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Chapter 11Chapter 11 Hormones Hormones

（（ 11 ））Pei YuPei Yu

College of pharmacyCollege of pharmacy Jinan UniversityJinan University

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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.

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Adjustment of Hormone Secretion Hormone secretion is doubly adju

sted 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.

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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

Effects of Hormone

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Effects of Hormone

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Which is important?

Prostaglandins( 前列腺素 )

Peptide Hormones

Steroid Hormones

Natural hormones and their analogues

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1. Prostaglandins1. Prostaglandins (( 前列腺素前列腺素 , PG), PG)

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Basic chemical Structure

This acid contains 20 carbon atoms.

7 carbons and carboxyl group in the upside chain

8 carbons in the downside chain

5-m-alicyclic

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Structure and Naming of PGsStructure and Naming of PGsO

HO

OH

O

OH

O

HOOH

OH

O

HOOH

OH

O

HO

O O O

O

OH O

HO HO

OH

HO

OH

PGA PGB PGC PGD PGE PGF PGF

PGE1 PGE2 PGF2

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9

1215 20

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 PGF2 or PGE2. The steric structure of alicyclic C-9 is distinguished as α or β after the numbers.

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Prostaglandin (PGE1)

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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, PGE2 and 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.

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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 ).

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PGs类型 药物名称 化学结构 用途

PGE1 前列地尔

Alprostadil

O

HOOH

O

OH

扩张血管，抑制血小板血

栓素的合成。用于治疗心

绞痛、心肌梗死、脑梗塞

PGE1

类似物

米索前列醇

Misoprostol

O

HOO

O

OH

抑制胃酸分泌，保护胃粘

膜。用于消化道溃疡和妊

娠早期流产

PGE2 地诺前列酮

Dinoprostone

O

HO OH

OH

O

收缩子宫平滑肌，用于妊娠早期流产

PGF2 卡前列素

Carboprost O

OHHO

OH

HO

收缩子宫，用于抗早孕、

扩宫颈及中期引产

Drugs of PGs

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PGF2酯

卡前列素甲酯

Carboprost

Methlate

O

OHO

OH

HO

收缩子宫平滑肌，用于抗

早孕、扩宫颈及中期引产

PGE2

衍生物

吉美前列素

Gemeprost

O

HOOH

O

OH

强烈收缩子宫平滑肌，用

于抗早孕、扩宫颈及中期

引产

PGI2 前列环素

Prostacyclin

HO

O

H

OH

O

OH

具有抗血小板凝集作用和

扩张血管作用，对冠脉有

强力扩张作用，用于治疗

冠心病、心绞痛、心肌梗

塞

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Misoprostol Misoprostol ((米索前列醇米索前列醇 ))

Chemical name: (±)-(11α,13E)-11,16-dihyroxy-16-methyl-9-oxop

rost-13-en-1-oic acid methyl ester Pale yellow oil. Soluble in CH2Cl2, methanol, eth

anol , ethyl acetate. Insoluble in water.

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Stereochemistry of Stereochemistry of MisoprostolMisoprostol

Misoprostol is a racemic mixture (1:1), the isomer with 11R and 16S configuration is active.

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Structure ofStructure of MisoprostolMisoprostol

Misoprostol is PGE1 analogue.

C-15 hydroxyl is removed

to C-16, more stable.

C-16 methyl

PGE1

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Metabolism ofMetabolism of MisoprostolMisoprostol

O

HO

OH

O

O

HO

OH

O

OH

O

HO

OH

O

OH

O

HO

OH

O

Misoprostol

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Clinical use ofClinical use of MisoprostolMisoprostol Inhibit gastric acid secretion and pr

otect 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.

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2.2. Peptide HormonesPeptide Hormones (( 肽类肽类激素激素 ))

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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 hundreds of amino acids.

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Insulin Insulin (( 胰岛素胰岛素 ))

Insulin’s MW. 5807.69 Insulin molecule consists of chain A and B, with 21 and 30 amino acid residue, respectively. The chains are connected by two disulfide linkages, and an additional disulfide linkage within chain A.

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Chinese scientistsChinese scientists first synthesis of Insulin 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…”

Comment words in Science Communication 1966,Vol 17, 3.

Insulin was synthesized in lab in 1965.

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

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Synthesis of Insulin in the labSynthesis of Insulin in the lab

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Insulin is synthesized by islet Insulin is synthesized by islet ßß-cells-cells

Proinsulin

Insulin C-peptide

In vivo

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The differences between insulin in The differences between insulin in human and animalshuman and animals

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Clinical Application of InsulinClinical 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.

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Calcitonin Calcitonin (( 降钙素降钙素 ))

32-amino-acid polypeptide hormone. Entire 32-amino acid residue are required for activity. Has a slight alkalinity .

Cyclization by S-S bond

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Discovery of CalcitoninDiscovery 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 ).

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3.3. Steroid HormonesSteroid Hormones(( 甾体激素甾体激素 ))

Estradiol ( 雌二醇 )

Testosterone propionate ( 丙酸睾酮 )

Progesterone ( 黄体酮 )

Dexamethasone acetate ( 醋酸地塞米松 )

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Backbone of Structure

甾SteroidSteroid

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Steroid Hormone’s ClassificationSteroid Hormone’s Classification Function classify: Sexual hormone and Cortical hormone( 皮质激素 ) ；

18 18

19

18

19

20 21

12

3

45

67

810

1112

13

14 15

1617

A B

C D

çÞÍé ´ÆçÞÍé ÐÛçÞÍé ÔÐçÞÍé

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Structure classify:Estranes( 雌甾烷 ), Androstanes( 雄甾烷 )and Pregnanes( 孕甾烷 )

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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 20mg ald

osterone( 醛甾酮 ).

In 1946, starting from bile acid( 胆汁酸 )(575kg) through 30

synthetic steps only can get 938mg Cortelan( 可的松 ), So its

price reached ＄ 12,000,000/kg .

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Configuration of Steroid

HO

H

R

H

OH

R

HO

H

R

trans-trans-trans cis-trans-trans cis-trans-cis

The configuration of steroid hormones introduced in this chapter are all trans-trans-trans.

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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 .

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Estradiol Estradiol (( 雌二醇雌二醇 ))

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

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Structural Analysis Estrane is the backbone of Estradiol; The ring A is an aromatic ring, there is no methyl at C-10 p

osition ; 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 .

3

1710A

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BiosynthesisBiosynthesis Estradiol is produced from Testosterone ( 睾酮 ), w

hose ring A is aromatized by Aromatase ( 芳香酶 , a kind of Cytochrome-P450’s Complex enzyme).

OH

HO

OH

O

HOOH

O

aromatase

EstradiolTestosterone

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Metabolism

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

H+B- = H+HSO4- or -CH(CH2OH)4COOH

OH

+ H+B-

OH

HO

O(B)

BO

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The Activity of Natural EstrogenThe Activity of Natural Estrogen Estradiol > Estrone > Estriol Ratio of activity is 1 ： 0.3 ： 0.1 Under the action of enzyme, three estrogens can tra

nsform to each other.

雌二醇脱氢酶

16-ôÇ» ø 16-ôÇ» ø

雌二醇脱氢酶

OH

HO HHO

O

HO

O

OH

OH

HO

OH

Estriol

Estradiol Estrone

Estrogen dehydrogenase

Estrogen dehydrogenase

16α-hydroxylase 16α-hydroxylase

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Structural ModificationStructural Modification

KOH,HC CH

OH

HOHO

O

OH

O

ÒÒȲ´Æ¶þ ¼Ethinylestradiol

Ȳ´ÆÃÑQuinestrol

OH

O

OH

Äá¶û ƼNilestriol

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

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OH

HO

OCOC5H11

C5H11COO

OCOC5H11

HO

OH

KO

OH

O

O

±½¼×Ëá ƶþ ¼Estradiol Bengoate

Îì Ëá ƶþ ¼Estradiol Valerate

Structural ModificationStructural Modification

Estradiol

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SynthesisSynthesis of Estradiolof Estradiol

O

O O

OH

O

O

O

O

HO

OO

KBH4

OH

HO

Estrone Estradiol

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Effects ofEffects of EstradiolEstradiol

Female reproduction

Sexual development

Male reproduction

Bone

Liver

Brain

Blood vessels

Oncogene ( 致癌基因 )

Pregnancy

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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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3.2 Non-Steroidal Estrogen &3.2 Non-Steroidal Estrogen & Selective Estrogen Receptor Modulator Selective Estrogen Receptor Modulator

Non-Steroidal estrogen are mainly

biphenylethylene compounds.SERMs compounds mainly

triphenylethylene compounds.

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　　 Diethylstilbestrol Diethylstilbestrol (( 己烯雌酚己烯雌酚 ))

Chemical name : （ E)-4, 4’-(1, 2-Diethyl-1, 2-ethenediyl)bisphenol Non-Steroidal Estrogen

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Construction features of DiethylstilbestrolDiethylstilbestrol

Trans-diethylstilbestrol is effective, the cis -configuration is ineffective .

Symmetric structure. It presents color reaction with FeCl3 due to the t

wo phenolic hydroxyl groups.

Trans cis

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Non-Steroid EstrogensNon-Steroid Estrogens

OH

HO

OH

HO

O

OOH

HO O

OH

HO

O

O

OH

HO

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MER-25 ÂÈÃ×·ÒClomif en

ËûĪÎô ·ÒTamoxifen

ON

Cl

ON

O

H

O

N

1958, MER-25 was discovered as anti-estrogen.

Clomifen was a pioneer’s product by less side effect .

Tamoxifen was produced later.

SSelective elective EEstrogen strogen RReceptor eceptor MModulatorodulator

Triphenylethylene structure

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Clomifen Citrate Clomifen Citrate (( 枸橼酸氯米芬枸橼酸氯米芬 ))

Selective affinity for ovary estrogen receptor. Promote ovulation( 排卵 ), has 20~80% success ratio to trea

t sterility( 不孕 ).

Low affinity with lacteal gland( 乳腺 ) estrogen receptor.

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Tamoxifen CitrateTamoxifen Citrate(( 枸橼酸他莫昔芬枸橼酸他莫昔芬 ))

Chemical name: (Z)-2-[4-(1, 2-diphenyl-1-butenyl)-phenoxy]-N, N-

dimethyl ethanamine citrate. Dimethylamino-ethoxyphenyl group exists in ma

ny drugs’ structure.

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SAR of TamoxifenSAR of Tamoxifen

ON

È¥µôÒ»ö-CH3¡¢Á½ö-CH3»òÓÃ-OHÖû»-N(CH3)2£¬»òÊÇÈ¥µôÕûö²àÁ´£¬¶¼»á½µµÍ ÓëÊÜÌå µÄÇ×ºÍ Á¦

Á½ö-OHÈ¡ ú£¬ÔöÇ¿ÓëÊÜÌåÇ×ºÍ Á¦

-OHÈ¡ ú£¬ÔöÇ¿ÓëÊÜÌåÇ׺ÍÁ¦£¬Èô³É¼×õ¥£¬½µµÍÇ×ºÍ Á¦

-CH3£¬F£¬ClÈ¡´ú£¬²»»á Ó¸ù±¾ÉϸıäÓëÊÜÌå Ç×ºÍ Á¦

-CH3ͬ ʱȡ´ú£¬Ç×ºÍ Á¦Ï½µ

Two hydroxyl groups can increase the affinity (to acceptor )

methyl , fluorine or chlorine groups will not change the affinity.

Hydroxyl can increase the affinity, while its methyl ester has lower affinity

The affiniy will die down if one or two methyl groups or the whole side-chain cut off, or dimethylamino replaced by hydroxyl.

Replaced by methyls simultaneously will cut down the affinity.

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RoloxifenRoloxifen(( 雷洛昔酚）雷洛昔酚）

Roloxifen is antagonism( 拮抗 ) to ovarian and breast estrogen receptor.

Roloxifen is used to treat osteoporosis( 骨质疏松症 ).

S

O

HO

OH

ON

雷洛昔芬Roloxif en

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Selectivity of Antioestrogens’ Target Organ

Antioestrogens Target organs Indication

Clomifen sex organ Sterility( 不孕 )

Tamoxifen lacteal gland Breast cancer ( 乳癌 )

Roloxifen skeleton Osteoporosis ( 骨质疏松 )

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