1. MPC DIV. FRIDAY SEMINAR
Introduction of carbohydrate based small molecule in the world of chemotherapeutics @
3:30 PM
Friday, 4 mar. 2016
CSN -014
An introduction of carbohydrate in the world of therapeutics and carbohydrate template in organic synthesis
Design and development of carbohydrate based potential chemotherapeutic agents and their Scope in Future Drug Discovery
KARTIKEY SINGH
UGC- SRF
MPC DIVISION,
CSIR-CDRI

2. Introduction: nature’s sweet code
Carbohydrates are ubiquitous, essential for life.
Besides their role in metabolism and as structural building blocks, they are fundamental constituents of every cell surface, where they are involved in vital cellular recognition processes.
Understanding the bioactive conformation and carbohydrates-protein interaction, allow the rational design of small drug like molecules with increased affinity, stability, and bioavailability.
Introduction of molecular diversity in carbohydrate is very high due to the occurrence of the two possible anomers and to the presence of commonly four or five attachment points per sugar unit with different stereochemistry.

3. Due to their relevant biological role and molecular diversity, carbohydrates are promising candidates for drug design and disease treatment.
Fig. 1: Fluid Mosaic model of Plasma Membrane

4. Figure 1. Cell surface carbohydrates are recognition molecules used in specific binding and interactions among cells, pathogens, and molecules.
Fig. 2: Cell surface carbohydrates are recognition molecules used in specific binding and interactions among cells, pathogens, and molecules

5. Different approaches to design carbohydrate based therapeutical agents
Design of carbohydrate-based therapeutics have following different approaches which are-
Native glycan approach:- This approach is used for the development of vaccines against viruses and bacteria. For example anticancer therapeutic vaccines and antibacterial vaccines were developed by this approach. This approach suffers from synthetic limitation and metabolic instability of the potential drug.

6. Glycomimetic approach:-Proper modifications of sugar unit allow a stronger interaction with the target receptor; this approach should guarantee a higher in vivo stability and better pharmacokinetic properties
Carbohydrate scaffolds approach:-this approach takes advantage of an unparalleled opportunity to generate libraries of high functional and structural diversity from carbohydrates.
Other's:- many other approaches involves the engineering of the drug structure onto a sugar moiety, linking of sugar moiety applying click chemistry , Glycosylation etc.

7. Glycomimetic approach
In this approach the new class of small drug molecules were developed by understanding the carbohydrate-protein interactions. This approach should guarantee a higher in vivo stability and better pharmacokinetic properties.
These compounds mimic the bioactive function of carbohydrates and address the drawbacks of carbohydrate leads, namely their low activity and insufficient drug-like properties.
Several modifications of the sugar backbone can be made towards glycomimetics.
Glycomimetic approach

8. Replacement of endocyclic oxygen-
Replacement of exocyclic oxygen-
In some cases, glycomimetics are modified in different
positions, through the introduction of pharmacophoric groups on the
sugar backbones.
In some cases, glycomimetics are modified in different positions, by the introduction of pharmacophoric groups on the sugar backbones

9. Glycosidase Inhibitors
Inhibition of carbohydrate-hydrolyzing enzymes α-glycosidase in the digestive tract that leads to a delay in digestion of ingested carbohydrates is one of the therapeutic approaches for the treatment of NIDDM type II.
Glycosidase enzyme-catalyzed hydrolysis of complex carbohydrates is a biologically widespread phenomenon in living systems.
Inhibition of glycosidase enzyme that involved in biosynthesis of glycoprotein have potential for many therapeutic application , such as treatment of cancer and viral infection.
Inhibition of α-glycosidase enzyme have therapeutic approach for the treatment of type II non-insulin- dependent diabetes mellitus (NIDDM).

10. Miglustat inhibits glucosylceramide synthase.
Miglustat (N-butyl-deoxynojirimycin), is the first iminosugar which is used primarily to treat Type 1 Gaucher disease.
Miglustat inhibits glucosylceramide synthase.
It is the first treatment approved by European Union for the treatment of progressive neurological manifestations in adult with Niemann-Pick type C disease (NPC).
NMDNJ and N-butyl-1-deoxy-galactonojirimycin are known for the treatment of Gaucher’s and Fabry’s diseases.
Miglustat (N-butyl-deoxynojirimycin, 42), a synthetic analogue of D-glucose, is the first iminosugar which is used primarily to treat Type 1 Gaucher disease under the trade name Zavesca. Miglustat inhibits glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids (GSL). Miglustat is used to treat adults with mild to moderate type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable and it is the first treatment to be approved for patients in the European Union for the treatment of progressive neurological manifestations in adult or pediatric patients with Niemann-Pick type C disease (NPC).

11. Inhibition of Golgi α -mannosidase II
Golgi -mannosidase II catalyzes the cleavage of two mannosyl linkages, an 1,3-linkage between M3 and M4 and an 1,6-linkage between M3 and M5, converting GnMan5Gn2 to GnMan3Gn2
Fig. 3: Golgi α -mannosidase II catalyzes the cleavage of two mannosyl linkages, an 1,3-linkage between M3 and M4 and an 1,6-linkage between M3 and M5, converting GnMan5Gn2 to GnMan3Gn2
PNAS , 2008, 05,

12. Figure 4: Role of glycans in cancer development and progression
Nature Reviews Cancer ,15, 540–55(2015)
Nature Reviews Cancer , 2015, 15, 540–55

13. Several glycosidase inhibitor-based molecules possess anticancer activity such as swainsonine and castanospermine.
Swainsonine inhibit Golgi α-mannosidase-II (GM-II)
Clinical trials suggested that swainsonine has therapeutic value because it reduces metastasis and improves clinical outcome in colon, breast, and skin cancers .
Unfortunately, there are side effects resulting from swainsonine treatment because it also inhibits a structurally related lysosomal mannosidase involved in catabolic processes.
Trends in carbohydrate research, 2015, 7, 1-21

14. Action of iminosugar as glycosidase inhibitor
Miglitol – α-Glycosidase inhibitor
Miglustat – Glucosylceramide synthase inhibitor
Swainosine – Golgi-α-mannosidase inhibitor
Miglitol – α-glycosidase inhibitor
Miglustat – glucosylceramide synthase inhibitor
Swinosine – golgi-α-mannosidase inhibitor

15. Neuraminidase inhibitor
Neuraminidase inhibitors (NAIs) are a class of drugs which block the  viral Neuraminidase enzyme.
Neuraminidase found on the surface of influenza virus that enables the virus to be released from the host cell.
Neuraminidase are  enzymes that cleave sialic acid groups from glycoprotein and are required for influenza virus replication.
Neuraminidase inhibitor

16. The paradigm of a glycomimetic drug in the classical sense is oseltamivir
Starting from a carbohydrate lead, drug likeness was achieved by systematically eliminating polar groups and metabolic soft spots that were not required for affinity.
J. Am. Chem. Soc. 1997, 119,
J. Am. Chem. Soc. 1997, 119,

17. Resistance development against old one demands new chemotherapeutic
Zin-Hyo Kim at all reported new class of neuraminidase inhibitor showing better activity against zanamivir and oseltamivir resistant strain.
Influenza NAs employ a covalent mechanism, author explored DFSAs as a possible new class of covalent mechanism–based influenza therapeutics.
Resistance devlopment against old one demands new chemotherapeutic
Science, 2013, Vol. 340, Issue 6128, pp.71-75

18. IC50 values(nM) in the enzyme inhibition assay for wild-type and mutant pairs.
IC50 values (nM) in the enzyme inhibition assay for wild-type and mutant pairs. Boldface
indicates resistance to zanamivir or oseltamivir. IC50 is the concentration of inhibitor that reduces enzyme
activity by 50% compared to the control uninhibited value. Values are the means of duplicate assays.
Science , 2013, Vol. 340, Issue 6128, pp.71-75

19. Neuraminidase inhibitor
FIG 5: Mechanistic action of neuraminidase inhibitors
Fig. 5: Mechanistic action of neuraminidase inhibitors
Science , 2013, Vol. 340, Issue 6128, pp.71-75

20. Drugs with simple carbohydrate moieties
Trends in carbohydrate research, 2015, 7, 1-21
Trends in carbohydrate research, 2015, 7, 1-21

21. Carbohydrate scaffolds approach
The ideal scaffold for this “biomimetic” approach has
Low molecular weight and a chemically stable nonbinding core with a number of functional groups of orthogonal reactivity.
The core must be rigid, allow a controlled 3-D and spatial orientation of pharmacophores required for tightest binding and the resulting molecule will require reasonable biological stability.
PK- parameters also required by the introduction of additional functional groups, for example, to improve solubility and permeability.
No scaffold is able to satisfy all these demands equally well.

22. In Aromatic Systems Easy to introduce substituent.
They are flat molecule making a true 3-D presentation of substituent is difficult.

23. In Peptides
Peptides provide an easy way to assemble a large variety of pharmacophores.
They are often not rigid enough.
The potential of peptides as drug candidates is limited by their poor pharmacokinetic properties
Labile in biological environments
Many peptides have a short half-life in vivo and a lack of oral availability

24. In Natural Products
In natural products such as alkaloids may have a well-defined rigid 3-D structure,
The introduction of substituents in the desired positions chemically challenging and may be unsuitable for the synthesis of compound libraries

25. Carbohydrate as scaffold
No. Of scaffolds AB
ABC
ABCD
1 (example: α-d-Glc) 20 60
120
2 (differing at only one stereocentre) 28 96
216
32 (max. number of unique patterns) 80
480
1920
ChemMedChem, 2006, 1, 1164 – 1194
ChemMedChem, 2006, 1, 1164 – 1194

26. β-D-Glucose Scaffold as a β-Turn Mimetic
Carbohydrate scaffolds as glycosyltransferase inhibitors
Johannes Zuegg
ChemMedChem, 2006, 1, 1164 – 1194
Nature Communications, 2015,  6, 7719 

27. Carbohydrate scaffolds as glycosyltransferase inhibitors
Nature Communications, 2015,  6, 7719 
Nature Communications, 2015,  6, 7719 

28. Carbohydrate based Antibiotics
Trends in carbohydrate research, 2015, 7, 1-21

29. From natural molecule to a synthetic drug
J. Med. Chem., 2008, 51 (5), pp 1145–1149
J. Med. Chem., 2008, 51 (5), pp 1145–1149

30. SGLT2 inhibitors for diabetes

31. Conclusion
Carbohydrate due to their structural diversity in term of functional group, stereochemistry and natural abundance are being seen can be used to develop new chemotherapeutic agents.
Role of glycoprotein's in cellular recognition give an advantage of development carbohydrate based small molecule in drug discovery.
More exploration of action of glycoprotein give more chance to develop new small molecule based therapeutics.
From small carbohydrate based lead molecule to structurally similar stable molecule provide greater efficacy towards the development of new drug.
Carbohydrate due to theire sturactura diversity in term of functional group, stereochemistry and natural abundence are being seen with curiosity to devlope new chemotherapeutic agents.

32. Knowledge is power 
Chemistry World, June 2008
It's in the hands of chemists to speed up the race from the lab to the clinic.
Chemistry World, June 2008, 62

33. Acknowledgement Dr. Rama Pati Tripathi (Supervisor)
Friday Seminar Committee
Lab mates
Friends
Dr. Rama Pati Tripathi (Supervisor)

34. Thank You
Thank You