1. 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:
Functional gps attached to steroidal nucleus
Overall shape conformation (dictated by stereochemistry)

2. Steroids Cholesterol Triterpenoid Modified triterpenoids
Tetracyclic of lanosterols lacking 3 CH3 C4 & C14
Cholesterol fundamental structure , modifications of the side chain produce large no. of comp
Two important groups of naturally occurring steroids: steroidal hormones & Cardiac glycosides
Cholesterol Triterpenoid

3. 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

4. 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
C-3 & 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

5. 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

6. 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

7. Sterols Zoosterols: side chain 8C→Cholesterol
Mycosterols: side chain 9C →Ergosterol
Phytosterols: side chain 10C →Sitosterol
Sitosterol
Ergosterol

8. 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)
LDL carry large amounts of cholesterol and deposit it around the body
HDL pick up free cholesterol & return it to the liver for degradation
High risk of atherosclerosis increases with increasing levels of LDL and reduced with increasing levels of HDL.
Blood LDL is a good indicator of the potential risk of a heart attack

9. Medicinal Value of Cholesterol
Cholesterol biosynthesis inhibited by HMG-CoA reductase in mevalonate pathway e.g. lovastatin and derivatives
Cholesterol is primary source for semi-synthetic medicinal steroids
Natural 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

10. Stigmasterol and sitosterol Stigmasterol 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

11. 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

12. 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

13. Vitamin D

14. 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

15. Cardiac Glycosides Cardiotonic glycosides History of Traditional Use:
Arrow poisons
Heart drugs
Rx of dropsy (accumulation of H2O in the body)
Modern Medicine Applications:
Rx of CHF (+ve inotropic effect)
Supra-ventricular fibrillation

16. Natural Sources Very limited distribution
Botanical Origin:
Very limited distribution
Mainly Asclepiadaceae & Apocynaceae
Digitalis lanata, D. purpurea (fox gloves) Scrophulariaceae الديجيتال
Strophanthus kombe, S. gratus Apocynaceae
Nerium oleander (Rose laurel) الدفلة Apocynaceae
Helleborus niger (Christmas Rose) Ranunclaceae زهرة عيد الميلاد المجيد
Urginea maritima (Squill) Liliaceae العنصل
Toad venoms

17. Chemistry-Pharmacology Relation
Therapeutic action depends on :
Structure of aglycone
Type & number of sugar units attached
Pharmacological activity is due to the aglycone but modified by nature of
Sugar for transportation & pharmacokinetics
Biosynthesized from cholesterol through shortening and cleavage of the side chain followed by oxidation and cyclyzation

18. Cardenolide Lactone Ring
Aglycone Classes
C23 & C24
Characteristic of C. Glyc:
A/B + C/D Cis
B/C Trans
3β- OH, 14β- OH
α,β- unsaturated lactone C-17
Additional OH at C12&C16
C19:CH3/CH2OH/COOH
Glycosidic C-3
[Spirostane saponins co-occur with cardenolide glycosides in D. purpurea]
Cardenolide Lactone Ring
Bufodienolide
Lactone Ring

19. Sugar moieties in cardiac glycosides
Glucose and
Rare/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, …

20. 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

21. Digitalis purpurea glycosides Scrophulariaceae (Foxglove)
Aglycone
1ry Glycosides Series
3β,-14β-diydroxylated
Digitoxigenin
Purpureaglycoside-A
3β,14β,16β-trihydroxylated
Gitoxigenin
Purpureaglycoside-B
16-formylgitoxigenin
Gitaloxigenin
Purpureaglycoside-E
(Glucogitaloxin)

22. Purpureaglycoside-A & Digitoxin

23. Chemistry of D. lanata leaves (Scophulariaceae)
temp ≤ 60ºC to prevent glycosidic link hydrolysis
> 60ºC result in 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

24. Lanatosides 3β,-14β-diydroxylated Lanatoside-A Digitoxigenin
Aglycone
1ry Glycosides Series
3β,-14β-diydroxylated
Digitoxigenin
Lanatoside-A
3β,14β,16β-trihydroxylated
Gitoxigenin
Lanatoside-B
3β,14β,12β-trihydroxylated
Digoxigenin
Lanatoside-C
3β,14β,12β,16β-tetrahydroxylated
Diginatigenin
Lanatoside-D
16-formylgitoxigenin
Gitaloxigenin
Lanatoside-E

25. 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

26. Digoxin

27. Digoxin Production Pharmaceutical 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

28. 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

29. 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↓

30. 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

31. Proscillaridin A
Large number of cardiac glycosides of bufadienolides class
Proscilaridin A