth was extracted with same solvent dichloromethane and dried over anhydrous sodium sulphate (Na2SO4). The organic layer was concentrated under reduced pressures to obtain a crude extract.

Fermentation of mestanolone (1) with Macrophomina phaseolina

Mestanolone (1) (1 g) was dissolved in 25 mL of methanol, distributed evenly in 50 flasks cultured with M. phaseolina (KUCC 730), and incubated for 12 days on a rotary shaker at 25 ± 2 °C. After completion of 12 days, dichloromethane was added into each flask to stop the fermentation. The content of the flasks was filtered to remove the fungal biomass. The broth (aqueous filtrate) was then extracted with dichloromethane (3 × 6 L). The organic layer was dried over anhydrous sodium sulfate (Na2SO4), and concentrated on a rotary evaporator. A brown crude extract (1.3 g) was obtained and loaded on a silica gel column. The column was eluted with 5% gradient of hexanes and acetone. Four fractions (1–4) were obtained, which yielded metabolites 2–6 (Fig. 1) after purification through reverse phase recycling HPLC (methanol[thin space (1/6-em)]:[thin space (1/6-em)]water; 70[thin space (1/6-em)]:[thin space (1/6-em)]30). Fraction 1 resulted into compound 2 (RT = 38 min, 9 mg). Compound 3 (RT = 34 min, 16 mg) was obtained from fraction 2. Compounds 4 (RT = 22 min, 3 mg) and 5 (RT = 32 min 7.8 mg) were obtained from fraction 3. Fraction 4 yielded compound 6 (RT = 50 min, 56 mg).

Fermentation of mestanolone (1) with Cunninghamella blakesleeana

Mestanolone (1) (500 mg) was dissolved in 20 mL of methanol, and dispensed equally in 40 flasks containing culture of C. blakesleeana (ATCC8688A). The flasks were kept on a shaker at 27 °C, and content was incubated for 12 days. The experiment was monitored through periodic TLC analysis. After 12 days of incubation, the substrate 1 seemed to be fully consumed. The contents of all flasks were collected, filtered off and then the aqueous media was extracted with CH2Cl2. The extract was then concentrated under reduced pressures. The crude extract (2.4 g) was then loaded on a silica gel column for fractionation. The mobile phase comprised gradients of hexane and acetone mixtures. Column chromatography yielded two fractions which were further purified by reverse phase recycling HPLC (methanol[thin space (1/6-em)]:[thin space (1/6-em)]water, 70[thin space (1/6-em)]:[thin space (1/6-em)]30). Fraction 1 yielded metabolite 7 (RT = 32 min, 7 mg) on purification while metabolite 8 (9.2 mg, RT = 27 min) (Fig. 2) was purified from fraction 2.

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