Rajah
Serfoji Govt. College (Autonomous), Thanjavur – 613 005
M.Sc., Chemistry
Code: R3PCH6 Organic Chemistry - III
UNIT - V Steroids
EQUILENIN
An estrogenic steroid produced
by pregnant mares.. It has a total of five double bonds in the A- and B-ring.
High concentration of equilenin is found in the URINE of pregnant mares.
High impact
information on EQUILENIN
Cotransfection experiments using estrogen receptor
(ERalpha and/orERbeta) expression vectors have indicated that neither receptor
can potentiate the Eqn-mediated induction of apoA-I promoter activity.
Transient transfection studies with human apoA-I promoter
constructsderived from pGL3-luciferase reporter plasmid were used to identify
the cis-acting element involved in Eqn-mediated induction.
The results demonstrated that the apoA-I electrophile/antioxidant
response element (EpRE/ARE) might be responsible for the increase in
apoA-Ipromoter activity by Eqn .
The separation of selected oestrogens (oestrone, equilin,
alpha-oestradiol, beta-oestradiol and d-equilenin) using capillary supercritical
fluid chromatography (SFC) was studied
An acetate at position 3 of d-equilenin is rapidly
hydrolysed by tissue esterase and the liberated d-equilenin couples with a
diazonium salt to forma coloured precipitate.
Biological context of EQUILENIN
Both E1 and E2 remained at low levels until Day 80,
increased significantly (P less than 0-05) by Day 120 to reach peak levels at
Day 210 or 240 and then declined until parturition .
Moreover, the emission of equilenine is completely
quenched by I-, in contrast with the napththyl-1-phenylamine and perylene
probes, which clearly demonstrates the accessibility of the catalytic site to
water molecules and ions .
The comparison of the fluorescence polarization changes
of perylene and equilenine (a competitive inhibitor of the isomerase) with the
ionic concentration indicates that there is no direct relation between the bulk
lipidic phase and the enzymatic binding site properties .
Associations of EQUILENIN with other chemical compounds
Levels of oestrone, equilin and equilenin (E1),
oestradiol (E2) LH, PMSG and prolactin were measured by radioimmunoassay in
serum from pregnant mares.
ANDROSTERONE
Androsterone, or
3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone and weak
androgen with a potency that is approximately 1/7 that of testosterone. In
addition, it can be converted to dihydrotestosterone (DHT) from
3α-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase, bypassing
conventional intermediates such as androstenedione and testosterone, and as
such, can be considered to be a metabolic intermediate in its own right.
Androsterone is also known to be an inhibitory androstane neurosteroid, acting
as a positive allosteric modulator of the GABAA receptor, and possesses
anticonvulsant effects.
Disease
relevance of androsterone
Urinary aetiocholanolone in patients with early breast
cancer from South East Scotland and South Wales .
LNCaP, a human prostate cancer cell line, metabolizes
testosterone into a variety of 5 alpha-reduced C19 steroids, such as
dihydrotestosterone (DHT), androstane-3 alpha, 17 beta-diol (3 beta, 17
beta-DIOL), and androsterone (ADT).
These observations suggest the involvement of the
17-oxosteroids, epically aetiocholanolone, in the pathogenesis of hereditary
coproporphyria .
High
impact information on androsterone
It is postulated that the conjugating activity of UGT
enzymes is the main mechanism for modulating the action of steroids and
protecting the androgen-sensitive tissues from deleteriously high
concentrations of DHT, ADT and 3alpha-DIOL.
The predominant androgen produced by progenitor,
immature, and adult Leydig cells differed, with AO being released by progenitor
cells (72.08 +/- 9.02% of total androgens), 3alpha-DIOL by immature Leydig
cells (73.33 +/- 14.52%), and T by adult Leydig cells (74.38 +/- 14.73%) .
Mouse rdh6 encodes cis-retinoid/androgen dehydrogenase
type 1 (CRAD1), a short-chain dehydrogenase, which recognizes as substrates
9-cis-retinol, 11-cis-retinol, 5 alpha-androstan-3 alpha,17 beta-diol and 5
alpha-androstan-3 alpha-ol-17-one, and is expressed most intensely in liver and
kidney.
Sertoli cells from immature rats metabolized (3H) 5 alpha-androstane-3
alpha, 17 beta-diol to (3H) 5 alpha-androstane-3 alpha, 16 alpha, 17 beta-triol
and (3H) 3 alpha-hydroxy-5 alpha-androstan-17-one.
UGT2B17 is a UDP-glucuronosyltransferase enzyme
expressed in several extrahepatic steroid target tissues, including the human
prostate, where it glucuronidates C19 steroids such as dihydrotestosterone
(DHT), androsterone (ADT), and androstane-3alpha, 17beta-diol (3alpha-diol).
Biological
context of androsterone
No correlation was found between the aetiocholanolone
patterns and the basal body temperature.
Associations
of androsterone with other chemical compounds
Urinary aetiocholanolone, androsterone and C19 and C21
5 beta/5 alpha metabolite ratios were analyzed by capillary gas chromatography.
Changes in the level of neutrophil alkaline
phosphatase (NAP) in a population of peripheral blood neutrophils were
determined in healthy subjects dosed with either aetiocholanolone (Aetio, 4
mg/m2 im) or prednisolone sodium succinate (Pred, 30 mg/m2 iv).
CORTISONE
Corticosteroids are a class of chemicals that includes
the steroid
hormones that are produced in the adrenal cortex of vertebrates, and synthetic analogues of these hormones.
Corticosteroids are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.
Glucocorticoids such as cortisol control carbohydrate, fat and protein metabolism,
and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of
other mechanisms.
Mineralocorticoids such as aldosterone control electrolyte and water levels, mainly by
promoting sodium retention in the kidney.
Biosynthesis
Corticosteroid
biosynthetic pathway in rat
The
corticosteroids are synthesized from cholesterol within the adrenal cortex.
Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450
family. They are located within the mitochondria and require adrenodoxin as a
cofactor (except 21-hydroxylase and 17α-hydroxylase).
Aldosterone
and corticosterone share the first part of their biosynthetic pathway. The last
part is mediated either by the aldosterone synthase (for aldosterone) or by the
11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they
share 11β-hydroxylation and 18-hydroxylation functions), but aldosterone
synthase is also able to perform an 18-oxidation. Moreover, aldosterone
synthase is found within the zona glomerulosa at the outer edge of the adrenal
cortex; 11β-hydroxylase is found in the zona fasciculata and zona glomerulosa.
PROSTAGLANDIN
The prostaglandins are a group of hormone-like lipid
compounds that are derived enzymatically from fatty acids and have important
functions in the animal body. Every prostaglandin contains 20 carbon atoms,
including a 5-carbon ring.
They are mediators and have a variety of strong
physiological effects, such as regulating the contraction and relaxation of
smooth muscle tissue. Prostaglandins are not endocrine hormones, but autocrine
or paracrine, which are locally acting messenger molecules. They differ from
hormones in that they are not produced at a specific site but in many places
throughout the human body. Also, their target cells are present in the
immediate vicinity of the site of their secretion (of which there are many).
The prostaglandins, together with the thromboxanes and
prostacyclins, form the prostanoid class of fatty acid derivatives, a subclass
of eicosanoids.
The abbreviation for "prostaglandin" is PG;
specific prostaglandins are named with a letter (which indicates the type of
ring structure) followed by a number (which indicates the number of double
bonds in the hydrocarbon structure). For example, prostaglandin E1 is
abbreviated PGE1 or PGE1, and prostaglandin I2 is abbreviated PGI2 or PGI2. The
number is traditionally subscripted when the context allows, but as with many
similar subscript-containing nomenclatures, the subscript is simply forgone in
many database fields that can store only plain text (such as PubMed
bibliographic fields), and readers are used to seeing and writing it without
subscript.
Function
There are currently ten
known prostaglandin receptors on various cell types. Prostaglandins ligate a
sub-family of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP1-2, and
TP, corresponding to the receptor that ligates the corresponding prostaglandin
(e.g., DP1-2 receptors bind to PGD2).
The diversity of receptors means that prostaglandins act
on an array of cells and have a wide variety of effects such as:
v
induce labor
v
decrease intraocular pressure
v
regulate inflammation
v
acts on mesangial cells
(specialised smooth muscle cells) in the glomerulus of
the kidney to
increase glomerular filtration rate
Prostaglandins are potent but have a short half-life
before being inactivated and
excreted. Therefore, they send only paracrine (locally
active) or autocrine (acting on the same cell from which it is
synthesized) signals.
Types
Type
|
Receptor type
|
Function
|
|
Unspecified
|
|||
Role
in pharmacology
Inhibition
o
Prostaglandin antagonist and Mechanism of action of
aspirin
o
Examples of prostaglandin antagonists are:
o
NSAIDs (inhibit cyclooxygenase)
o
Corticosteroids (inhibit phospholipase A2 production)
o
COX-2 selective inhibitors or coxibs
o
Cyclopentenone prostaglandins may play a role in
inhibiting inflammation
Clinical uses
Synthetic
prostaglandins are used:
o
To induce childbirth (parturition) or abortion (PGE2
or PGF2, with or without mifepristone, a progesterone antagonist);
o
To prevent closure of patent ductus arteriosus in
newborns with particular cyanotic heart defects (PGE1)
o
To prevent and treat peptic ulcers (PGE)
o
As a vasodilator in severe Raynaud's phenomenon or
ischemia of a limbIn pulmonary hypertension
o
In treatment of glaucoma (as in bimatoprost ophthalmic
solution, a synthetic prostamide analog with ocular hypotensive activity)
o
To treat erectile dysfunction or in penile
rehabilitation following surgery (PGE1 as alprostadil).
o
To treat egg binding in small birds
o
As an ingredient in eyelash and eyebrow growth beauty
products due to side effects associated with increased hair growth.
There are four rings in a steroid skeleton and hence there are three fusion points. A/B, B/C and C/D rings share two carbons each (fusion). Every fusion center can either be cis- or trans-fused.
For two-ring system, the structures of cis - and trans-fused rings look like this: When the two hydrogens are oriented opposite to each other with the ring system thought to as forming a plane, the ring fusion is called trans. When there are directed on the same side, it is called cis.
The structures most likely feasible are :
o
trans-trans-trans
(most natural and synthetic steroids have this skeleton, e.g., 5a-dihydrotestosterone)
BIOSYNTHESIS OF
CHOLESTEROL
All animal cells
manufacture cholesterol for their use, with relative production rates varying
by cell type and organ function. About 20–25% of total daily cholesterol
production occurs in the liver; other sites of higher
synthesis rates include the intestines, adrenal glands,
and reproductive organs. Synthesis within the body starts with one molecule of acetyl CoA and one molecule of acetoacetyl-CoA,
which are hydrated to form 3-hydroxy-3-methylglutaryl
CoA (HMG-CoA). This
molecule is then reduced to mevalonate by the enzymeHMG-CoA reductase. This is the regulated, rate-limiting and irreversible step in
cholesterol synthesis and is the site of action for the statin drugs
(HMG-CoA reductase competitive inhibitors).
Mevalonate is
then converted to 3-isopentenyl pyrophosphate in three reactions that require ATP. Mevalonate is decarboxylated to isopentenyl pyrophosphate, which is a key
metabolite for various biological reactions. Three molecules of isopentenyl
pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl
transferase. Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene
synthase in the endoplasmic
reticulum. Oxidosqualene cyclase then
cyclizes squalene to form lanosterol.
Finally, lanosterol is converted to cholesterol through a 19-step process.
Konrad Bloch and Feodor Lynen shared the Nobel
Prize in Physiology or Medicine in
1964 for their discoveries concerning the mechanism and regulation of
cholesterol and fatty acid
metabolism.
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