chemistry of natural products (cnp)

1. CHEMISTRY OF VARIOUS NATURALLY
OCCURING COMPOUNDS
DRUGS ACTING ON CVS SYSTEM…
By : Mansi Panwar
M.Pharmacy( Pharmaceutical chemistry)
Punjabi University Patiala

2. DRUGS ACTING ON CVS SYSTEM ..
1. LOVASTATIN : (MEVINOLIN ,MEVACOR)
• It is a hypolipidaemic drug falls under HMG CoA( 3-hydroxy 3-
methyl glutaryl coenzyme A) reductase inhibitors category
collectively known as STATINS.
• It is a competitive inhibitor of HMG-CoA reductase which governs
the conversion of HMG-CoA to MEVALONATE and that further to
cholesterol at end of pathway
• SOURCE: Aspergillus terreus (fungus)
• Lovastatin is a secondary lactone metabolite Produced by this fungus .
• It is first statin produced and commercialised.

3. History :
• In 1973 fungal metabolites were isolated by a Japanese biochemist of
Sankyo company to check if they show some activity in reducing
the cholesterol levels or can block CH biosynthesis in general.
• As a result of which they isolated a compound from Penicillium
citrinum and named it COMPACTIN or MEVASTIN . Despite of
having a good inhibition activity against HMG-COA reductase it
failed in showing its activity in rats as showed aginst dog and
monkeys.
• In 1978, Alfred Albert’s e.tal at Merk research laboratories
discovered a new Natural product in a fermentation broth of
Aspergillus terreus And named it MEVINOLIN which later became
LOVASTATIN.

4. • Other sources of lovastatin includes Pleurotus ostreatus (oyster mushroom
contain 2.8 % lovastatin on dry wt. Basis
• STRUCTURE :
Its structure consists of hexahydronapthalene ring ,,a lactone
Ring , and a butyryl gp Attached to
decalin ring via ester linkage .
• butyryl gp substitution is
Specific for type 1 statins .

5. • STATIN PHARMACOPHORE is modified hydroxyglutaric acid
component ,which structurally resemble HMG-CoA and Mevaldyl CoA
transition state intermediate .
• It binds to same active site as substrate HMG-COA and inhibit the enzyme
HMG-CoA REDUCTASE .
• HMG –CoA is stetreoselective so Statins need to have
3R,5Rstereochemistry.
• The 3,5 dihydroxycarboxylate is essential for inhibition activity.
• Compounds containing lactone ring
Are prodrugs need in vivo hydrolysis.
• The double bond between C6,C7 can
Either increase or decrease the activity.

6. • IN butyryl gp substitution , stereochemistry of ester side Chain is importantt for
activity (ester linkage changes to ether linkage would results in decrease of activity
• Beta-OH gp at R1 enhances hydrophilicity and cellular specificity .
• Replacement of hexahydronapthalene ring with cyclohexane results in 10,000 fold
decrease in activity as this ring is needed for anchoring of compound to enzyme
active site .
• Methyl substitution at R2 possition increase activity (simvastatin is more potent
than lovastatin ).

7. • ANALOGUES OF LOVASTATIN :
• Lovastatin is lipophilic and given orally
In lactone precursor form .
• Absorption is Incomplete and first pass
metabolism is extensive.
.Metabolites are excreted in bile .
ONE OF ITS SERIOUS ADVERSE EFFECT IS MUSCLE DAMAGE (myopathy).

8. TEPROTIDE:
• It is a peptide isolated from venom of Brazilian viper (Bothrops jararaca) proven to
have Anti – hypertensive properties .
• It inhibits Angiotensin converting enzyme (ACE ) which convert angiotensin (i ) to
angiotensin( ii) .
HISTORY:
It was first observed by Sergio Ferreira in 1965 and isolated by Ferreira et al. In 1970
.but it was synthesized by Ondetti et al.
It was chosen as lead because of its long lasting in vivo activity .
• Study on dogs and rats show anti-hypertensive activity but has limited use because of
its expense and lack of oral activity .

9. • The presence of four proline and a pyroglutamate render this peptide resistant to hydrolysis ,but not
to a sufficient degree to allow it’s oral administration.
In the search for a better molecule scientists compare ACE with bovine Carboxypeptidase A.(the only
difference lies in both is that bovine carboxypeptidase A loses one amino acid and ACE loses two
amino acid during conversion).
On reaction with the substrate it was identified that enzyme had similar function (however altered by
one amino acid unit)
• Carboxypeptidase structure consist of : 1. Hydrophobic pocket 2. Ionic bond with –CooH 3. H-bond
with peptidic C- terminal 4. Zinc in coordination bond with carbonyl group .

10. •
carboxypeptidase A structure consists of : 1 hydrophobic
• Pocket 2.ionic bond with –CooH 3.H-bond With peptidic C-terminal
4.zinc ( in coordination bond with
Carbonyl )
• Interaction of ACE with N-succinyl amino acid (succinyl prolines )
leads to conclusion that : inhibitor
Should be able to interact with 1.proline carboxy (ionic
Bond) 2.amide function (hydrogen bond) 3.carboxy of
Succinyl moiety (coordination with zinc atom)

11. • Therefore ,N-succinyl amino acid were prepared .N-l-proline derivatives show some activity .
• Hydrophobic pocket was created by substituting the succinylProline moiety with methyl group i.e. –
CH3 at beta to amide was more active .
• Coordination with Zinc was achieved by replacing the carboxy function by a mercapto group.
• Hence ...captopril came into existence .
• There is gain in affinity observed with substitution of mercapto
Group but hydrophobicity can be achieved by introduction of
Another hydrophobic agent phenylethylresidue (enalprilat )But
Results in poor absorption by oral route so it’s is given as enalpril
i.e. Ethyl ester .
• The main side-effect associated with ACE inhibitors is dry cough due to
Accumulation of bradykinin due to inhibition of its degradation
By ACE .
About 70%of orally administered drug is absorbed.
Presence of food reduces it’s bioavailability .
Penetration in brain is poor .
It is partly metabolised and partly excreted unchaged in urine .

12. DICOUMAROL:
• Dicoumarol (3,3’-Methylene –bis - 4hydoxycoumarin) is a naturally occurring
coumarin based compound which has been used as oral anticoagulant .
• It is metabolically produced from coumarin which was first isolated from broth
Tonka bean ( Dipteryx odorata ) and the sweet clover (Melilotus alba and
Melilotus officinallis ).
• Dicoumarol derivative ,warfarin 3-(- acetonyl benzyl )-4-hydroxy coumarin ),is
commonly used as a natural anticoagulant for prevention of treatment of
excessive blood clotting disorder .

13. HISTORY :
• It was isolated by Karl Links laboratory at University of Wisconsin,6yr a
farmer had bought a dead cow and a milk can full of uncoagulated blood
to an agricultural extension station of the university .
• The cow had died of internal bleeding after eating moldy sweet clover
.Links work led to develop of rat poison warfarin and then to the
anticoagulant still in clinical use today .
Mechanism of action:
It competitively inhibits the vit k regeneration to its active form by
inhibiting vit- k epoxide enzyme which convert it to vit -k hydoxyquinone
and this make it enable to contribute to final gamma – carboxylation of
glutamate residue of prothrombin and factor VII ,IX,and X. This
carboxylation is essential for the ability of the clotting factors to bind to
calcium and bound to phospholipid surfaces , necessary for coagulation
sequence to proceed.

14. • Coumarin is water insoluble , however 4-hydroxy
• Substitution confers weakly acidic properties to the
Molecule that makes it wate rsoluble under slightly
Acidic conditions .
• Coumarin and 4-hydroxy coumarin dont posess
Anticoagulant activity as there are some properties
A compound must possess .
1. 4-hydroxyl group
a 3-substituent
a bis molecule

15. • SYNTHESIS OF DICOUMAROL :
• Warfarin [3-acetonyl-benzyl( 4-hydroxy coumarin)] ( first used as rat poison) is
marketed as sodium salt.
• It possess a chiral center .
• it’s S(-) enantiomer is 5-8 more potent
than R(+) enantiomer.
.but it is commercially available in racemic form .

16. ANALOGUE OF DICOUMAROL
• Tromexan or palentan(ethyl biscoumacetate ) chemically ethyl bis(4-
hydroxy-3-yl –acetate) coumarin. It is used as oral anticoagulantAnd
of quicker in action.
• It can be prepared bY condensing 4-hydroxycoumarin And Glyoxalic
acid In the following way:
• DICOUMAROL is 4-hydroxy coumarin
Derivative but warfarin,arenocumarol are
Synthetic 4-hydroxy coumarin derivative but
Substitution Of pyrone ring at 3-possition .
• DICOUMAROL ABSORB SLOWLY AND
UNPREDICTABLY .ITS METABOLISM IS DOSE
DEPENDENT –t1/2 PROLONGED AT HIGHER DOSES AND HAS POOR
GI.T. TOLERANCE.

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