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Chapter 11 Hormones （ 1 ）

Chapter 11 Hormones （ 1 ）. Pei Yu College of pharmacy Jinan University. Hormones. Natural Hormones are endogenous （内源的） active compounds in human. Hormone drugs are mainly used to heal the diseases which are caused by endocrine （内分泌） disturbance.

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Chapter 11 Hormones （ 1 ）

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  1. Chapter 11 Hormones（1） Pei Yu College of pharmacy Jinan University

  2. Hormones • Natural Hormones are endogenous（内源的）active compounds in human. • Hormone drugs are mainly used to heal the diseases which are caused by endocrine（内分泌）disturbance. • “Hormone” is a kind of chemical messenger secreted by endocrine epithelia（内分泌腺上皮细胞), which enters into blood or lymph fluid（淋巴液）and reach special locations or target organs in vivo.

  3. Adjustment of Hormone Secretion • Hormone secretion is doubly adjusted by nerves-endocrine system（神经-内分泌双系统). Hypothalamus（下丘脑）secrete hormones promoting trophic hormone (促激素释放激素). Anterior pituitary(腺垂体) secrete “trophic hormone(促激素)” Target organ accept hormone. • Adjusted by the long and short feedback(反馈) mechanisms.

  4. Effects of Hormone One hormone may regulate the production and release of other hormones. Many of the responses to hormone signals can be described as regulating metabolic activity of an organ or tissue. • Stimulation or inhibition of growth • In puberty(青春期)hormones can affect mood and mind • Induction or suppression of apoptosis (programmed cell death) • Activation or inhibition of the immune system • Regulating metabolism • Preparation for a new activity (e.g. fighting, fleeing, mating) • Preparation for a new phase of life (e.g. puberty, menopause) • Controlling the reproductive cycle

  5. Effects of Hormone

  6. Which is important? • Prostaglandins(前列腺素) • Peptide Hormones • Steroid Hormones • Natural hormones and their analogues

  7. 1. Prostaglandins(前列腺素, PG)

  8. Basic chemical Structure 7 carbons and carboxyl group in the upside chain 5-m-alicyclic 8 carbons in the downside chain This acid contains 20 carbon atoms.

  9. Structure and Naming of PGs • Naming PGA, PGB…PGF and so on by different substituting groups（hydroxyl or oxygen atom) of 5-member ring on PG structure. • The number of double bonds in the side chain is labeled as E or F ’s footnote, such as PGF2or PGE2. • The steric structure of alicyclic C-9 is distinguished as α or β after the numbers.

  10. Prostaglandin (PGE1)

  11. Pharmacological Action • PGE, PGF and their derivates could make strong uterine contraction（子宫收缩）for women. -used as pregnancy terminate and oxytocin(催产素). • PGE1, PGE2and PGA can inhibit the secretion of gastric juice, protect gastric parietal cells (胃壁细胞). -used to cure gastric ulcer(胃溃疡), hemorrhagic(出血的)gastritis(胃炎)and enteritis(肠炎). • PGI2 has several activities to platelet function. -to develop antithrombotic(抗凝血的)agents.

  12. In research of biosynthesis of arachidonic acid (AA, 花生四烯酸) and metabolism of PG derivates, the relationship between PG and inflammation is discovered. • Thromboxane(血栓素)A2 can promote platelet aggregate to form thrombus(血栓). • This discovery can explain the mechanism of non-steroidal anti-inflammatory drug, and use Aspirin to prevent thrombogenesis(血栓形成).

  13. Drugs of PGs

  14. Misoprostol (米索前列醇) • Chemical name: (±)-(11α,13E)-11,16-dihyroxy-16-methyl-9-oxoprost-13-en-1-oic acid methyl ester • Pale yellow oil. Soluble in CH2Cl2, methanol, ethanol , ethyl acetate. Insoluble in water.

  15. Stereochemistry of Misoprostol • Misoprostol is a racemic mixture (1:1), the isomer with 11R and 16S configuration isactive.

  16. Structure ofMisoprostol Misoprostol is PGE1 analogue. C-15 hydroxyl is removed to C-16, more stable. PGE1 C-16 methyl

  17. Metabolism ofMisoprostol

  18. Clinical use ofMisoprostol • Inhibit gastric acid secretion and protect gastric mucosa(胃粘膜). • Treat gastric ulcer(胃溃疡)and early abortion. • Combined with NSAID diclofenac in an analgesic product that is potentially safe for long-term antiarthritic(抗关节炎)therapy.

  19. Peptide Hormones(肽类激素)

  20. Peptide hormones • Formed by amino acids with peptide bonds. • Minimal peptide hormone contains 3 amino acids, as Thyrotropin-Releasing Hormone（TRH，促甲状腺激素释放激素). • Most peptide hormones contain ten to hundredsof amino acids.

  21. Insulin (胰岛素) • Insulin’s MW. 5807.69 • Insulin molecule consists of chain A and B, with 21and30amino acid residue, respectively. • The chains are connected by two disulfide linkages, and an additional disulfide linkage within chain A.

  22. Chinese scientists first synthesis of Insulin “The first protein which is synthesized artificially was born in the PRC… Our scientists get an international championship in the aspect of theory research … It symboled the time of synthesize protein artificially beginning…” Insulin was synthesized in lab in 1965. Comment words in Science Communication 1966,Vol 17, 3.

  23. Prof. Xing qiyi (Middle), Zhang Pang (right) and French Scientist Prof. Julia in 1993

  24. Synthesis of Insulin in the lab

  25. Insulin is synthesized by islet ß-cells Proinsulin Insulin C-peptide In vivo

  26. The differences between insulin in human and animals

  27. Clinical Application of Insulin • Insulin injection, USP, is made from Zinc insulin crystals. • Insulin can regulate glucose metabolism in vivo，it is an effective drug to treat diabetes. • Combined preparation of insulin and other drugs such as Adenosine(阿糖腺苷)Triphosphate Coenzyme is used to treat consumptive disease(虚劳). • Pork insulin is mostly used in clinic.

  28. Calcitonin (降钙素) Cyclization by S-S bond • 32-amino-acid polypeptide hormone. • Entire 32-amino acid residue are required for activity. • Has a slight alkalinity .

  29. Discovery of Calcitonin • It is secreted by parafollicular cell (滤泡旁细胞, C-cell) of the thyroid glands (甲状腺) in response to hypercalcemia (高钙血症). • Human calcitonin was separated in 1967, salmon calcitonin was separated in 1968. One year later, both of them were synthesized successfully . • Calcitonin mainly used in hypercalcemia(高钙血症)and osteoporosis(骨质疏松症).

  30. Steroid Hormones(甾体激素) • Estradiol (雌二醇) • Testosterone propionate(丙酸睾酮) • Progesterone(黄体酮) • Dexamethasone acetate(醋酸地塞米松)

  31. Backbone of Structure 甾 Steroid

  32. Steroid Hormone’s Classification Function classify: Sexual hormone and Cortical hormone(皮质激素)； Structure classify: Estranes(雌甾烷),Androstanes(雄甾烷)and Pregnanes(孕甾烷)

  33. Production in early period • Deal with 15,000 liters urine, only 15 mg androsterone(雄甾酮) was provided. • 20mg flavolutan(黄体酮)from 20,000 sow ovaries(母猪卵巢). • 500kg calf adrenal glands(小牛肾上腺) can provide 20mgaldosterone(醛甾酮). • In 1946, starting from bile acid(胆汁酸)(575kg) through 30 synthetic steps only can get 938mgCortelan(可的松), So its price reached ＄12,000,000/kg .

  34. Configuration of Steroid trans-trans-transcis-trans-transcis-trans-cis The configuration of steroid hormones introduced in this chapter are all trans-trans-trans.

  35. 3.1 Steroid Estrogen(雌激素) Natural Estrogens : Estradiol (雌二醇), Estrone (雌酮) and Estriol (雌三醇). Estrogens Classify: Steroid estrogen and Non-steroid estrogen .

  36. Estradiol (雌二醇) • Chemical name：Estra-1, 3, 5 (10) triene-3, 17 - diol • Systematic (IUPAC) name： (8R,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17 decahydro cyclopenta[a]phenanthrene-3,17-diol

  37. Structural Analysis • Estrane is the backbone of Estradiol; • The ring A is an aromatic ring, there is no methyl at C-10 position ; • Hydroxyl group at C-3 (with slight acidity) and hydroxyl group at C-17 are in the same plane, keeping their distance of 0.855nm . 17 10 A 3

  38. Biosynthesis • Estradiol is produced from Testosterone (睾酮), whose ring A is aromatized by Aromatase (芳香酶, a kind of Cytochrome-P450’s Complex enzyme). Estradiol Testosterone aromatase

  39. Metabolism • Estradiol is conjugated with sulfate or glucuronide and becomes water soluble, excreted via the kidney.

  40. The Activity of Natural Estrogen • Estradiol > Estrone > Estriol • Ratio of activity is 1：0.3：0.1 • Under the action of enzyme, three estrogens can transform to each other. Estrogen dehydrogenase 16α-hydroxylase 16α-hydroxylase Estrogen dehydrogenase

  41. Structural Modification In order to use conveniently (oral, prolong action... )

  42. Structural Modification Estradiol

  43. Synthesisof Estradiol Estrone Estradiol

  44. Effects ofEstradiol • Female reproduction • Sexual development • Male reproduction • Bone • Liver • Brain • Blood vessels • Oncogene (致癌基因) • Pregnancy

  45. Estradiol Medications • The following are marketed versions of estradiol: • Oral versions: Estrace, Progynova, Estrofem… • Transdermal preparation: Alora, Climara, Vivelle… • Ointments: Estrasorb Topical, Estrogel, Elestrin… • Injection: Lunelle monthly injection, Estradiol valerate... • Vaginal ointment: Estrace Vaginal Cream… • Vaginal ring: Estring (estradiol acetate), Femring…

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