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Lecture №21

Lecture №21. Hormones of the sexual glands: androgens and their semi-synthetic derivatives, estrogens and their synthetic analogues. Prostaglandins as pharmaceuticals, their properties, application. ass. Medvid I.I. Androgenic hormones.

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Lecture №21

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  1. Lecture №21 Hormones of the sexual glands: androgens and their semi-synthetic derivatives, estrogens and their synthetic analogues. Prostaglandins as pharmaceuticals, their properties, application. ass.Medvid I.I.

  2. Androgenichormones • Malesexhormonescalledandrogens (fromtheGreekword'Andros' - a manand "Genetic" - birth). Androgenic hormonesare producedbymalegonads (testicular) duringthe puberty (sexual maturity period). • Androgensarenecessaryfortheformationofsexualsphereanddevelopmentofsecondarysexualcharacteristicsinmen.Theyalsoaffecton variousbiochemicalprocesses, notrelatedto thecharacteristicsofsex - causeanaboliceffects, affect ontheexchangeofcarbohydrates, lipids, cholesterol, electrolytesandotherstaff. • Naturalandrogenistestosterone, whichwasat firstdedicatedin 1931 y. andsynthesizedin 1934 y. • Testosteronecreatesmaleandhislackin theoldageinmandestroysthebody, creatingthe conditionsforheartattacksandstrokes. • Testosterone - unstablesubstanceandisnotusedas a medicine.Inmedicine, testosteronederivatives (esters) are used, whichareabsorbedslowlyandare more stanle;andalso syntheticsubstitutes, suchasmethyltestosterone.Theyallhavemedicinalpropertiesofthenaturalhormone.

  3. Subsequentresearchestablishedthatthetestosteroneeffectisprolongedafterthe esterificationby fattyacid.Estercreatesoriginaldepotattheinjectionsitefromwhichtheyweregraduallyabsorbed, whiletestosteroneisquicklyremovedfromthebodybythekidneys.Oneofthemostactiveandstableat thestorage of testosteroneestersistestosteronepropionate. • Methyltestosterone (17α-methyltestosterone),althoughby theforceofactionis weaker thentestosteronepropionate, butnotdestroyedbyenzymesofthegastrointestinaltractandremainsactivity at theoraladmission. • Androgensareusedformenwithsexualunderdevelopment, functionaldisordersofsexualsphere(eunuchoidism) andinoldagewithvascularandnervedisorders. • Appliedby olderwomen (over 60) at thetumorsofreproductiveorgans, mammaryglandsofuterinebleeding, aswellasradiotherapyof ovariancancerandbreastcancer.

  4. Derivatives of androstane; Availability of oxo-group(=О) inposition 3; In position 4 – double bond; Hydroxy-group (-ОН) (can be esterificated) in position17. Androstane Testosterone Chemical signs of androgens

  5. General identification reactions onandrogenic hormones • On steroid system : Boscot’s reaction and reaction with concentrated sulfate acid. • On keto-group in the position 3: reactions of the oximes, hydrazones, isonicotinoyl hydrazones, phenyl hydrazones formation. • Esters of androgenic hormones (testosterone propionate): alkaline hydrolysis; hydroxamic reaction. • Alcoholic hydroxyl in 17β-position:formation of esters with character melting temperature.

  6. Testosterone propionate (Testosteroni propionas) (SPhU 1.2) 3-Oxandrost-4-ene-17β-ylpropanoate or 17β-propioneoxyandrostene-4-one-3 Produce synthetically, based on cholesterol, which is produced with the processing of lanolin and pork fat of animals. Characters. White or almost white crystalline powder or colorless crystals. Practically insoluble in water, freely soluble in alcohol and acetone, soluble in fatty oils.

  7. Identificationoftestosteronepropionate • Absorption spectrophotometry in IR-spectrum. • On steroid system – Boscot’s reaction. Intenseyellowfluorescence. • Thedrugisdissolvedin СН3СООН conc.,addby dropsbrominewater - itsbleachingoccurs (reactionondoublebond). • Establish a meltingpointoftestosteronederivedas a result ofalkalinehydrolysis. • On ester group – hydroxamic reaction (red-browncolor). • On oxo-group in position 3 – oxime formation, whichcan be identified bythetemperatureofmelting. • UV-spectrophotometry.

  8. Assay of testosterone • UV-spectrophotometry (index method). • Photocolorimetry (basedonthereactionbetweenthedrugwithisoniazidandestablishment isonicotinoylhydrazone, coloredinyellow). Storage and application In tightly corked container, protected from moisture and light action. • Androgenicdrugforthe treatmentofclimacteric, vascularandnervedisordersandcancersofbreastandovariesinwomen. Enterby i/m wayinoilsolutions. • Issue – amp. 1,0 and 5,0 % solution in oil. • Omnadren– oil solution for injectionamp.1 ml №5 (contains a mixtureoftestosteroneesters: propionate, phenylpropionate, capronate, isocapronate). • Andriol (testosterone undecanoate) – caps. 40 mg № 30; • Androgel (testosteron) – gel for the external usage 2,5 or 5 g №10. • Proviron (mesterolone, derivative of 5-androstanone (3)) – tabl.by 25 mg №20.

  9. Testosterone enanthate (Testosteroni enanthas) 17-enanthoxyandrostene-4-one-3 Applied in same cases as testosterone propionate. Act slower but longer as testosterone propionate. Enter byi/mway as 20% solution in oilone time every 2-4 weeks. Included to the Testoenatum mixture pro injectionibus amp. by 1 mlof 10% solutionin peach oil (contains 24 mg oftestosterone propionate and 111 mg of testosterone enanthate).

  10. Methyltestosterone (Methyltestosteronum) 17α-methyl-17β-oxyandrostene-4-one-3 Synthetic testosterone replacement. Characters. White crystalline powder, odorless. Practically not soluble in water, slightly soluble in ether and oils, soluble in acetone, easily soluble in ethanol.

  11. Identification ofmethyltestosterone • On steroid system – Boscot’s reaction. Intenseyellowfluorescence. • At thedissolvingof thedruginconc. H2SO4 orange-yellow colorappears, andafteraddingof water - orange-yellow colorwithgreenfluorescence (steroidcycle). • On alcoholic group ОН – acetilation reaction, acting of (СН3СО)2О in pyridine; at thedilutionwithwaterselect methyltestosterone acetate with melting temperature 173-176º С (with decomposition). • On oxo-groupin position 3 –thesubstanceisboiledinmethanolwith H2NOH*HCl – sediment of oxime falls (melting temperature – 210-216ºС).

  12. Assay of methyltestosterone UV-spectrophotometry atλ=240 nm. Storage and application In tightly corked container, protected from moisture and light action. Androgenic medication. In 2-3 times less active than testosterone propionate, but remains activity at the inside usage (sublingual). Issue: tabl. by 5-10 mg.

  13. Anabolic steroid structure means • Anabolicdrugs calledsubstance thatinthebodystimulatethesynthesisofproteins. Undertheirinfluenceincreasingbodyweight, improvesthegeneralconditionofpatients. By theirstructureanabolicdrug aresimilartomalesexhormones, which haveanabolicactivityas side effect. • Apply of androgenswith anabolicactionisnotpossibletotreatwomenandchildren. Thereforeitbecamenecessarytosynthesizethesubstance, whichwouldberatherweakandrogeniceffectbut a strongerorequalwithandrogensanabolicactivity. Itturnedoutthatthiscanbeachievedatsomechangesof molecularstructureofmalesexhormones.

  14. There are three major ways of androgenic activity lowering : 1) Transfering of double bond from position 4 to position 5 : 2) Introduction of the additional double bond in position 1: 3) Elimination of methyl group at position 19. Derivatives of 19-nortestosterone are the best anabolic drug.

  15. Methylandrostendiol (Methylandrostendiolum) Methandriol* 17α-methylandrostene-5-diol-3β,17βor 3β,17β-dioxy-17α-methylandrostene-5 Characters. White crystalline powder, odorless. Practically not soluble in water, soluble in ethanol, sparingly soluble in chloroform.

  16. Identification ofmethylandrostendiol • At thedissolvingof thedruginconc.H2SO4 orange-yellow colorappears, withgreenfluorescence (steroidcycle). • On alcoholic group ОН – acetylation reaction, after the action of (СН3СО)2О in pyridine –17-monoacetate ofmethylandrostendiol appears with melting temperature –174-180º С. • To the solution of drug in 80% СН3СООН carefullyaddconc. H2SO4 –ontheborderofphasesappearsorangecolor, theupperphaseischaracterizedby yellow-green fluorescence. • UV- spectroscopy. • Specificopticalrotation.

  17. Assay ofmethylandrostendiol Gravimetry. Storage and application In tightly corked container, protected from moisture and light action. • Bychemicalstructureresemblesmethyltestosterone, buthasweakerandrogenicanaboliceffectandstrongeranabolic activity. • Applyat the disordersofproteinmetabolismaftersevereinjuries, operations, atthe exhaustion, afterinfectiousdiseases,atthelaggrowthinadolescents. Treatmentofwomenshouldbeunderthesupervisionofthegynecologisttoprevent theeffectsvirilization. • Adoptintheformoftabletsforsublingualabsorptionby 25-50 mgperday. Notusedinprostatecancer, liverdiseases. • Release in the form oftabletsby 10 and 25 mg.

  18. Methandrostenolone (Methandrostenolonum) Анабол, Methandienone* 17α -methyl-17β-oxy-1,4-androstanediene -3-oneor 1,2-dihydromethyltestosterone Characters. White crystalline powder, are allowed a weak yellowish shade. Very little soluble in water, slightly soluble in ether, easily soluble in ethanol, chloroform.

  19. Identification ofmethandrostenolone • UV-spectroscopy. • At thedissolvingof thedruginconc.H2SO4 dark-redcolor formed. • On oxo-group in position 3: after theinteractionofthedrugwith 2,4-dinitrophenylhydrazine 2,4-dinitrophenylhydrazone of methandrostenolonw formed, which has orange-red color. Test on purity • Thepresenceofside steroids as contaminant (methyltestosterone) is establishedby TLC. • Seleniumadmixture (notmorethan0,01%)-themethodofcombustioninoxygenfollowedbyspectrophotometry.

  20. Assay of methandrostenolone UV-spectrophotometry. In tabletsmethandrostenolone is detected by photocolorimetric method by the interaction with conc. H2SO4 . Storage andapplication In tightly corked container, protected from moisture and light action. • Androgenic action is in100 times weaker then intestosterone propionate, anabolic activity– the same . • Applyat theproteinmetabolismdisorder, chronicadrenalinsufficiency, toxicgoitre, diabeticangiopathy, steroiddiabetes, chroniccoronaryinsufficiencyandmyocardialinfarction, rheumaticheartlesions, atheroscleroticcardiosclerosis, stomachulcersandduodenalulcers, osteoporosis, bonefractures, eczema, psoriasisandothers. • Producein the form of tablets by 1 and 5 mg.

  21. Phenobolin (Phenobolinum), Nerobolil, Durabolin, Nandronolone phenylpropionate* 17β-phenylpropioneoxy-19-norandrostene-4-one-3 or 19-nortestosteronephenylpropionate Characters.White, sometimes with a creamy tinct crystalline powder. Practically insoluble in water, slightly soluble in ethanol, freely soluble in chloroform and acetone.

  22. Identification ofphenobolin • Melting temperature (95-99 °С). • IR-spectroscopy. • TLC. Assay UV-spectrophotometry. Storage andapplication In tightly corked container, protected from light action. • Phenobolin –active anabolic mean with long action (7-15 days after single injection). Detects very weak androgenic effect, in women virilyzation phenomena almost not observed. Applied in those cases, as methandrostenolone, not used for the treatment of prostate cancer. • Enter by the i/m way in oil solution by 25-50 mg 1 time every 7-10 days. • Issue:by 1 ml of 1% and 2,5% solutions in oil.

  23. Retabolil (Retabolilum), Nandrolone 17β-decanoyloxy-19-noradrenostene-4-one-3 or 19-noradrenostenedecanoate Strong and long (3 weeks) anabolic effect. Low toxicity, androgenic effect is lover than in phenobolin.Enterby the i/m way by 25-50 mg 1 timeevery 2-3 weeks.Producein the form of 5 % oil solution inamp. by 1 ml.

  24. Femalesexhormonesandsyntheticsubstitutes • Femalesexhormonescalledestrogens (fromtheGreekword "estrus" - estrusand "Gennao" - birth). Thesehormonesareproducedinmaturingovarianfolliclesandparticipateintheimplementationofmenstruation. Theyarenecessaryfortheformation of female sexandfemalesecondarysexualcharacteristicsandfunctionsforhavingchildren. • Thenaturalestrogenisestradiolandestron. Amongthemestronis a medical drugandestradiolusedintheformof estersandotherderivatives, becouseestradiolitselfveryrapidlyinactivatesinthebody. • Asmedical drugsestrogens areusedinlowovarianfunction (primaryandsecondaryamenorrhea), underdevelopmentoftheuterus, sterility, post-castartiondisorders, surgicalremovalofovaries. Estrogensare usedtotreatparahormonecancerinmenandincreasedof laboractivity (causingcontractionoftheuterus). • Donotapplytowomenagedupto 60 yearsformalignantandbenigntumorsofthegenitalorgansandmammaryglands.

  25. Estrone Estradiol Earlier estrone (folliculine) and estradiol are obtained from the urine of pregnant women, then - from the urine of pregnant animals. Now them are obtained synthetically from cholesterol.

  26. Estrane Derivatives of estrane. Presence of the tree double bounds in the positions 1, 3, 5(10). Group –ОН (oxy-group) in position 3. Group –ОН (can be esterificated) oroxo-group (=О) in position17. Chemical signs of estrogens

  27. General identification reaction onestrogenic hormones • On steroid system: Boscot’s reaction and reaction with concentrated sulfate acid. • Estersof estrogenic hormones (estradioldipropionate): hydrolysis with the following identification of the products of hydrolysis; hydroxamic reaction. • Phenolic hydroxyl - reactions: а) electrophilic substitution (bromination, nitration, formation azo-dye, aurin stain); b) saltand complex formation with heavy metals salts (for example, FeCl3); c) Esters formation (for example, with benzoyl chloride), which have character melting temperature.

  28. Estrone (Oestronum) Folliculine 3-oxyestratriene-1,3,5(10)-one-17 Characters.White crystalline powder. Practically insoluble in water, soluble in ethanol and ether, easily soluble in chloroform.

  29. Identification of estrone • Boscot’s reaction – green fluorescence appears. • Estrone solution inconc. H2SO4 ). has golden-yellow colorwith intense green fluorescence (steroid cycle). • At the interaction withNH2OH*HCl oxime precipitate falls (with melting point 228-233ºС). • At the interaction with з diazoreagentformation of azo-dye is observed (reaction on phenolic hydroxyl). • At the action ofC6H5COCl phenolic hydroxyl esterificates and formed ester has melting temperature of 220ºС. Activity of estrone determined biologically (evocation of oestrus) in neutered female mice and rats. In 1 mg are 10000 UA.

  30. Assay of estrone • Polarimetry (solutionofthedrugindioxane). • Photocolorimetry (bythereactionofazo-dye formation). Storage and application In tightly corked container, protected from light action. • Enterby thei/m wayintheformofoilsolutionsat thelowovarianfunction (primaryandsecondaryamenorrhea), infertility, cancerandunderdevelopmentofsecondarysexualcharacteristics, overtermpregnancy, thesurgicalremovalofovaries. • Issue:amp. by 1 mlof 0,05% or 0,1 % oil solution.

  31. Estradioldipropionate * (Oestradioli dipropionas) 3,17-dipropioneoxyestratriene-1,3,5(10) Characters. White crystalline powder. Practically insoluble in water, very little soluble in ethanol and oils.

  32. Identification of estradioldipropionate • IR- andUV-Spactroscopy. • At the Boscot’s reaction green fluorescence appears. • At the heating with conc. H2SO4 there is a brown coloration, which by dilution with water and heated changes to pink. • On esteric groups conducted hydroxamic reaction (looktestosterone propionate). • At the hydrolysis by КОН in ethanol estradiol forms, which falls in the form of precipitate at the dilution with water and acidification by НСl. Melting temperature of estradoil is 177 ºС. • Propanoic acid, which formed after the acidic hydrolysis, can be identified by the reaction with ethanol - ester formed, which has a characteristic odor.

  33. Assay of estradoil dipropionate Alkalimetry, the reverse titration. Substance is hydrolyzed alcohol by the alcoholic solution of potassium hydroxide, an excess of which is titrated by hydrochloric acid solution by phenolphthalein, Ем = ½ М.m.

  34. Storage and application • In tightly corked container, protected from light action. • In two times more active than estrone, has a strong and prolonged effect, apply in those cases, as estrone. Enter by i/m way by 1 ml of 0,1% solution in oil every 1-2 days. • Estradiol is a part of the following preparations“Estramone” (transderm. plaster, 4 mg 20 cm2 №6); “Estrogel” (gel for the local usage 0,6 mg/g 80 g); “Estrimax” (tabl. 2 mg №28). • Complex preparations – “Pausogest” (estradiolhemihydrateand norethisteroneacetate); “Climodiene” (estardiol valerate anddienogest). • Estriol is a part of “Ovestine” (tabl., vag. cream, vag. suppos.).

  35. Ethinylestradiol (Aethinyloestradiolum) Ethynilestradiol* 17α-ethinylestratriene-1,3,5(10)-diol-3,17β Characters. White or creamy white fine crystaline powder, odorless. Practically insoluble in water, slightly soluble in alkali, soluble in alcohol, chloroform, soluble in acetone, ether and dioxane.

  36. Identification of ethinylestradiol • IR- andUV-spectroscopy, TLC • Todetectethynilgroupsubstanceis dissolvedinH2SO4, addFeNH4(SO4)2 solution–reddish-brown precipitate fallsafterthe dilutionwithwater pink-redsediment falls. • At the Boscot’s reactionorangefluorescence appears, in 50-100 timesstrongerthanestronefluorescence. • At the action of conc. H2SO4 orange-red colorforms with yellow-green fluorescence . • At the interaction with benzoyl chlorideethinylestradiol-3-benzoate formswith melting temperature of 199-202ºС (phenolic hydroxyl).

  37. Assay ofethinylestradiol • Alkalimetry by the substituent(lookpregnine). • Spectrophotometry or photocolorimetry by the formation of bis-diazocompound in alkaline medium at the interaction with diazoreagent : Ethinylestradiol is stored in tightly corked container in a dark place.

  38. Application of ethinylestradiol • Ethinylestradiol - one of the most active estrogenic agents. Introduction of ethinyl residue to the estradiol molecule increases stability and activity, that is why ethinylestradiol is taking internally. • Apply at the hypogenitalizm (primary amenorrhea, underdevelopment of the uterus), ovarian hypofunction and secondary amenorrhea by 0,05-0,1 mg; for elimination of neuro-vascular disorders of estrogenic insufficiency receiving by 0,01-0,02 mg per day; to treat cancer prostate and breast cancer in women over 60 years - to 3 mg per day over a long time. In the treatment of prostate cancer in men may be feminization. • Issue:tabl. by 0,01 and 0,05 mg under the “Microfolin” and “Esterlan”. • Is a part of oral contraceptive preparations.

  39. Synthetic steroidal structure estrogens • Substances that have estrogenic activity, were found not only among the steroid, but in some aromatic compounds. Admitting that the effect of estrogen depends on the presence of aromatic nuclei in the molecule. • Important role belongs to hydroxyl and keto-groupsgroups that can form hydrogen bonds and interact with proteins in the body. • For the detection of estrogenic action is importantthe distance between the functional groups. It is determined that the distance between the hydroxyl groups (in position 3 and 17) in estradiol is 1,1 nm, in meso-form of synestrol 1,2 nm, in the trans-isomerof diethylstilbestrol – 1,22 nm. At the same cis-isomerof diethylstilbestrol, in which the distance between the hydroxyls is 0,75 nm, is physiologically inactive. • The formation of ethers and esters do not reduce estrogen activity, but increases the period of action.

  40. Synestrol (Synoestrolum)Hexestrol Meso-3,4-di-(p-oxyphenyl)-hexane Characters. White crystalline powder, can have a yellowish tint, odorless. Practically insoluble in water, soluble in ethanol, chloroform, vegetable oils, alkali solutions. Estrogenic activity of synestrol is equal to estrone activity. Is used for the treatment of those diseases as estrone. Issue:tabl. by 1 mg; amp by 1 ml of 0,1% and 2% oil solutions.

  41. Diethylstilbestrol(Diaethylstilboestrolum) Trans-3,4-di-(p-oxyphenyl)-hexene-3 Characters. White crystalline powder, odorless. Practically insoluble in water, soluble in ethanol, ether, vegetable oils, alkali solutions. Two times more active than estrone, but due to the side effect it is used only for the treatment of breast cancer in women older than 60 years. Issue: amp. 3% oil solutions by 1 ml.

  42. Identification ofsynestrol anddiethylstilbestrol • At the interaction of synestrol chloroform solution with conc. H2SO4(In the presence of formalin) chloroform layer is painted in a cherry-red color (phenyl radicals). Diethylstilbestrol solution inconc. H2SO4 has the orange color, which gradually disappears after the dilution with water. • When you add bromine water solution to synestrol in conc. СН3СООН yellow precipitate forms. Diethylstilbestrol with bromine water in the presence of liquid phenol at the heating forms the emerald-green color, after adding of few pieces of sugar and heating coloration turns into dark blue, and cherry-brownish. • At the adding of to the synestrol chloroform layer FeCl3solution and pyridine –there is a blue coloration, which by the adding of pyridine in excess turns green. Alcohol solutions of diethylstilbestrol colored in green, which gradually turns into yellow (phenolic hydroxyl). • At the interaction of drugs with (СН3СО)2О or С6Н5СОСldiacetates (dibenzoates) form, which have characteristic temperature of melting.

  43. Assay ofsynestrol and diethylstilbestrol • Method of acylation.Basedonthe obtaining ofesters (diacetylderivatives) byheatingwithaceticanhydrideinthepresenceofpyridine. Excess of (СН3СО)2О is transformed to СН3СООН andtitrate acid byNaOH solution, indicator - phenolphthalein, Еm = ½ М.m. Inparallelcontrolexperimentis conducted:

  44. Assay of synestrol in oil solution is conducted solution after the extraction by aqueous solution of sodium hydroxide by the reverse bromatometry method with control experiment, Еm = 1/8 М.m.:

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