steroids
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Steroids
• Wide range of biologically active natural products e.g. sterols, steroidal saponins, cardioactive glycosides, bile acids, corticosteroids, mammalian sex hormones
• Different activities of compounds with common structural skeleton is attributed partially to:
1) Functional gps attached to steroidal nucleus 2) Overall shape conformation (dictated by
stereochemistry)
SteroidsModified triterpenoids Tetracyclic of lanosterols lacking 3 CH3 gps @ C4 & C14Cholesterol fundamental structure , modifications of the side chain produce large no. of compTwo important groups of naturally occurring steroids: steroidal hormones & Cardiac glycosides
Cholesterol Triterpenoid
A B
C DA B
C D
HO
E17
12
34
56
7
89
10
11 12
13
14 15
16
1718
19
2021 22
23
2425 26
27
4
20
OH
Medicinal Value of Plant Steroids
• Important source of steroidal drugs
• Minor % prepared from animal steroids & total synthesis
• Norgestrel, C13 ethyl, totally synthetic (nothing in nature like this structure)
• Aromatic steroids & C19 nor steroids are animal e.g. Norethisterone
OH
5O 4 Norethisterone
HC CHH19
OH
5O 4 Norgestrel
H CH
CH
Steroidal Saponins• Same triterpenoidal saponins characters• Less widely distributed in nature• Plant families Dioscoreaceae, Liliaceae, Agavaceae • Sapogenins 27 Carbons• Side chain of cholesterol modified to spiroketal or hemiketal• All have C25 stereoisomerisation• Sugars @ C-3 & some @ C-26• Less sugar molecules (Triterpenoidal saponins??)• > sugars result in > haemolytic effect• Raw material for the partial synthesis of steroidal hormones:
”Marker degradation”[Diosgenin →Progesteron; ONLY 5 step reaction!]
• Other raw materials: sitosterol, stigmasterol
Dioscorea (Dioscoreaceae)
• D. alata & D. esculenta, D. rotundata edible• Roots of some spp are rich in steroids considered
bitter & inedible (Excellent source for drug manufacture)
• Diosgenin is major sapogenin (60% of steroidal production derived from diosgenin)
• Powdered Dioscorea (wild yam) root or extract as Rx for menopause (alternative to HRT) efficacy ????
• Diosgenin conversion in humans to progesterone
Diosgenin• The aglycone of the saponin from the tubers of Dioscorea spp
(Dioscoreaceae) e.g. D. composita, D. mexicana• Important source for pharmaceutical industry as the starting
molecule of steroids synthesis e.g. progesterone, testosterone, cortisone
• Microorganisms introduce OH gp at specific position in steroid skeleton
O
O
O
22
25
26
3Diosgenin
O
OO
OH
OHOH
OHOH
O
O
D-Gluc
L-Rha
L-Rha
1 4
1 2
Alpha
Alpha
Dioscin
SpirostaneBeta 1
Sterols
• Zoosterols: side chain 8C→Cholesterol• Mycosterols: side chain 9C →Ergosterol• Phytosterols: side chain 10C →Sitosterol
HO 5 6Cholesterol
ErgosterolSitosterol
Cholesterol • Principle animal sterol • Alcoholic triterpene (lanosterol) converted to cholesterol
• Essential constituent of cell membranes in all animal tissues• Maintains membrane fluidity, microdomain structure & permeability• Precursor for steroid hormones, bile acids, Vit. D & lipoproteins “LDL & HDL”
(proteins + phospholipids carrying cholesterol in blood to tissues) • Associated with cardiovascular diseases, atherosclerosis,
hypercholesterolaemia, gallstone diseases (mostly cholesterol precipitated from bile)
HO 5 6Cholesterol
HOH
98 14
Lanosterol
H
3 CH3+2 H
Medicinal Value of Cholesterol • Cholesterol biosynthesis inhibited by HMG-CoA reductase in
mevalonate pathway e.g. lovastatin and derivativesCholesterol is primary source for semi-synthetic medicinal
steroidsNatural sources for industry: • Brains and spinal cords of slaughtered cattle (by-product of
meat industry)• Extracted lanolin & fatty layer of sheep’s wool (lanolin
saponification provides alcohol fraction 34% cholesterol + 38% lanosterol/dihydrolanosterol
• Wool alcohols are used as ointment base
Stigmasterol and sitosterolStigmasterol first isolated from calabar beans, then from soya bean oil
Both are raw materials for the semisynthetic production of steroids. Stigmasterol easily converted to progesteron which is in turn starting material for other steroids
HO
H
H
H
22 24
241242
STIGMASTEROLHO
H
H
H
22 24
SITOSTEROL
HH
RS
Sitosterol• Analogue of stigmasterol with saturated side-chain • Sources: soya-bean and oils e.g. maize oil• Can not be degraded using chemical methods (no
double bond side chain)• Microbial degradation• Starting molecule for sex hormone synthesis
especially 19-norsteroids & spironolactones • Topical products for eczema, dry skin, burn scars• Hypocholesterolemic properties
Vitamin D • Derived from Δ5,7-sterols • Chemically related to steroids (ring B open)• Cholecalciferol= Vit D3 from liver, milk, butter,
fish-liver; skin of man!• Ergocalciferol= Vit D2 by UV radiation of
ergosterol from yeast, overirradiation produces toxic substances: Toxisterols
• Vit D essential for the utilization of Ca and P• Overdose: renal calculi, metastatic calcification
Vitamin D
HO
H
HO
UV
17
HO
HUV
17
HO
7-Dehydrocholesterol
Colecalciferol (Vit. D3)
Ergosterol
Ergocalciferol (Vit D 2)
Vit D
• Vit D2 + Lumisterol → Vit D1
• Ergosterol (Pro Vit D2)→ Vit D2
• 7-dehydrocholesterol → Vit D3
• 22:23 dihydro-Vit D2 → Vit D4
• 7-dehydro-sitosterol → Vit D5
• 7-dehydrostigmasterol → Vit D6
• 7-dehydrocampesterol → Vit D7
Cardiac Glycosides Cardiotonic glycosidesHistory of Traditional Use:Arrow poisonsHeart drugsRx of dropsy (accumulation of H2O in the body)Modern Medicine Applications:Rx of CHF (+ve inotropic effect) Supra-ventricular fibrillation
Natural Sources
Botanical Origin:
Very limited distribution Mainly Asclepiadaceae & Apocynaceae Digitalis lanata, D. purpurea (fox gloves)
Scrophulariaceae الديجيتال Strophanthus kombe, S. gratus ApocynaceaeNerium oleander (Rose laurel) الدفلة ApocynaceaeHelleborus niger (Christmas Rose) Ranunclaceae
المجيد الميالد عيد زهرةUrginea maritima (Squill) Liliaceae العنصل Toad venoms
Chemistry-Pharmacology Relation
Therapeutic action depends on :1. Structure of aglycone2. Type & number of sugar units attached3. Pharmacological activity is due to the aglycone but
modified by nature of sugar @C34. Sugar for transportation & pharmacokinetics5. Biosynthesized from cholesterol through
shortening and cleavage of the side chain followed by oxidation and cyclyzation
Aglycone Classes• C23 & C24Characteristic of C. Glyc:1. A/B + C/D Cis2. B/C Trans3. 3β- OH, 14β- OH4. α,β- unsaturated lactone
ring @ C-175. Additional OH at C12&C166. C19:CH3/CH2OH/COOH 7. Glycosidic bond @ C-3 [Spirostane saponins co-occur
with cardenolide glycosides in D. purpurea]
O
HO
H
O
OH
H
H
Cardenolide (C 23)
12
3
4
5
6
78
910
1112
1314
15
16
1718
19
2120 22
23
HO
H OH
OH
H
O
O
2
3
4
56
8
9
1112
1314
15
16
1718
19
2120 22
2324
Bufadienolide (C24)
7
10
Cardenolide Lactone Ring
Bufodienolide Lactone Ring
Sugar moieties in cardiac glycosides
Glucose andRare/uncomon sugars:• 6-deoxysugars• 2,6-deoxysugars• Their 3-O-methylethers• i.e: L-rhamnose, D-digitoxose, D-digitalose, D-
cymarose, D-diginose, D-sarmentose, …
Glycones of cardiac glycosides
• 2,6-dideoxyhexoses (digitoxose & cymarose)• 6-deoxyhexoses (L-Rhamnose & D-Digitalose) • 3-Methylether hexoses (Digitalose & Cymarose) • D-Glucose, D-Fructose in 1ry Glycosides
O
OH
OH
23
45
6
OH
D-Digitoxose
O
OH
OH
23
45
6
OCH3
O
OH
OH
23
45
6
OCH3OH
D-DigitaloseD-Cymarose
Digitalis purpurea glycosidesScrophulariaceae (Foxglove)
1ry Glycosides Series Aglycone
Purpureaglycoside-A 3β,-14β-diydroxylated
Digitoxigenin
Purpureaglycoside-B 3β,14β,16β-trihydroxylated
Gitoxigenin
Purpureaglycoside-E
(Glucogitaloxin)
16-formylgitoxigenin
Gitaloxigenin
Purpureaglycoside-A & Digitoxin
OO
O
O
O
OO
O
O
O
HO
HO
HOHOOH
HO OH
OH
14
3
1612
H
H
Purpureaglycoside A
D-glucose
D-digitoxose
3
HD-digitoxoseD-digitoxose
Digitoxin
Chemistry of D. lanata leaves (Scophulariaceae)
• Dried @ temp ≤ 60ºC to prevent glycosidic link hydrolysis
• > 60ºC result in dehydration @ C14 (inactive 14-anhydro comp.)
Cardiac glycosides: Fresh Plant: 1ry glycosides=Lanatosides A-E series (Aglycone + 3 digitixoses +Acetyl + Glucose)Dry Plant: 2ry Glycosides=Lanatosides loses terminal
glucose (Aglycone + 3 digitixoses + Acetyl)• Aglycone: Cardenolides [C23] in both
Lanatosides1ry Glycosides
SeriesAglycone
Lanatoside-A3β,-14β-diydroxylated
Digitoxigenin
Lanatoside-B3β,14β,16β-trihydroxylated
Gitoxigenin
Lanatoside-C3β,14β,12β-trihydroxylated
Digoxigenin
Lanatoside-D3β,14β,12β,16β-tetrahydroxylated
Diginatigenin
Lanatoside-E16-formylgitoxigenin
Gitaloxigenin
Differences between two Digitalis species
• The primary glycosides are not identical since in D. lanata -even the aglycon is the same- there is an acetyl group attached to the third sugar on OH at C-3
• Hydrolysis of the terminal glucose in D. lanata yields Acetyldigitoxin, acetylgitoxin, acetyldigoxin, acetylgitaloxin while in D. purpurea: Digitoxin, gitoxin, gitaloxin
• Digoxigenin and its glycosides found only in D. lanata (Lanatoside C)
• Digitoxin is the main secondary glycoside of D. purpurea while digoxin is the main secondary glycoside of D. lanata
Digoxin
OO
O
O
OO
O
O
HO
HO
HO
HOOH
14
3
1612
H
H
3
H
HO
D-digitoxoseD-digitoxose
D-digitoxose
Digoxin ProductionPharmaceutical industry: Deacetylated the 2ry glycoside from dry leaves of
D. lanata to produce digoxin OR Terminal glucose is removed first then
deacetylate 2ry glycoside from fresh plant Deacetylation first then hydrolysis of terminal
glucose is a 2nd option
Digoxin
Lanatoside-C hydrolysed into acetyldigoxin by the action of β-glucosidase
Digoxin is the deacetylated derivative of 2ry glycoside from Lanatoside-C
Rx CHF & atrial fibrillation
OO
O
O
O
OO
O
O
O
HO
HO
OHOOH
O
HO OH
OH
14
3
1612
H
H
Lanatoside-C
D-glucose
3-acetyl-D-digitoxose
3
H
HO
D-digitoxoseD-digitoxose
Acetyldigoxin
Medicinal Applications• Illegal to sell crude drug or extracts of Digitalis
(bacterial contamination of the leaves)• Digitalization is usually required • Drug monitoring through radioimmunoassay using
specific antibodies • Sheep derived digoxin-specific antibody fragments
for Rx of digoxin overdose• Digitoxin is highly lipid soluble, completely absorbed
from GI tract (95%); halflife time :7days• Digoxin less lipid soluble, GI absorption 75%; halflife
time:1.5 days• Polarity of cardiac glycosides↑, oral absorption↓
Urginea maritima (Squill) • Bulb (formerly Scilla
maritima)• Family Liliaceae • Used as expectorant as
Gee’s linctus• Large doses toxicity
(vomiting & digitalis-like action on heart)
• Grows on Mediterranean & Canary Islands shores
Proscillaridin A• Large number of cardiac glycosides of
bufadienolides class
Proscilaridin A
O
ORhamnose
O
OH
14
3
17
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