Chemistry:Androstenediol

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Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepiandrosterone (DHEA). It is closely related to androstenedione (androst-4-ene-3,17-dione).

Biological activity

Androstenediol is a direct metabolite of the most abundant steroid produced by the human adrenal cortex, DHEA. It is less androgenic than the related compound, Δ4-androstenediol, and has been found to stimulate the immune system. When administered to rats, androstenediol, in vivo, has approximately 1.4% of the androgenicity of DHEA, 0.54% of the androgenicity of androstenedione, and 0.21% of the androgenicity of testosterone.[1]

Androstenediol possesses potent estrogenic activity, similarly to DHEA and 3β-androstanediol.[2] It has approximately 6% and 17% of the affinity of estradiol at the ERα and ERβ, respectively.[3] Although androstenediol has far lower affinity for the ERs compared to the major estrogen estradiol, it circulates at approximately 100-fold higher concentrations, and so is thought may play a significant role as an estrogen in the body.[4]

v · d · e Affinities of estrogen receptor ligands for the ERα and ERβ
Ligand Other names Relative binding affinities (RBA, %)a Absolute binding affinities (Ki, nM)a Action
ERα ERβ ERα ERβ
Estradiol E2; 17β-Estradiol 100 100 Script error: The function "median" does not exist. (0.04–0.24) Script error: The function "median" does not exist. (0.10–2.08) Estrogen
Estrone E1; 17-Ketoestradiol Script error: The function "median" does not exist. (0.7–60) Script error: The function "median" does not exist. (1.36–52) Script error: The function "median" does not exist. (0.3–1.01) Script error: The function "median" does not exist. (0.35–9.24) Estrogen
Estriol E3; 16α-OH-17β-E2 Script error: The function "median" does not exist. (4.03–56) Script error: The function "median" does not exist. (14.0–44.6) Script error: The function "median" does not exist. (0.35–1.4) Script error: The function "median" does not exist. (0.63–0.7) Estrogen
Estetrol E4; 15α,16α-Di-OH-17β-E2 4.0 3.0 4.9 19 Estrogen
Alfatradiol 17α-Estradiol Script error: The function "median" does not exist. (7–80.1) Script error: The function "median" does not exist. (2–42) 0.2–0.52 0.43–1.2 Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol Script error: The function "median" does not exist. (4.94–63) 50 ? ? Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol Script error: The function "median" does not exist. (29–103) 79–80 ? ? Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol 1.0 13 ? ? Metabolite
2-Hydroxyestradiol 2-OH-E2 Script error: The function "median" does not exist. (7–81) 11–35 2.5 1.3 Metabolite
2-Methoxyestradiol 2-MeO-E2 0.0027–2.0 1.0 ? ? Metabolite
4-Hydroxyestradiol 4-OH-E2 Script error: The function "median" does not exist. (8–70) 7–56 1.0 1.9 Metabolite
4-Methoxyestradiol 4-MeO-E2 2.0 1.0 ? ? Metabolite
2-Hydroxyestrone 2-OH-E1 2.0–4.0 0.2–0.4 ? ? Metabolite
2-Methoxyestrone 2-MeO-E1 <0.001–<1 <1 ? ? Metabolite
4-Hydroxyestrone 4-OH-E1 1.0–2.0 1.0 ? ? Metabolite
4-Methoxyestrone 4-MeO-E1 <1 <1 ? ? Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol 2.0–6.5 35 ? ? Metabolite
2-Hydroxyestriol 2-OH-E3 2.0 1.0 ? ? Metabolite
4-Methoxyestriol 4-MeO-E3 1.0 1.0 ? ? Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate <1 <1 ? ? Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate 0.0004 ? ? ? Metabolite
Estradiol 3-glucuronide E2-3G 0.0079 ? ? ? Metabolite
Estradiol 17β-glucuronide E2-17G 0.0015 ? ? ? Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S 0.0001 ? ? ? Metabolite
Estrone sulfate E1S; Estrone 3-sulfate <1 <1 >10 >10 Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate 10 ? ? ? Estrogen
Estradiol 17β-benzoate E2-17B 11.3 32.6 ? ? Estrogen
Estrone methyl ether Estrone 3-methyl ether 0.145 ? ? ? Estrogen
ent-Estradiol 1-Estradiol 1.31–12.34 9.44–80.07 ? ? Estrogen
Equilin 7-Dehydroestrone Script error: The function "median" does not exist. (4.0–28.9) 13.0–49 0.79 0.36 Estrogen
Equilenin 6,8-Didehydroestrone 2.0–15 7.0–20 0.64 0.62 Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol 7.9–113 7.9–108 0.09 0.17 Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol Script error: The function "median" does not exist. (18–41) 14–32 0.24 0.57 Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol 35–68 90–100 0.15 0.20 Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol 20 49 0.50 0.37 Estrogen
Δ8-Estradiol 8,9-Dehydro-17β-estradiol 68 72 0.15 0.25 Estrogen
Δ8-Estrone 8,9-Dehydroestrone 19 32 0.52 0.57 Estrogen
Ethinylestradiol EE; 17α-Ethynyl-17β-E2 Script error: The function "median" does not exist. (68.8–480) Script error: The function "median" does not exist. (2.0–144) 0.02–0.05 0.29–0.81 Estrogen
Mestranol EE 3-methyl ether ? 2.5 ? ? Estrogen
Moxestrol RU-2858; 11β-Methoxy-EE 35–43 5–20 0.5 2.6 Estrogen
Methylestradiol 17α-Methyl-17β-estradiol 70 44 ? ? Estrogen
Diethylstilbestrol DES; Stilbestrol Script error: The function "median" does not exist. (89.1–468) Script error: The function "median" does not exist. (61.2–295) 0.04 0.05 Estrogen
Hexestrol Dihydrodiethylstilbestrol Script error: The function "median" does not exist. (31–302) 60–234 0.06 0.06 Estrogen
Dienestrol Dehydrostilbestrol Script error: The function "median" does not exist. (20.4–223) 56–404 0.05 0.03 Estrogen
Benzestrol (B2) – 114 ? ? ? Estrogen
Chlorotrianisene TACE 1.74 ? 15.30 ? Estrogen
Triphenylethylene TPE 0.074 ? ? ? Estrogen
Triphenylbromoethylene TPBE 2.69 ? ? ? Estrogen
Tamoxifen ICI-46,474 Script error: The function "median" does not exist. (0.1–47) Script error: The function "median" does not exist. (0.28–6) 3.4–9.69 2.5 SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT Script error: The function "median" does not exist. (1.7–257) Script error: The function "median" does not exist. (0.98–339) Script error: The function "median" does not exist. (0.1–3.61) 0.04–4.8 SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ? 7.14–20.3 15.4 SERM
Clomifene MRL-41 Script error: The function "median" does not exist. (19.2–37.2) 12 0.9 1.2 SERM
Cyclofenil F-6066; Sexovid 151–152 243 ? ? SERM
Nafoxidine U-11,000A 30.9–44 16 0.3 0.8 SERM
Raloxifene – Script error: The function "median" does not exist. (7.8–69) Script error: The function "median" does not exist. (0.54–16) 0.188–0.52 20.2 SERM
Arzoxifene LY-353,381 ? ? 0.179 ? SERM
Lasofoxifene CP-336,156 10.2–166 19.0 0.229 ? SERM
Ormeloxifene Centchroman ? ? 0.313 ? SERM
Levormeloxifene 6720-CDRI; NNC-460,020 1.55 1.88 ? ? SERM
Ospemifene Deaminohydroxytoremifene 2.63 1.22 ? ? SERM
Bazedoxifene – ? ? 0.053 ? SERM
Etacstil GW-5638 4.30 11.5 ? ? SERM
ICI-164,384 – Script error: The function "median" does not exist. (3.70–97.7) 166 0.2 0.08 Antiestrogen
Fulvestrant ICI-182,780 Script error: The function "median" does not exist. (9.4–325) Script error: The function "median" does not exist. (2.05–40.5) 0.42 1.3 Antiestrogen
Propylpyrazoletriol PPT Script error: The function "median" does not exist. (10.0–89.1) 0.12 0.40 92.8 ERα agonist
16α-LE2 16α-Lactone-17β-estradiol 14.6–57 0.089 0.27 131 ERα agonist
16α-Iodo-E2 16α-Iodo-17β-estradiol 30.2 2.30 ? ? ERα agonist
Methylpiperidinopyrazole MPP 11 0.05 ? ? ERα antagonist
Diarylpropionitrile DPN 0.12–0.25 6.6–18 32.4 1.7 ERβ agonist
8β-VE2 8β-Vinyl-17β-estradiol 0.35 22.0–83 12.9 0.50 ERβ agonist
Prinaberel ERB-041; WAY-202,041 0.27 67–72 ? ? ERβ agonist
ERB-196 WAY-202,196 ? 180 ? ? ERβ agonist
Erteberel SERBA-1; LY-500,307 ? ? 2.68 0.19 ERβ agonist
SERBA-2 – ? ? 14.5 1.54 ERβ agonist
Coumestrol – Script error: The function "median" does not exist. (0.0117–94) Script error: The function "median" does not exist. (0.41–185) 0.14–80.0 0.07–27.0 Xenoestrogen
Genistein – Script error: The function "median" does not exist. (0.0012–16) Script error: The function "median" does not exist. (0.86–87) 2.6–126 0.3–12.8 Xenoestrogen
Equol – 0.2–0.287 Script error: The function "median" does not exist. (0.10–2.85) ? ? Xenoestrogen
Daidzein – Script error: The function "median" does not exist. (0.0018–9.3) Script error: The function "median" does not exist. (0.04–17.1) 2.0 85.3 Xenoestrogen
Biochanin A – Script error: The function "median" does not exist. (0.022–0.15) Script error: The function "median" does not exist. (0.010–1.2) 174 8.9 Xenoestrogen
Kaempferol – Script error: The function "median" does not exist. (0.029–0.10) Script error: The function "median" does not exist. (0.002–3.00) ? ? Xenoestrogen
Naringenin – Script error: The function "median" does not exist. (<0.001–0.01) Script error: The function "median" does not exist. (0.11–0.33) ? ? Xenoestrogen
8-Prenylnaringenin 8-PN 4.4 ? ? ? Xenoestrogen
Quercetin – <0.001–0.01 0.002–0.040 ? ? Xenoestrogen
Ipriflavone – <0.01 <0.01 ? ? Xenoestrogen
Miroestrol – 0.39 ? ? ? Xenoestrogen
Deoxymiroestrol – 2.0 ? ? ? Xenoestrogen
β-Sitosterol – <0.001–0.0875 <0.001–0.016 ? ? Xenoestrogen
Resveratrol – <0.001–0.0032 ? ? ? Xenoestrogen
α-Zearalenol – Script error: The function "median" does not exist. (13–52.5) ? ? ? Xenoestrogen
β-Zearalenol – Script error: The function "median" does not exist. (0.032–13) ? ? ? Xenoestrogen
Zeranol α-Zearalanol 48–111 ? ? ? Xenoestrogen
Taleranol β-Zearalanol Script error: The function "median" does not exist. (13–17.8) 14 0.8 0.9 Xenoestrogen
Zearalenone ZEN Script error: The function "median" does not exist. (2.04–28) Script error: The function "median" does not exist. (2.43–31.5) ? ? Xenoestrogen
Zearalanone ZAN 0.51 ? ? ? Xenoestrogen
Bisphenol A BPA Script error: The function "median" does not exist. (0.008–1.0) Script error: The function "median" does not exist. (0.002–4.23) 195 35 Xenoestrogen
Endosulfan EDS <0.001–<0.01 <0.01 ? ? Xenoestrogen
Kepone Chlordecone 0.0069–0.2 ? ? ? Xenoestrogen
o,p'-DDT – 0.0073–0.4 ? ? ? Xenoestrogen
p,p'-DDT – Script error: The function "median" does not exist. ? ? ? Xenoestrogen
Methoxychlor p,p'-Dimethoxy-DDT Script error: The function "median" does not exist. (<0.001–0.02) 0.01–0.13 ? ? Xenoestrogen
HPTE Hydroxychlor; p,p'-OH-DDT 1.2–1.7 ? ? ? Xenoestrogen
Testosterone T; 4-Androstenolone <0.0001–<0.01 <0.002–0.040 >5000 >5000 Androgen
Dihydrotestosterone DHT; 5α-Androstanolone Script error: The function "median" does not exist. (<0.001–0.05) 0.0059–0.17 221–>5000 73–1688 Androgen
Nandrolone 19-Nortestosterone; 19-NT 0.01 0.23 765 53 Androgen
Dehydroepiandrosterone DHEA; Prasterone Script error: The function "median" does not exist. (<0.001–0.04) 0.019–0.07 245–1053 163–515 Androgen
5-Androstenediol A5; Androstenediol 6 17 3.6 0.9 Androgen
4-Androstenediol – 0.5 0.6 23 19 Androgen
4-Androstenedione A4; Androstenedione <0.01 <0.01 >10000 >10000 Androgen
3α-Androstanediol 3α-Adiol 0.07 0.3 260 48 Androgen
3β-Androstanediol 3β-Adiol 3 7 6 2 Androgen
Androstanedione 5α-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Etiocholanedione 5β-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Methyltestosterone 17α-Methyltestosterone <0.0001 ? ? ? Androgen
Ethinyl-3α-androstanediol 17α-Ethynyl-3α-adiol 4.0 <0.07 ? ? Estrogen
Ethinyl-3β-androstanediol 17α-Ethynyl-3β-adiol 50 5.6 ? ? Estrogen
Progesterone P4; 4-Pregnenedione <0.001–0.6 <0.001–0.010 ? ? Progestogen
Norethisterone NET; 17α-Ethynyl-19-NT Script error: The function "median" does not exist. (0.0015–<0.1) Script error: The function "median" does not exist. (0.01–0.3) 152 1084 Progestogen
Norethynodrel 5(10)-Norethisterone Script error: The function "median" does not exist. (0.3–0.7) <0.1–0.22 14 53 Progestogen
Tibolone 7α-Methylnorethynodrel Script error: The function "median" does not exist. (0.45–2.0) 0.2–0.076 ? ? Progestogen
Δ4-Tibolone 7α-Methylnorethisterone 0.069–<0.1 0.027–<0.1 ? ? Progestogen
3α-Hydroxytibolone – Script error: The function "median" does not exist. (1.06–5.0) 0.6–0.8 ? ? Progestogen
3β-Hydroxytibolone – Script error: The function "median" does not exist. (0.75–1.9) 0.070–0.1 ? ? Progestogen
Footnotes: a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Chemistry

Androstenediol, also known as androst-5-ene-3β,17β-diol, is a naturally occurring androstane steroid.[5] It is closely related structurally to androstenedione (A4; androst-4-ene-3,17-dione), dehydroepiandrosterone (DHEA; androst-5-en-3β-ol-17-one), and testosterone (androst-4-en-17β-ol-3-one), as well as to 3β-androstanediol (5α-androstane-3β,17β-diol).[5]

Derivatives and analogues of androstenediol, such as the 17α-substituted methandriol (17α-methylandrostenediol) and ethinylandrostenediol (17α-ethynylandrostenediol) as well as the naturally occurring 19-norandrostane derivative norandostenediol (19-nor-5-androstenediol), have been synthesized and studied. Methandriol and its esters are androgens and anabolic steroids while ethinylandrostenediol is an estrogen.

Synthesis

The chemical synthesis entails the reduction of the 17-keto group of DHEA:[6][7][8]

Esters

A number of esters of Androstenediol have been prepared:

  • 3-Ac: [1639-43-6]
  • 17-Ac: [5937-72-4]
  • Di-Ac: [2099-26-5]
  • Androstenediol dipropionate [2297-30-5]. Bisexovis, Bisexovister, Ginandrin, Stenandiol.

Research

Radiation countermeasure

Androstenediol has been investigated for use as a radiation countermeasure. Its value as a radiation countermeasure is based mainly on its stimulation of production of white blood cells and platelets.[9] Its potential use as a radiation countermeasure was developed by the Armed Forces Radiobiology Research Institute (AFRRI) and subsequently studied by AFRRI and Hollis-Eden Pharmaceuticals under the proposed brand name Neumune for the treatment of acute radiation syndrome.[9][10]

The clinical trials with rhesus monkeys were successful. According to the Hollis-Eden report, only 12.5% of the 40 Neumune-treated animals died versus 32.5% in the placebo group.[11]

Hollis-Eden had applied for a contract from the U.S. Government under the BioShield Request for Proposals (RFP) for radiation countermeasures. After being encouraged for 2.5 years that Neumune was in the competitive range, on March 9, 2007, the RFP was canceled by HHS. According to HHS, "the product was no longer in the competitive range".[12][13] No further explanation was given. As a result, Hollis-Eden has now withdrawn from the radiation countermeasure field.

Additional images

Steroidogenesis, with androstenediol at bottom left.

References

  1. ↑ "Androgen action and the sex accessory tissues". The Physiology of Reproduction.. New York: Raven Press. 1988. pp. 1081–1119. 
  2. ↑ "Estrogen and androgen receptor mediated stimulation and inhibition of proliferation by androst-5-ene-3 beta,17 beta-diol in human mammary cancer cells". The Journal of Steroid Biochemistry and Molecular Biology 46 (5): 597–603. November 1993. doi:10.1016/0960-0760(93)90187-2. PMID 8240982. 
  3. ↑ "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology 138 (3): 863–870. March 1997. doi:10.1210/endo.138.3.4979. PMID 9048584. 
  4. ↑ Cancer. Springer Science & Business Media. 30 January 2007. pp. 43–. ISBN 978-3-540-33120-9. https://books.google.com/books?id=fdtDAAAAQBAJ&pg=PA43. 
  5. ↑ 5.0 5.1 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 86–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA86. 
  6. ↑ Butenandt, Adolf; Hanisch, Günter (1935). "Über die Umwandlung des Dehydro-androsterons in Δ4-Androsten-ol-(17)-0n-(3) (Testosteron); ein Weg zur Darstellung des Testosterons aus Cholesterin (Vorläuf. Mitteil.)". Berichte der deutschen chemischen Gesellschaft (A and B Series). 68 (9): 1859–1862. doi:10.1002/cber.19350680937.
  7. ↑ Ruzicka, L.; Wettstein, A. (1935). "Sexualhormone VII. Über die künstliche Herstellung des Testikelhormons Testosteron (Androsten-3-on-17-ol)". Helvetica Chimica Acta. 18 (1): 1264–1275. doi:10.1002/hlca.193501801176.
  8. ↑ Zeynizadeh, Behzad Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2003 , vol. 58, # 12. p. 1220 – 1226.
  9. ↑ 9.0 9.1 "Androstenediol stimulates myelopoiesis and enhances resistance to infection in gamma-irradiated mice". Int. J. Immunopharmacol. 22 (1): 1–14. 2000. doi:10.1016/s0192-0561(99)00059-4. PMID 10684984. 
  10. ↑ "5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis". J. Radiat. Res. 53 (6): 840–853. 2012. doi:10.1093/jrr/rrs060. PMID 22843381. 
  11. ↑ Hollis-Eden Pharmaceuticals Reports Publication of Results Demonstrating the Ability of NEUMUNE(R) to Increase Survival in a Primate Model of Lethal Radiation Injury, February 26, 2007.
  12. ↑ Government Nukes Hollis-Eden's Radiation Drug, by Val Brickates Kennedy and Angela Moore, March 8, 2007
  13. ↑ US cancels radiation contract with Hollis-Eden , March 9, 2007




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