The document discusses the active constituents of Trigonella foenum-gracum (fenugreek) that are used in diabetic therapy. It identifies five major active constituents: flavonoids, 4-hydroxyisoleucine, steroidal saponins, trigonelline, and galactomannan. Each constituent is described in terms of its chemical structure, mechanism of action in reducing blood glucose levels, and potential role in treating diabetes.

1. Active Constituents of Trigonella foenum-
gracum Used in Diabetic Therapy

2. Synonym : Fenugreek, Methi
Biological source : Consist of seeds and leaves of Trigonella
foenum-gracum
Family : Fabaceae
Trigonella foenum-gracum

3. Geographical source :
Major fenugreek producing countries are
Afghanistan, Pakistan, India, Iran, Nepal, Bangladesh, Argentina, Egypt, France,
Spain, Turkey, and Morocco
The largest producer is India.
In India it is cultivated at Rajasthan, Gujarat, Uttarakhand, Uttar
Pradesh, Madhya pradesh, Maharashtra, Haryana and Punjab
Rajasthan accounts for 80% of India's output
Parts Used:
Seeds and Leaves

4. 1. Flavonoids,
2. 4-hydroxyisoleucine (unusual amino acid)
3. Diosgenin & Yamogenin (saponin) ,
4. Trigonelline (alkaloid) and
5. Galactomannan (Soluble fiber)
Chemical constituents

5. It has been reported that alcoholic extract of fenugreek seeds has an antidiabetic efficacy in
streptozotocin-induced diabetic rats
Extraction
Seeds or leaves of Fenugreek
Crushed & sieved through 40 mesh size
coarse powder
100 grams of powdered seeds or leaves were taken
Extracted with ethanol using soxhlet apparatus for 24 Hrs
Extract is cooled and filtered
The filtrate was evaporated in vacuum
residue

6. Refluxed with 80%w/v ethyl acetate for 1/2 an hour
Solvent is decanted
Residue is dissolved in 90%w/v methanol
Filtered
concentrated and precipitated in acetone
Saponin
HPLC
Mobile phase
Acetonitrile-water(75:25)
Trigonelline,
Flavonoids
Coulmn chromatoraphy
4-hydroxy
isoleucine
Residue
Isolation

7. Different types of flavonoids are
 Quercetin and kaempferol,
 Luteolin,
 Naringenin,
 Vitexin
1. FLAVONOIDS

8. Quercetin
3,5,7-Trihydroxy-2-(4-hydroxyphenyl)-4H-
chromen-4-one
Kaempferol
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-
chromen-4-one
2-(3,4-Dihydroxyphenyl)- 5,7-dihydroxy-4-
chromenone
Luteolin
Naringenin
5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one

9. Quercetin-3-glucoside Vitexin
Secondary metabolite
Consist of two phenyl ring (A & B) and one heterocyclic ring (C)
They are derivative of 2- phenylbenzopyrans

10. Hydroxylation and planarity at position 7 in several flavonoids
PPAR activation
SAR
1
5
6
7
8
(Peroxisome proliferator activated receptor)
Transcription of insulin
responsive gene
2
4
1
5
6
7
8
3

11. Glucosylation at position 3 & 8 , shows significant
antidibetic activity
Hypoglycemic behavior of Quercetin-3-glucose is more
instead of rhamnose
Quercetin-3-glucoside
Vitexin
3
8

12. Mechanism of action
(Flavonoids)

13. It is a Natural Nonproteinogenic amino acid present in T. foenum graecum seeds
(Not encoded in the genetic code of any organism)
4-OH Ile possess insulinotropic biological activity
(Stimulates the production of insulin)
4-hydroxyisoleucine
(2) 4-hydroxyisoleucine

14. It increases glucose-induced release of insulin by direct
effect on pancreatic islets
Insulin response is strictly dependent on the glucose
concentration and hence avoid undesirable side effects
such as hypoglycemia
 blood glucose level = Insulin promoting response
Mechanism of Action

15. It is difficult to isolate 4-hydroxyisoleucine in
pure form therefore 4- hydroxyisoleucine enriched
fraction of the fenugreek extract is being used as
an antidiabetic agent
This product is sold under the trade name
Sugaheal®

16. 4-Hydroxyisoleucine is a branch amino acid.
4 hydroxy isoleucine present in two diastereo isomers:
Major (2S, 3R, and 4S) configuration (about 90% of the total
content of 4-OH Ile)
 Minor (2R, 3R, 4S) configuration.
Chemistry of 4-Hydroxyisoleucine

17. Synthesis of 4-OH Ile by the Aldolase–Transaminase Coupling Reaction
Synthesis of 4-Hydroxy-isoleucine

18. 1
2
3
4
5
6
7
Preparation of semi synthetic derivatives:

19. 1. 2-Amino-4-hydroxy-3-methyl Pentatonic acid methyl ester,
2. 2-Amino-4-hydroxy-3-methyl Pentanoic acid ethyl ester,
3. 2-Amino-4-hydroxy-3-methyl Pentanoic acid Benzyl ester,
4. 2-Amino-4-hydroxy-3-methyl Pentanoic acid -4-nitro Benzyl ester,
5. 2-Amino-4-hydroxy-3-methyl Pentanoic acid-2-Nitro Benzyl ester,
6. 2-Amino-4-hydroxy-3-methyl Pentanoic acid 2,4 dinitro Benzyl ester,
7. 2-Amino- 4-hydroxy-3-methyl Pentanoic acid butyl ester
Its semisynthetic derivatives are confirmed by IR, MASS and NMR
They showed improved biological activities than parent compound
1, 2, and 7 showed greater anti-diabetic activity

20. Activity
SAR
4- hydroxyisoleucine
Carboxyl
group
Ether

21. 3. Steroidal saponin
Biologically active steroidal sapogenin present in fenugreek
Diosgenin
Yamogenin

22. Tigogenin
Neotigogenin

23. Mechanism of Action

24. 4. Trigonelline (alkaloid)
 Trigonelline a methylbetaine derivative of nicotinic acid
 Molecular formula C7 H7 NO2

25. Trigonelline
Improved the insulin signaling pathway in the muscle
Activating
IR-PH
(insulin receptor pleckstrin homology)
pAKT
GLUT4
(insulin regulated glucose transporter)
Mechanism of action

26. Synthesis

27. 5. Galactomannan (Soluble fiber)
Structurally composed of a 1,4-β-D-mannosyl backbone substituted by a single
galactose unit ᾳ-linked at the C-6 oxygen
Major polysaccharide with rigid hydrophilic backbone (polymanose) and galactose
units
1
4
Galactopyranose units

28. Have different galactose:mannose ratios and distributions of
galactopyranosyl units along the mannan chains
In fenugreek galactose:mannose ratio is 1:1
MECHANISM OF ACTION
Also exert hypoglycemic effect by increasing production of
GLP-1 stimulates insulin release, glucagon production and
delay the gastric emptying
 α-Amylase and Sucrase activity
GLP-1 act on G-protein coupled receptor of their own
Activate Adenyl cyclase cAMP
Exocytosis of insulin