Steroids Flashcards
What do steroids act as?
Hormones and surfactants
What are steroids derived from?
Triterpenoids
How many isoprene units are in farnesyl pyrophosphate?
3
How is squalene oxide formed?
Squalene + O2 + NAPDH
Why are epoxides reactive?
Very strained angles
Why can squalene oxide ring close?
Rotatable bonds allow a cascade of electrons
What carbocation is most stable?
Tertiary carbocation
What are anti-migrations?
Each group migrates axially and is anti-periplanar to the one before
Why is ring-closed squalene likely to occur?
Due to stable tertiary carbocation and chair, boat, chair conformation of 6 membered ring
Lanesterol to cholesterol
Alkene reduced, new alkene introduced and methyl groups lost to form CO2
Structure of all steroids
3 - 6 membered rings
1 - 5 membered ring
Ring junctions in steroids
All ring junctions are trans except A/B rings which can be cis or trans
What is the structural drawing of ring junctions?
Trans - groups attached on opposite faces
Cis - groups attached on the same face
What are sterols?
Steroids with an alcohol
What are the origins of saponins?
Plant origin
What is the structure of saponins?
Extra 5-membered ring and spiroketal attached to extra ring
Why are saponins like surfactants?
Sugar units act as surfactants as they dissolve in water but the saponin rings are lipophilic
What do saponins cause?
Haemolysis
What is the ring conformation of cardioactive glycosides?
Cis fused ring system between C/D and A/B
What is the additional ring on cardioactive glycosides?
Unsaturated lactone at C-17β
What is digitoxigenin?
A cardioactive glycoside used as arrow poison
Why are cardioactive glycosides cardioactive?
Sugar unit increases solubility and binding to heart muscle
Why do bile acids occur in salt form?
Carboxylic acids so form bile salts
What groups are on bile acids?
3a & 7a OH’s
C5 carboxylic acid side chain
What are the 2 types of hormones?
Sex and adrenocortical
Where are adrenocortical hormones produced?
Adrenal cortex
What are the 2 types of adrenocortical hormones?
Glucocorticoids and mineralocorticoids
Structure of glucocorticoids?
C21 pregnane structure
17β ketone group with OH
11β OH
Conjugation in A ring with =O
Structure of mineralocorticoids?
C21 pregnane sgtrucutre
17β ketone group
13β COOH
Conjugation on A ring with =O
What do mineralocorticoids do?
Control electrolyte balance in kidneys
Retention of Na+/Cl-
Excretion of K+
How is H2O solubility of steroids increased?
Addition of OH and ionised groups
How are steroids transported?
Attached to a large protein
Bond to a small compound such as a sugar or salt
What is pinocytosis?
Cell takes up fluid along with small dissolved molecules
What is the process when steroids pass through cell membrane?
Steroid diffuses through cell membrane
Attaches to steroid receptor complex
Dimerises
Translocates to nucleus
Binds to chromatin and alters DNA and cell function
What does Sex Hormone Binding Globulin transport?
Testosterone and estradiol
What does corticosteroid-binding Globulin transport?
Hydrocortisone, aldosterone and progesterone
What do LDL contain?
LDL contains higher levels of cholesterol and triglycerides
Why are LDL light?
Contains hydrocarbons
How many times more cholesterol does LDL have than HDL?
4x
What is Phase I of cholesterol metabolism?
Oxidation using CYP450
Alkyl groups lost and COOH formed - polar
Reduction of double bond - gives A/B ring cis geometry
What is Phase II of cholesterol metabolism?
Addition of polar groups glycine or taurine
Where is cholesterol metabolised?
Liver
Where are bile salts stored?
Gallbladder
Why are bile salts surfactants?
OH groups on alpha face and methyl groups on beta face
What % of bile salts are recycled?
95%
How many times can each bile salt molecule be reused?
20x
What controls stock of bile salts?
Enterohepatic recycling
What are the therapeutic properties of glucocorticoids?
Diseases with overactive immune system
Reduces swelling, heat and tenderness in cancer treatment
What is transactivation with Glucocorticoids?
GC binds to cytosolic GC receptors
Receptor-ligand complex translocates to cell nucleus
Binds to GCR elements
Results in regulation of gene expression
What are the effects of proteins that result from transactivation of glucocorticoids?
Anti-inflammatory
Increases gluconeogenesis
What is gluconeogenesis?
Glucose synthesis from proteins and fats
What is transrepression with Glucocorticoids?
GCRs inteact with specific transcription factors
Prevents transcription of pro-inflammatory genes including cytokines and chemokines
What is a negative effect of GCs?
GCs can affect wanted and unwanted (regulatory) genes
How do GCs immunosupress?
Suppress cell mediated immunity
Suppresses gene code for cytokines
Reduces T cell proliferation
Can induce T cell apoptosis
How do GCs have an anti-inflammatory effect?
Potent
Inhibit prostaglandins and leukotrienes
Supress COX I and COX II expression
How does the hydrocortisone negative feedback loop work?
Low hydrocortisone levels stimulate corticosteroid releasing factor
Stimulates ACTH from pituitary
ACTH stimulates biosynthesis of hydrocortisone
Where is corticosteroid releasing factor released from?
Hypothalamus
What happens when hydrocortisone levels are high?
CRF and therefore ACTH are not produced
Side effects of glucocorticoids
Weight gain
Irregular periods
Cataracts
Increased skin fragility
Side effects of mineralocorticoids
Hypertension
Salt and Water retention
What does conjugation of A ring in corticosteroids do?
Increases glucocorticoid
activity over mineralocorticoid
Halogenation in corticosteroids?
increases both gluco &
mineralocorticoid activity
Addition of sodium phosphate in corticosteroids
Increases aqueous solubility for IV
Methylation at 16 in corticosteroids?
increases glucocorticoid
activity but not mineralocorticoid
What effect do synthetic progestins have on hypothalamus?
Feedback effect prevents ovulation and stops uterine contractions
How can estrogen be improved?
Alkylate phenol on ring A to create prodrug
Alkylate c17 to prevent OH becoming ketone
What are the key functional groups on oestrogens?
No side chain
Aromatic Ring A
No methyl group at C10
Ketone or OH at C17
What are the key functions on progestogens?
Side chain at C17
Conjugation with A ring and =O
What are the key functions on androgens?
No side chain
Conjugation with A ring and =O
17β-OH
What is estrogen metabolised to?
Estriol and estrone
How is progesterone altered to be suitable for oral use?
Addition of Me at C6
Elongate side chain at C13
What is Mestranol a pro-drug of?
Ethinylestradiol
