Sulfonium-Ion Glycosidase Inhibitors and Their Derivatives

1. GRADUATE SEMINAR
Ande Chennaiah
13107064
Supervisor: Prof. Y. D. Vankar
Department of Chemistry
IIT Kanpur
Naturally Occurring Sulfonium-Ion
Glycosidase Inhibitors and Their
Derivatives
1

2. OUTLINE
 Introduction about glycosidase inhibitors
 Synthesis of Salacinol and their analogues
 Synthesis and structure elucidation of kotalanol
 synthesis of Ponkoranol
 Six and seven membered Salacinol analogues

3. Glycosidases
3

4. 4
Mechanism of inverting glycosidases
Biol. Rev. Cambridge Philosophic. Soc. 1953, 28, 416-436

5. Mechanism of retaining glycosidases
5

6. Effect of cationic character on anomeric carbon
Stereo-electronic
requirements
at this bond
Role of O-H in stabilization
6
The glycoside inhibitors are designed based on following consideration
Half chair Confirmation in
transition state

7. Types of glycosidase inhibitors
1. Carbasugars
2. Iminosugars
3.Thiosugars
4.Sulfonium ion Sugars
(-)-Swainsonine
Kojibioside
7

8. In 1984, Bernad Bellea et al proposed that S-methyl sulforphanol ( sulfonium ion analogue
Of Morphine) has biological activity .
In 1992, H. Siriwardena et al synthesized pyrrolizidine analogue of sulfonium ion showing
glycosidase inhibitory activity.
Can. J. Chem. 1985, 63, 1268-1274. 8

9. J. Chem. Soc., Chem. Commun. 1992, 1531-1533
Synthesis of 1,2-Dihydroxy-7-thia-3a-thioniaperhydropentalene Chloride
9

10. Similarity:-
Cationic character of the trivalent sulfur atom resembles that of the anomeric carbon of the
Transition state structure .
The permanent charge on sulfur would provide the necessary electrostatic stabilization to
bind competitively to glycosidase enzyme.
Tetrahedron Lett. 1994, 35, 8243.
Sulfonium ion GlycosidasesTransition state of GlycosidasesSulfimide derivative
Ki = 1.7 mM
10

11. Sulfonium-Ion Glycosidase Inhibitors Isolated from Salacia Species
11

12. 12
Salacinol
 Isolated in 1997, from Salacia reticulata by Yoshikawa et al
 Diabetics drank herbal extract, obtained by storing water overnight in a mug
made from the root of this plant
 Studies have shown that S. reticulata It is a potent -glycosidase inhibitor
Tetrahedron Lett. 1997, 48, 8367

13. 13

14. Synthesis of Thioarabinitol
14
Tetrahedron Lett, 1994, 35, 8243-8246.

15. Synthesis of 2,4-O- Benzylidine D-1,3 cyclic sulphate from D- Glucose
15

16. Synthesis of 2,4-O- Benzylidine- L-1,3 cyclic sulphate from L-Glucose
16
Carbohydr. Res. 1974, 35, 87-96

17. 17

18. Hughes-Ingold solvent effect:-
If the transition state for a reaction has a larger charge than the reactants, then the rate and
yield of reaction will increase as the polarity of the solvent increases.
18
Synlett , 9, 2003, 1259-1262.

19. Bio.org. Med. Chem. Lett. , 2009, 19 , 2195–2198. 19

20. IR : 1262 Cm-1
13C = 80.6 ppm
No sulphate
peak in IR
13C= 75.3 ppm
De-O-Sulfonated SalacinolSalacinol
Enzyme Inhibition:-
It is noteworthy that desulfonated salacinol maintained almost equal
activities to salacinol irrespective of species of the counteranion towa-
rds - Glucosidase enzyme.
20

21. Carbohydr. Res. 2005, 340, 2612
21
Synthesis of D-lyxitol and D-ribitol analogues of the Salacinol

22. 22
Carbohydr. Res. 2005, 340, 2612–2619.

23. 23

24. Activity:-
 It is important to notice that the above D-Lyxitol and D- Ribitol analogues of salacinol
are not
Showing any inhibitory activity.
 Thus the D- arabinitol configuration in heterocyclic ring of salacinol is critical for
activity.
24

25. Substrate
Salacinol Acarbose
Maltase 0.31 0.12
Sucrase 0.32 0.37
Isomaltase 0.47 75
Ki(µM) values of salacinol and acarbose for rat small intestinal
disaccharidase
Ki (mg/ml) Ki (mg/ml)
Tetrahedron Lett, 1997, 38, 8367-8370. 25

26. Kotalanol
26

27. Synthesis of kotanalol from D-Persitol
Nat. Prod. Rep., 2010, 27, 481–488.
27

28. Synthesis of De-O-Sulfonated Kotanalol from D-Mannitol
Di-O-benzylidene
D-mannitol
28
Nat. Prod. Rep., 2010, 27, 481–488

29. 29

30. Structure determination of Kotanalol
1)
2) Through nOe analysis
30
Nat. Prod. Rep., 2010, 27, 481–488

31. S
From Salacinol
Experimental proof
31

32. Ki = 0.17 mM Ki = 0.25 mM
It can be fixed as “ S “
S R
Stereochemistry at C-4 and C-6
32

33. R Configuration at C-5' 13C-d 80.5 ppm 13C-d 81.8 ppm
33

34. R Configuration at C-5' 13C-d 80.5 ppm 13C-d 81.8 ppm
34

35. Nat. Prod. Rep., 2010, 27, 481–488 35
g-Gauche effect

36. Substrate Kotalanalol Acarbose
Maltase 0.23 0.12
Sucrase 0.18 0.37
Isomaltase 1.8 75
Ki(µM) values of kotalanol and acarbose for rat small intestinal
disaccharidase
Tetrahedron Lett. 1997, 38, 8367-8370. 36

37. Heteroanalogues of Kotalanol and De-O-Sulfonated Kotalanol
Org. Lett. 2010, 12,1088-1091.
37

38. The lesser steric congestion around the “ Se “ center as the Se–C bond was being formed,
owing to the Se–C bond being longer than the S–C bond, observed the formation of both
diastereomers for selenium.

39. Synthesis of PMB-protected D- selenoarabinitol
J. Org. Chem., 2005, 70,753-755. 39

40. Synthesis of PMB-protected D-iminoarabinitol
J. Org. Chem, , 2006, Vol. 71, 3009.

41. 41

42. Synthesis of De-O- sulfonated Compounds
Enzyme Inhibition Study
42

43. 43

44. Ponkoranol
Retrosynthesis
J. Org. Chem.2006, 71, 1111-1118.
44

45. Synthesis of corresponding cyclic sulphates
45

46. Ki = 0.25 mM Ki = 0.17 mM
46

47. De-O-Sulfonated ponkoranaol
Retrosynthesis
47

48. Synthesis:-
1st Method
2nd Method
Org. Lett, 2010, 12, 1632-1635.

49. 49
Synthesis of 5’ stereoisomer of Ponkoranol

50. 50
Replacingthe sulfatemoiety by a methyl ether in Ponkoranol

51. Enzyme inhibition study
Inhibitor Ki Value
3’-O-methyl Ponkoranol 0.50 ± 0.04mM
De-O-sulfonated Ponkoranol 43 ± 3 nM
Ponkoranol 5’ stereoisomer 15 ± 1 nM
51

52. 6 and 7 membered Salacinol analogues

53. Tetrahedron: Asymmetry, 1996, 7, 3087-3090.
53
Carbohydr. Res.1971, 18, 342-344.

54. 54
Synthesis of acetylated Thioglucopyranose

55. J. Org. Chem., 1975, 58, 4.
JACS., 2006, 128, 227-239.

56. 56

57. Enzyme Inhibtion:-
None of the above compounds shown considerable inhibition
57

58. 58

59. 59

61. Enzymes
α-Glucosidase
(Rice)
1.41 1.32 NI
α-Glucosidase
(Baker yeast)
NI NI NI
β-Galactosidase
(A. oryze)
NI 0.85 NI
α-Manosidase
(Jack beans)
0.46 1.34 1.83
Evaluation of enzyme inhibition properties (Ki in mM)
61

62. Conclusion
62
 In the last 20 years, the rate of discoveries in this field has increased enormously!
 Some of these molecules have been considered as therapeutics for diabetes and are
under clinical trials. Ex- Salacinol and De-O-sulfonated Kotalanol
The synthesis and study of sulfoinum ion glycosidase inhibitors is quite a
Young discipline, has large scope for synthetic organic chemists to develop
novel molecules as better and selective glycosidase inhibitors