CASE STUDY 6 Steroidal Anti-Inflammatory Agents
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■ CASE STUDY 6 Steroidal anti-infl ammatory agents CS6.1 Introduction to steroids Steroids are hydrophobic compounds owing to their extensive hydrocarbon skeleton. Th is is an important Steroids are important endogenous hormones found in characteristic as the hormonal steroids have to cross cell many life forms. Th ey all share a common tetracyclic membranes in order to interact with intracellular steroid structure, as shown in Figure CS6.1, but they vary in receptors (see section 4.9 and Box 8.2). All of the impor- the substituents and functional groups that are present. tant endogenous steroids have polar functional groups, Th e stereochemistry of the rings in fully saturated ster- such as alcohols, phenols, and ketones. Th ese play a cru- oids is identical in mammalian steroids, where the three cial role in the binding of steroids to their target recep- 6-membered rings have chair conformations. Th ere are tors, but their presence does not alter the hydrophobic several asymmetric centres present, but only one stereo- nature of the molecule as a whole. Because most steroids isomer occurs naturally for any particular steroid. For are hormones, they are present in very small quantities example, cortisol has seven asymmetric centres, but only in the body (less than 1 mg). Th e exception is cholesterol, the stereoisomer shown in Figure CS6.1 exists naturally. which is present in much larger quantities (250 g) and Some of the terminology used in the nomenclature of has a number of non-hormonal roles (Case study 1). steroids is worth explaining at this point. Substituents In this case study, we will be concentrating on those are oft en described as being alpha (α) or beta (β). steroids released from the adrenal cortex of the adrenal α-Substituents are below the general ‘plane’ of the steroid, gland—the adrenocorticoids . Th ere are two types of as represented in Figure CS6.1, and are represented by adrenocorticoids—the glucocorticoids and the miner- hatched wedges in two-dimensional diagrams, whereas alocorticoids . Th e former act on carbohydrate, fat, and β-substituents are above the plane and are represented by protein metabolism, mainly in the liver, muscles, and brain solid wedges. For example, in cortisol, the axial methyl cells. Th ey also have an important anti-infl ammatory groups (C18 and C19) are β-substituents, whereas the eff ect which is separate from their metabolic eff ects. Th e axial hydrogens at positions 9 and 14 are in the a position. mineralocorticoids regulate electrolyte balance through Th e position of double bonds in steroids is usually sodium ion retention in kidney cells. Th e major endog- identifi ed by the symbol delta (Δ). For example, Δ 4 signi- enous glucocorticoids are corticosterone , cortisone , and fi es the double bond between C4 and C5 in cortisol. If cortisol (also known as hydrocortisone ) (Figs CS6.1 and there is any ambiguity, then the numbers of both carbons CS6.2). Aldosterone is the major endogenous mineralo- are indicated. For example, cholesterol has a double bond corticoid. An imbalance of these steroids can lead to cer- between C5 and C6, rather than C5 and C10, so this is tain diseases. For example, an excess of glucocorticoids indicated as ΔC 5(6) . causes Cushing’s syndrome , whereas a defi cit results in (a) (b) OH 21 12 17 Me 18 O 11 13 H 20 H Me H H H Me D 16 H HO OH 1 C H H H * * 10 = H H 11 * 17 2 9 14 H 19Me H 8 15 H A B H H H H H * * 3 7 H H H 10 * * 5 H H 4 6 Axial bonds are in grey O 3 5 equatorial bonds are in blue 4 6 Cortisol (Hydrocortisone) FIGURE CS6.1 ( a ) General tetracyclic structure of a steroid with numbering; ( b ) structure of cortisol (asymmetric centres indicated by stars). See also molecular modelling Exercises CS6.1 and CS6.2 . Patrick97397.indb 689 11/28/2012 9:20:54 PM 690 Case Study 6 Steroidal anti-infl ammatory agents OH OH OH O O O CHO Me Me Me HO O OH HO 11 11 17 11 Me Me H Me Me H HH H H 3 O O O Pregnane skeleton (C21) Corticosterone Cortisone Aldosterone FIGURE CS6.2 Adrenocorticoids. Addison’s disease . An excess of mineralocorticoids leads cortisol. A large number of analogues have been synthe- to Conn’s syndrome . sized which have identifi ed the features of cortisol that Th e glucocorticoids have an important clinical role in are important for corticosteroid activity. In essence, all replacement therapy for Addison’s disease, and have also the functional groups are important, and the removal of been used as anti-infl ammatories and immunosuppres- any of these groups either reduces or eliminates activity. sants in the treatment of a number of conditions, such However, further studies have shown that the intro- as asthma, hypersensitivity, rheumatoid arthritis, cancer, duction of extra substituents can increase activity, which and diseases which have an autoimmune or infl amma- allows the removal of one of the original functional groups. tory eff ect. Th e adrenocorticoids are examples of steroids Introducing a 9α-fl uoro substituent to give fl udro- having a pregnane skeleton—steroids having a two- cortisone increased activity 10-fold, but it also increased carbon side chain at position 17 of the tetracyclic steroid mineralocorticoid activity 300–600 times. In contrast, the skeleton (Fig. CS6.2). introduction of an extra double bond at the Δ 1 position One of the most important applications of gluco- increased activity fourfold without increasing mineralo- corticoids in medicine is as anti-infl ammatory agents. corticoid activity—see prednisolone and prednisone Unfortunately, the endogenous glucocorticoids suf- (Fig. CS6.3). Introducing substituents such as methyl fer from the fact that they have mineralocorticoid and or fl uorine at the 6α-position has also been found to be immunosuppressant eff ects, which can cause oedema and benefi cial because these groups serve to block metabo- increased susceptibility to infection. Moreover, the endog- lism at that position. For example, methylprednisolone enous glucocorticoids aff ect a large number of enzymes has a 6α-methyl group. in diff erent cell types in order to control metabolism. A methyl group was introduced at C-16 to see whether Th is means that they have a large number of undesired it would block the metabolic reduction of the C-20 keto side eff ects if they are taken as drugs to control infl am- group of hydrocortisone analogues—a reaction that is mation. Consequently, glucocorticoids are best used as known to lead to inactive metabolites. Th ere is no evi- topical anti-infl ammatory agents. A lot of research has dence that such protection actually occurs and there is gone into designing glucocorticoids that act locally at the no obvious increase in glucocorticoid activity, but the site of administration and are metabolized rapidly in the presence of the methyl group does suppress the miner- blood supply such that they cannot act on other targets. alocorticoid properties of sodium and water retention. It Having said that, there are some glucocorticoids which is thought that the 16-methyl substituent blocks the abil- can be administered orally and which have been designed ity of these analogues to bind to the mineralocorticoid to have fewer side eff ects. receptor. Further research revealed that the introduction of C-16 substituents, such as a methyl or hydroxyl group, counteracted the mineralocorticoid eff ect of a 9-fl uoro CS6.2 Orally active analogues substituent. Th is resulted in the development of triamci- nolone , dexamethasone , betamethasone , and fl umeta- of cortisol sone pivalate (Fig. CS6.3), all of which have increased glucocorticoid activity and negligible mineralocorticoid In 1947, it was found that cortisone could relieve the side eff ects. symptoms of rheumatoid arthritis. However, cortisone is readily converted in the liver to cortisol and it is now Test your understanding and practise your molecu- thought that the eff ects of cortisone are actually due to lar modelling with Exercises CS6.2 and CS6.3 . Patrick97397.indb 690 11/28/2012 9:20:55 PM Case Study 6 Steroidal anti-infl ammatory agents 691 OH OH OH O O O Me Me Me HO HO HO OH OH OH 11 11 11 Me Me H 1 H Me H 9 HH HH F H O O O Cortisol Fludrocortisone Prednisolone OH OH OH O O Me O Me HO OH Me O 11 HO OH Me H OH 11 Me H Me H 16 OH 9 HH HH 6 F H O O O Me Prednisone Methylprednisolone Triamcinolone O OH OH O O O O Me Me Me HO OH HO OH HO OH Me H 16 Me Me H 16 Me Me H CH 9 9 3 F H F H F H O O O F Dexamethasone Betamethasone Flumetasone pivalate FIGURE CS6.3 Analogues of cortisol. CS6.3 Topical glucocorticoids as under the skin, they have equal activity. It is not yet clear anti-infl ammatory agents whether the acetonide is acting as a prodrug and is rap- idly metabolized once it reaches the tissues or whether CS6.3.1 Cortisol analogues the acetonide group increases binding to a hydrophobic region in the glucocorticoid receptor. Fluocinolone ace- Glucocorticoids are oft en applied topically to treat skin tonide , fl uocinonide , and fl unisolide (Fig. CS6.4) are infl ammations. Triamcinolone acetonide (Fig CS6.4) clinical agents that contain the same acetonide group is one such agent. Th e acetonide group links the alcohol (see also fl udroxycortide; Box CS6.1).