cardiotonic steroids

1. 1
Presented by:-
M. Tech. (Pharm.) Sem. 1st
17PTPCM2717
DEPARTMENT OF PHARMACEUTICAL EDUCATION AND
RESEARCH (NIPER)
SECTOR- 67, S.A.S NAGAR, PUNJAB

2. Flow of presentation
Introduction
Cardiotonic Steroid’s
Previous synthetic approaches
New synthetic approaches
Total Synthesis and Biological evaluation of
Cardiotonic Steroids
Conclusion
2

3. Introduction
• Steroids are a structurally privileged class of bioactive natural products
found ubiquitously in nature
• These compounds are used naturally for a wide array of purposes
including hormonal/cell signaling, lipid membrane stability, and
defense mechanisms
• These steroidal core has treated human ailments such as cancer, heart
failure, inflammation, allergies, metabolic diseases, and other health
related areas like contraception and physical fitness
3
Biochemistry 6th Edition; 2016

4. Cont..
4
Biochm. Mol. Biol. Educ. 2008, 36, 244–248
Biochem. Mol. Biol. Educ. 2008, 36, 244–248

5. Cardiotonic Steroids
• Cardiotonic steroid mainly represent a important steroidal class which
consist a basic ring name is Cyclopentano- perhydro phenanthrine
β- face
α- face
5
Chemistry - A European Journal. 2012, 3092–3120.

6. Cont..
Natural sources
Chemical sources
Heart failure and cardenolide MOA
Binding mode of cardenolides
Reported activity of cardiotonic steroids
6

7. Natural source
• It was first reported in 1542, when the German physician and
professor of botany Leonard Fuchs compiled a herbarium of all plants
known at the time. He gave the plant its name (from digitulus meaning a
“small finger”)
• The most well-known plant containing cardiac steroids is the foxglove
• There are two type of natural source –
 Animal source
 Plant source
7
Molecules. 2000, 51–81

8. Cont..
1. Animal sources:-
8
Chem. - A Eur. J. 2012, 18, 3092 – 3120.

9. Cont..
2. Plant soureces :-
9
Chem. - A Eur. J. 2012, 18, 3092 – 3120.

10. Chemical source
10
Naunyn. Schmiedebergs. Arch. Pharmacol. 1985, 329 , 414–426

11. Heart failure and cardenolide MOA
Cardenolides act on the heart by binding and inhibiting the catalytic α-subunit
(isoforms α1, α2, α3, and α4) of the Na+/K+-ATPase pumps found on the
surface of cardiac myocytes
11

12. Binding mode of cardenolides
X-ray crystallographic analysis of Na+/K+-ATPase–cardenolide binding has
been achieved and revealed valuable insights into the nature of the binding
interactions involved. In one case, pig kidney Na+/K+-ATPase (α1 isoform)
was complexed with ouabain and the x-ray was resolved to 3.4 Å resolution.
12
Proc. Natl. Acad. Sci. 2013, 110 , 10958–10963.

13. Reported activity of cardiotonic steroids
CANCER TYPE COMPOUNDS CELL TYPE
Breast digitoxin, digoxin, proscillaridin A,
Oubain, digoxigenin, gitoxin,
gitoxigenin
MCF-7, MDA-MD-435
Prostate Oleandrin, oubain, digoxin, bufalin,
cinobufagenin
PC-3, LNCaP, DU145
Melanoma Digoxin, oleandrin, digitoxin,
proscillaridin A, oaubain, digitonin
UACC-62, BRO
13

14. Cont..
Lung Digitoxin, digoxin, oaubain,
unbs1450, oleandrin
A-549, NCI-H-398, Calu 1,
sklu 1, NCI-H6, H69AR
Leukemia Bufalin, oleandrin, digitoxin,
proscillaridin A, ouabain
HL60, U937, CCRF-CEM,
CEM-VM-1
Neuroblastoma
Digoxin, ouabain SH-SY5Y, Neuro-2a
Renal Digitoxin, digoxin, digitoxigenin,
proscillaridin A, ouabain
TK-10, ACHN
Myeloma
Digitoxin, digoxin, proscillaridin a,
digitoxigenin, ouabain, digitonin,
lanatocide C
8226-S, 8226-LR5, 8226-
DOX-40
Pancreatic Oleandrin PANC-1
14Nat Rev Drug Discov 2008, 7, 926–935.

15. Previous synthetic approaches
Bachmann’s synthesis of Equillin.
Daniewski and co-workers reported the
first synthesis cardenolide core.
First total synthesis of a natural
cardenolide
Deslongchamp’s synthesis of ouabain
15

16. Cont..
Bachmann’s synthesis of Equillin :-.
16
J. Am. Chem. Soc. 1940, 62 , 824–839

17. Cont..
Deslongchamp’s synthesis of ouabain :-
Preliminary Studies on a Michael/Aldol Cascade
17
Chem. - An Asian J. 2009, 4 , 725–741

18. Cont..
Glycosylation of Ouabagenin to Ouabain
18
Org. Lett. 2002, 4 , 4693–4696.

19. New synthetic approaches
1. Rationale for new synthetic approach :-
• One of the main hurdles associated with these approaches is modularity; and the
design of more drug-oriented approaches remains a formidable challenge.
• When a synthetic route is conceived specifically to access a single complex target, it
is often not amenable to diversification and the accessible chemical space
surrounding the target is limited.
• For the purpose of exploring new therapeutic agents, it is highly desirable that a
methodological approach features access to an entire class of natural products.
• In this regard, modularity and plasticity should be ingrained in the synthetic
foundation of the approach. Designing such a method requires a convergent
technique
2. Methodological design overview :-
19
Molecules. 2000, 51–81

20. Cont..
3. Michael donor fragment design :-
4. Michael acceptor fragment design :-
20

21. Cont..
5. Cyclization of michael adducts into steroidal cores :-
6. Origin of stereodivergent cyclization results :-
Two-step Cyclization Approach to cis-β-C/D Steroidal Core.
21

22. Cont..
Suggested Pathways for Diastereoselective Michael Adduct Cyclization
22

23. Cont..
Synthesis of cis-β-C/D Steroidal Cores Via Two-step Protocol
23
J. Am. Chem. Soc. 2015, 137 , 14341–14348

24. Total synthesis and biological evaluation
24
Angew. Chemie - Int. Ed. 2013, 52 , 5300–5304.

25. Cont..
Retrosynthesis of Selected Targets via Key Intermiate
25
J. Am. Chem. Soc. 2015, 137 , 14341–14348.

26. Conclusion
26
•A variety of uniquely structured β-ketoesters and 2-substituted enones could
be successfully coupled under these conditions. This allowed the synthesis
of a library of Michael adducts in excellent selectivity
•At this stage cyclization studies were undertaken to affect a double aldol
reaction and complete the steroidal nucleus
•They discovered stereo divergent conditions for producing the steroidal
cores. Depending on the conditions used, produces cis-α-C/D or cis-β-C/D
ring junctions.
J. Am. Chem. Soc. 2015, 137 , 14341–14348.

27. Cont..
27
Summary of Stereo divergent Cyclization Results

28. Cont…
28
Target and Required Modification :-

29. Structure activity relationship (SAR)
29