Chapter 2 - Steroids PDF

PHM 2110- Medicinal Chemistry 1 Steroids Content        Steroids ✓ A steroid is an organic compound with four rings arranged in a specific molecular configuration. Cyclopentano...

PHM 2110- Medicinal Chemistry 1 Steroids Content        Steroids ✓ A steroid is an organic compound with four rings arranged in a specific molecular configuration. Cyclopentano phenanthrene ✓ Three six-member cyclohexane rings (rings A , B and C ) and one five-member cyclopentane ring ( D ring). ✓ Steroids are characterized by the presence of 1,2 - cyclopentanophenanthrene nucleus in their structure  Numbering of Steroids ✓ The steroid core structure is composed of seventeen carbon atoms(17), bonded in four "fused" rings. ✓ Steroids vary by the functional groups attached to this four- ring core and by the oxidation state of the rings.  Numbering of Steroids Angular methyl groups- to attach the chain length  Nomenclature of Steroids ✓ Designated by trivial names ✓ In the 1950s, nomenclature rules for steroids were being developed, and the most recent IUPACIUB Joint Commission rules for systematic steroid nomenclature were published in 1989 Methyl group is usually found at C-10 and C-13. An alkyl group may be found at C-17 Sterols carries a hydroxyl group at C-3  Numbering of Steroids Side chain at 17th position  Properties of Steroids ✓ They have relatively flat and rigid molecular framework. ✓ They have high crystalline properties. ✓ Enormous number of derivatives have been produced. ✓ They are both hydrophilic and lipophilic. ✓ They contain no fatty acids ✓ Cholesterol is the best known steroid, occurs exclusively in animals.  Properties of Steroids Hydrocarbon nucleus Hydrophilic group Hydrocarbon tail  SAR of Steroids ✓ Aromatic ring with c-3 OH is essential for activity ✓ The 17B-hydroxyl with constant distance from 3-OH is essential for activity ✓ Unsaturation of ring B decreases the activity ✓ 16 and 17 position when modified enhances the activity  Nomenclature of Steroids Almost all steroids are named as derivatives of any one of the following basic steroidal ring. Steroidal ring Number of Carbon Structure (α or β) gonane 17  Nomenclature of Steroids Steroidal ring Number of Carbon Structure (α or β) Estrane 18 Example estrogens (estradiol, estrone, estriol)  Nomenclature of Steroids Steroidal ring Number of Carbon Structure (α or β) 19 androstane Example Androgens; Testosterone  Nomenclature of Steroids Steroidal ring Number of Structure Carbon (α or β) Pregnane 21 Progesterone Corticosteroids  Nomenclature of Steroids Steroidal ring Number of Carbon Structure (α or β) Cholane 24 Example Bile acids  Nomenclature of Steroids Steroidal ring Number of Structure Carbon (α or β) 27 cholestane Example Cholesterol Gonane- C17 Estrane- C18 Estrogens 1.) ESTRONE Estrane- C18 Estrogens 2.) ESTRADIOL Estrane- C18 Estrogens 3.) ESTRIOL  Androstane-C19 Name: Androst-4- en- 17β- ol- 3-one Testosterone  Pregnane-C21 Name: Progest-4-en-3,20-dione Progesterone  Pregnane-C21 OH Name: 17α,21-dihydroxypregn-4-en-3,11,20- trione Cortisone  Cholane-C24 Name: 3,7,12- Trihydroxy cholan- 24- oic acid Bile acid-cholic acid Cholestane-C27 Name: Choles- 5- en- 3β- ol Cholesterol  Configuration of Steroids β Configuration Substituent attached to the ring system from above are designated as β. Lines are thickened  Configuration of Steroids α configuration Substituent attached to the ring system from below are designated as α. Lines are brokened or dotted  Configuration of Steroids Unknown configuration If the configuration of the substituent is not known its bond to the nucleus is represented by a wavy line Configuration of Steroids 2 1 3  Stereochemistry of Steroids The stereo chemistry of the rings markedly affects biological activity of a given class of steroids There are six asymmetric carbon atoms 5,8,9,10,13,14 in the nucleus. Therefore 64 optically active forms are possible.  Stereochemistry of Steroids It can exist in two conformations namely chair form and boat form. Chair conformation is more stable than boat conformation due to less angle strain. Hence all cyclohexane rings exist in chair form  Stereochemistry of Steroids The absolute stereochemistry of the molecule and any substituents is shown with solid bond (β-configuration) and dotted bond (α-configuration). The aliphatic side chain at C-17 position is always assumed to be β- configuration. The term cis and trans are sometimes used to indicate the backbone stereochemistry between the rings. A/B FUSION Fusion of rings A and B may either trans or cis to give 2 isomeric C27hydrocarbon  Classification of Steroids Sterols: ✓ Also known as steroid alcohols ✓ Occur naturally in plants, animals, and fungi, ✓ Most familiar type of animal sterol is cholesterol TYPES: ✓ Phytosterols – plant sterol ( campesterol, sitosterol, and stigmasterol) ✓ These block cholesterol absorption sites in the human intestine, (reduce cholesterol in humans) ✓ Zoosterol – animal sterol (cholesterol) ✓ Ergosterol – cell membrane of fungi Camptosterol Sitosterol Stigmasterol Cholesterol Ergosterol  Classification of Steroids ✓ Cholesterol is the most abundant steroid in animals. ✓ It’s a major component of cell membranes, and affects the fluidity of the membrane due to its bulky structure. ✓ Is a precursor for biosynthesis of many other steroids. ✓ The liver synthesizes more cholesterol when dietary intake is low. ✓ Excessive blood cholesterol is associated with atherosclerosis and formation of gallstones  Classification of Steroids BILE ACIDS ✓ Are steroid acids found predominantly in the bile of mammals and other vertebrates ✓ Are conjugated with taurine or glycine in the liver, forming bile salts ✓ Primary bile acids are those synthesized by the liver ✓ Secondary bile acids result from bacterial actions in the colon Functions: ✓ Promote emulsification, digestion and absorption of fats  Formation of Bile Acids The primary bile acids are Cholic acid and Chenodeoxycholic acid that are synthesized in the liver from cholesterol. The primary bile acids are conjugate with glycine and taurine to form: ✓ Glycocholic acid ✓ Taurocholic acid ✓ Glycochenodeoxycholic acid ✓ Taurochenodeoxycholic acid The conjugated bile salts are synthesized in liver and accumulated in the gall bladder, where they are secreted into the small intestine and serve as an emulsifying agent for digestion and absorption of fat. Enterohepatic circulation- bile salts are reabsorbed and returned to the liver via portal vein. The fecal excretion of bile salts is the only route for the excretion of cholesterol from the Formation of Bile Acids Bile acid synthesis  Classification of Steroids CARDIAC GLYCOSIDE Consist of mostly C23-steroidal compounds; called cardiac glycosides because they modify heart actions. MEDICINAL IMPORTANCE: They are cardiotonics used to treat congestive heart failure (CHF) and atrial fibrillation ✓ They increase force of contraction of cardiac muscles without increase oxygen consumption ✓ Increase cardiac output ✓ The diastolic phase last longer so decrease heart rate ✓ Have diuretic effect due to increase amount of blood passing through the kidney  Classification of Steroids ✓ Digitalis glycosides: digoxin, digitoxin, gitoxin ✓ The cardiac glycosides occur mainly in plants from which the names have been derived: ✓ Digitalis purpurea, ✓ Digitalis lanata, ✓ Strophanthus kombe are the major sources of the cardiac glycosides. STRUCTURE: These are composed of two structural features : ✓ sugar (glycone) moiety - 3 to 4 sugars attached at C-3 OH. These sugars predominantly exist in the cardiac glycosides in the β-conformation ✓ the non-sugar (aglycone - steroid) moieties The R group at the 17-position defines the class of cardiac glycoside. Structure of Cardiac Glycosides  Classification of Steroids STEROID HORMONES ✓ A steroid that acts as a hormone ✓ Can be grouped into five groups by the receptors to which they bind: Mineralocorticoids Corticosteroids Glucocorticoids Steroid hormones Androgens Progestogens Estrogens Sex hormones Cholesterol to Steroids  Glucocorticoids Originate in the adrenal cortex and affect mainly metabolism by: ✓ decrease inflammation ✓ increase resistance to stress. Cortisol: dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex. Involved in stress adaptation, elevates blood pressure and Na+ uptake. Glucocorticoids  Mineralocorticoids ✓ Originate in adrenal cortex and maintain salt and water balance. ✓ Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake. Mineralocorticoids  ADRENAL HORMONES Glucocorticoids Mineralocorticoids Anti-inflammatory Na+ reabsorption Immunosupression Glucocorticoids in the body- Natural C21 pregnane nucleus 4-3-keto 17th- COOH 17th- α-OH 11th- keto CORTISONE  Glucocorticoids in the body C21 pregnane nucleus 4-3-keto 17th- COOH 17th- α-OH 11th- OH Ketone Reduced to Hydroxyl group When ketone is reduced to hydroxyl group the HYRDOCORTISONE glucocorticoid activity increases Therefore: hydrocortisone is more active than cortisone ✓ For a steroid to show anti-inflammatory activity the ketone group at C-11 must be converted to hydroxyl group. ✓ In the body cortisone is converted to hydrocortisone which has anti- inflammatory activities ✓ Cortisone and hydrocortisone has both glucocorticoid activity and small mineralocorticoid activity ✓ However modifications must be made to synthesize products with mainly glucocorticoid activity Structural changes for synthetic derivatives 21 17 1 16 2 9 These modifications will either 6 alter the glucocorticoid or mineralocorticoid activity of the drug  Mod: Introduction of double bond ✓The shape of the ring will be changed ✓Glucocorticoid activity of 1 the drug will increase 2 ✓Potency will be increased Introduction of double bond Cortisone Prednisone Which of the following has greater glucocorticoid activity?  Introduction of double bond Hydrocortisone Prednisolone  Activity Prednisone Prednisolone Which of the following is considered more active? Which of the following is considered a prodrug? Mod: 6 -methyl α group ✓Glucocorticoid activity of the drug will increase ✓Potency will be increased Methylprednisolone CH3 Mod: R group at 9 th position R group: Halogen (F, Cl) – will increase mineralocorticoid and glucocorticoid activity The OH group can be oxidized to ketone, however the halogen group prevents this conversion; glucocorticoid activity is retained Mod: R group at 9 th position ✓ Has increased mineralocorticoid activity- 400 times ✓ Has increased glucocorticoid activity ✓ Treatment of Addison’s disease Fludrocortisone Mod- 16 th position R group: ✓ 16α or β CH3 ✓ 16 α OH ▪ Will decrease mineralocorticoid activity ▪ Will retain glucocorticoid activity  Mod- 16 th position BETAMETHASONE DEXAMETHASONE Mod- 16 th position BECLOMETHASONE Mod- 16 th position TRIAMCINOLONE Mod- 16, 17 Ketal ✓ Increased anti- 17 inflammatory activity 16 Mod- 16, 17 Ketal CICLESONIDE Mod- 16, 17 Ketal Budesonide Mod- 21st position 21 OH- Increase mineralocorticoid activity OR- in ester form the drug has more glucocorticoid activity and less mineralocorticoid activity  Estrogens ✓ Estrogens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs. ✓ The natural estrogenic hormones are estradiol, estrone, and estriol, produced in the gonads, adrenals, and placenta ✓ Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics  Androgens ✓ Androgens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (male) ✓ Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics  Progestins Progestins originate from both ovaries and placenta, and mediate menstrual cycle and maintain pregnancy Progesterone: a progestogen, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteal phase of the menstrual cycle.  Summary Steroids R Chain Sterols R is an aliphatic side chain. They contain usually one or more hydroxyl groups(-OH) attached in alicyclic linkage Cardiac glycosides R is a lactone ring. The gylcosides also contains sugars linked through oxygen in other parts of the molecule. Bile acids R is essentially a five-carbon side chain ending with a carboxylic acid moiety Sex hormones R bears a ketonic (C=O) or hydroxyl group(- OH) and mostly possess a two carbon side chain