Steroids with Chemistry, Nomenclature, Stereochemistry and Classification of Steroids. .ppt

Steroids with Chemistry, Nomenclature, Stereochemistry and Classification of Steroids. .ppt

• 1.
  STEROIDS By: Dr. Kiran B.Dhamak Department of Pharmaceutical Chemistry
• 3.
  Formation of SteroidHormones  Sources of steroid hormone formation in the body can be divided into two types.  One source is the endocrine glands. In women, they include the adrenals, ovaries, and placenta, which is an incomplete endocrine gland. In men, the endocrine glands include the adrenals and testes.  A second source of steroid hormones in the body is peripheral tissues. These are nonendocrine tissues such as the liver, intestine, fat, skin, kidneys, and brain.
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  Chemistry of Steroids From the chemical standpoint, hormones can generally be divided into three types: proteins (e.g., FSH and LH), peptides (e.g., GnRH and ACTH), and steroids (e.g., progesterone and estradiol).  The basic units of proteins and peptides are amino acids, whereas steroids contain the gonane structure.  Proteins are relatively large molecules and are water soluble, whereas steroids are small molecules and are generally soluble in organic solvents.  Peptides are somewhere in between these two classes of hormones with respect to molecular weight and solubility.
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   The basicstructure of steroids, gonane (cyclopentanoperhydrophenanthrene), has 17 carbons which are arranged as three six-member carbon rings to which a five-member carbon ring is attached. Each carbon has one or two hydrogens attached. The gonane structure can be represented without showing the carbons and hydrogens.
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   Steroids canbe divided into different groups of parent compounds, based on the number of carbons that they contain.  In addition to gonanes, which consist of 17 carbons, estranes consist of 18 carbons (C18 steroids) and include estrogens.
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   Androstanes have19 carbons (C19 steroids) and include androgens.  Pregnanes contain 21 carbons (C21 steroids) and include progesterone and corticosteroids. This chapter focuses primarily on C18, C19, and C21 steroids.  Cholanes have 24 carbons and include bile acids, and cholestanes have 27 carbons and include cholesterol as well as cholesterol-like compounds.  The compounds in this group are also referred to as sterols.
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  The Nomenclature ofSteroids  Steroids are compounds possessing the skeleton of cyclopentaphenanthrene or a skeleton derived there from by one or more bond scissions or ring expansions or contractions.  Methyl groups are normally present at C-10 and C- 13.  An alkyl side chain may also be present at C-17.  Sterols are steroids carrying a hydroxyl group at C- 3 and most of the skeleton of cholestane. Additional carbon atoms may be present in the side chain.
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  Numbering and ringletters  Steroids are numbered and rings are lettered as in formula.
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   If oneof the two methyl groups attached to C-25 is substituted it is assigned the lower number (26).; if both are substituted, that carrying the substituent cited first in the alphabetical order is assigned the lower number.
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   The absolutestereochemistry of a steroid is defined by the parent name for some chiral centres and by , , R or S for other centres.  When the configuration at one or more centres is not known, this is indicated by the Greek letter(s)  (xi) prefixed by the appropriate locant(s).
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   Orientation ofprojection formulae  When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a.
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   An atomor group attached to a ring depicted as in the orientation 2a is termed  (alpha) if it lies below the plane of the paper or  (beta) if it lies above the plane of the paper.
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   The configurationof the H at C-5 is always indicated in the name.  Circles were sometimes used to indicate - hydrogens and dark dots to indicate -hydrogens.  Compounds with 5 -cholestane, belong to allo series while compounds from 5 - cholestane, belong to the normal series.  If the double bond is not between sequentially numbered carbons, in such cases both carbons are indicated in the name.
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   When amethyl group is missing from the side-chain, this is indicated by the prefix ‘nor’ with the number of the C-atom, which has disappeared.  The symbol  is often used to designate a C=C bond in a steroid. If C=C is in between carbon 5 & 4, the compound is referred to as a 4 steroids; and if the C=C bond is between positions 5 and 10, the compuond is designated as 5(10) steroid.
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  Stereochemistry  The absolutestereochemistry of the molecule and any substituent is shown with solid () and dashed ()bonds, a (axial) bond is perpendicular to the plane of molecule while (equatorial bond) is horizontal to the plane of the molecule.
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   The aliphaticside chain at position 17 is always assumed to be of  configuration.  The terms cis and trans are occasionally used to indicate the backbone stereochemistry between rings.  For example, 5 -steroids are A/B trans ; and 5 - steroids are A/B cis. The terms syn and anti are used analogously to trans and cis.
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   Cholestane, androstaneand pregnane can exist into two conformations i.e.  Chair form  Boat form
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   Chair conformationis more stable than boat conformation due to less angle strain and hence all cyclohexane rings in the steroid nucleus exist in the chair conformation.
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  Adrenocorticoids  The adrenal glandsare flattened, cap like structures located on the top of kidneys.
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   The innercore of it is known as medulla, which secretes catecholamines (e.g. Adrenaline), while the shell of the gland is known as cortex, which synthesizes steroid hormones known as adrenocorticoids or adrenal cortex hormones.
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   Like mostendocrine glands, adrenal cortex is regulated by the Hypothalamo-Pituitary glands.
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   The activationof the hypothalamic-pituitary-adrenal (HPA) axis.  Response to a stress stimulus is routed to the hypophysiotropic neurons in the paraventricular nucleus (PVN) of the hypothalamus.  These neurosecretory cells release corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which travel through the median eminence and hypophyseal portal vessels.  Once CRH reaches the anterior pituitary, it binds CRF type 1 receptors of pituitary corticotroph cells.  Adrenocorticotropic hormone (ACTH) is released into circulation, binds its receptors in the zona fasiculata of the adrenal cortex, and causes release of glucocorticoids.  Glucocorticoids in circulation act on target cardiovascular tissues (including, the heart, the vasculature, adipose tissue and muscle) then feedback to the level of the central nervous system (CNS) to inhibit activation of the HPA axis.
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   The adrenalcortex synthesizes two classes of steroids.  Glucocorticoids e.g. Cortisone, Hydrocortisone, Prednisone, Prednisolone  Mineralocorticoids e.g. Aldosterone
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  Glucocorticoids  These steroidsregulate the carbohydrate, protein and fat metabolism and are intimately involved in the operation of the process that enable the body to resist the infection and stress.  Glucocorticoids are a type of corticosteroid hormone that is very effective at reducing inflammation and suppressing the immune system.  Glucocorticoids are secreted naturally by our adrenal gland in response to stress and have numerous effects on our bodies that are essential for life. Glucocorticoid drugs are synthetic versions of these hormones.
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   Glucocorticoids areused to treat conditions that have inflammation as a symptom, such as:  Allergies Arthritis  Asthma Autoimmune disorders such as multiple sclerosis and rheumatoid arthritis  Cancer Inflammatory bowel disease  Lichen planus Lupus  Psoriasis Severe mouth ulcers  Skin inflammation and rashes  Ulcerative colitis.  Postoperative or chemotherapy- induced nausea and vomiting  Postoperative swelling or inflammation
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  Cortisone Hydrocortisone
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  SAR of Glucocorticoids Substituents which significantly increases anti- inflammatory and glucocorticoids activity are:  1-dehydro (1 ) e.g. Prednisone, Prednisolone
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   6-Fluoro e.g.Fluprednisolone Fluprednisolone  Substituents which significantly decreases mineralocorticoid activity are:  16-hydroxy  16 and 16-methyl  16, 17-ketals  e.g. Cortisone, Cortisone acetate
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   Substituents whichmarkedly increases both glucocorticoid and mineralocorticoid activity.  9-Fluoro e.g. Betamethasone  21-hydroxy  2-methyl  9-chloro H
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  Mechanism of Action
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   The majorityof effects produced by glucocorticoids result from initial steroid binding to intracellular glucocorticoid receptors followed by translocation to the nucleus and changes in gene transcription.  In their steroid-free (unbound) state, intracellular glucocorticoid receptors (GR) are bound to stabilizing proteins that include heat-shock protein 90 (Hsp90) and immunophilin.  The unbound form of the receptor is not capable of affecting gene transcription.
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   Binding ofsteroid initiates a conformational change that results in an exchange of chaperone proteins, which permits attachment of the steroid- GR complex to the dynein protein trafficking pathway. This results in translocation of the steroid- GR complex from the cytoplasm into the nucleus.  Once in the nucleus, the steroid- GR complex dimerizes and binds to glucocorticoid response elements (GRE) associated with the regulatory region of glucocorticoid-sensitive genes.
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   Binding ofthe glucocorticoid- GR dimer either represses, or stimulates the transcription of sensitive genes, resulting in changes in synthesis of mRNA, followed by changes in protein synthesis. These steps are necessary for producing most cellular responses to glucocorticoids, and typically take hours to days to develop.  Both a reduction in the synthesis of inflammatory cytokines, as well as upregulation in the synthesis of annexin A1 are known to play important roles in mediating the antiinflammatory and immunomodulatory effects of glucocorticoids.
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   In somesituations glucocorticoids are able to produce more rapid responses by binding to membrane-associated receptors and exerting effects that do not involve changes in gene regulation.
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  Mineralocorticoids  A classof steroid hormones that cause retention of sodium (and water).  Aldosterone is the most important endogenous mineralocorticoid.
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   Aldosterone isproduced in the zona glomerulosa region of the adrenal cortex. Because of it comes from a zone of the adrenal cortex, it is also considered a type of corticosteroid.  Aldosterone physiological role is essential in maintenance of adequate fluid volume needed for normal cardiac output and arterial blood pressure.  Without adequate levels of mineralocorticoids, diminished cardiac output can result in fatal shock.  In contrast, elevated levels of aldosterone associated with long term stimulation of the Renin- Angiotensin-Aldosterone-System (RAAS) is involved in the development of vascular remodeling and systolic heart failure.
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  Internal structure ofthe adrenal gland showing the cortical layers and medulla
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  SAR of Mineralocorticoids Naturally occurring, highly active mineralocorticoids have no OH function at positions 11 and 17. In fact, OH groups in any position reduce the sodium retaining activity of adrenocorticoid. Fludrocortisone acetate
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   According tothe hormone-receptor binding studies, the C and D rings, involving positions 11,12,13,16,17,20 and 21 are more important for binding than the rings A and B.  More specifically, the -surface of rings A, C and D, as well as the the 17 -ketol side chain, is essential for sodium retaining activity.  Generally 9-F, 9-Cl, 9-Br substituents cause increased mineralocorticoid activity where order of activity is F>Cl>Br.
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   Insertion ofa 16-OH group results in reverse effect i.e. sodium excretion rather than Na retention.  A double bond between positions 1 and 2 (-1 cortcoids), also decreases the activity.  21-F, 16-CH₃,16-CH₃, 16-CH₃O, 6-Cl, and 17-OH groups are reported to inhibit the sodium retention property.  12-F, 2-CH₃ and 21-OH groups moderately elevate the mineralocorticoid activity.
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  Mechanism of Action
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   Like othersteroids, aldosterone probably acts to initiate transcription of RNA that serves as template for the synthesis of carrier protein or proteins that subsequently facilitate the crossing of Na⁺ ions through the rate limiting permeability barrier of the mucosal surface.  Progesterone, the diuretic agent Spironolactone, Actinomycin and Puromycin block the aldosterone stimulated transport of Na⁺. Such inhibitors have no effects on the non-hormonal basal transport system of Na⁺
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  Biosynthesis of Steroids