Methods of developing new secondary metabolites

Vintha M. Thadhani1, Syed G. Musharraf2, Afshan Begum2, M. Iqbal Choudhary2 & Veranja Karunaratne3

1Institute of Chemistry, Colombo, Sri Lanka; 2ICCBS, University of Karachi, Pakistan,3University of Peradeniya,

Sri Lanka

LichensSymbiotic association of fungus & algaeWorldwide distribution Able to grow under extreme conditionsAbout 20,000 lichen species identified . Still many lichen rich areas remain unexploredTotal number may well be close to 100,000.

Secondary metabolites of lichensOccurs exclusively in these symbiotic organismsEven with the advances of analytical methods,

there is comparatively less isolation of new lichen metabolites may be due to the limited biosynthetic pathways.

Approximately only 1050 lichen metabolites have been isolated to date.

Polyketides- common classes of compounds reported from lichens

Secondary metabolites of lichens- Rich source of biologically active compounds

We have already reported various biological activities of lichen compounds including, – antioxidant, – α-glucosidase inhibitory,– urease inhibitory, – antimicrobial, – cytotoxicity etc

Common secondary metabolites of lichens

Biotransformation of major lichen metabolites-Zeorin

Zeorin isolated in 3.4% yield from Cladonia sp.

Subjected to various bioassaysPatent obtained for α-

glucosidase inhibitory activity.

Biotransformation through Cumingharella elegans

Yielded 1,3-diacylglycerol & diacylperoxide.

1,3-diacylglycerol

1-(5-dodecenoyl), 3-(5-decanoyl)glycerol

Diacylperoxide

5-decenoic acid-1,1-diacylperoxide

Semisynthesis of minor metabolites

Complete synthesis of dibenzofurans-Reported

R

CO2H

RO OH

OR

CO2R

HO

R

O

O

+

CO2R

OR

OH

R

RO

R

Carboxylic ac id Benzyl esterDepside

esterification

O

R

CO2H

R

CO2R

ORRO

Smiles rear rangement

Diphenyl ether

1

2

3

4

5

6 7

1

2

3

4

5

6

7

1

23

4

5

67

1'

2'3'

4'

5'

6'7'

1

23

4

5

6 7

1'

2'3'

4'

5'

6'7'

(A) (B)

Pd(OAc)2/TFA

Depsides isolated in major quantities

O

OCH3

OHHO

CH3

OH

OH

O

Lecarnoric acid

O

OCH3

OHHO

CH3

OH

O

OCH3

CH3

CHO Atranorin

O

OCH3

OHHO

CH3

OH

O

O

CH2OH

OH

OH

Erythrin

Smiles rearrangement possible only with erythrin

O

OR

OHR/HO

R

OH

OR

O

O

OR

O-R/HO

R

OH

O

O

R

O-

OR

R/HO

R

OH

O

O

R

O

K2CO3

DMSO

Smiles rearrangement

Diphenyl ether

para depside

1

23

4

5

6

1'

2'3'

4'

5'

6'

Analogues of 5-decarboxydibenzofurans

CO2H

O

CH3CH3

HO OH

CO2R CO2H

O

CH3

HO

CH3

OH

CO2CH3NaOH/MeOH

Reflux

Diphenyl ether 1 Diphenyl ether 2R = -CH2CH(OH)CH(OH)CH2OH

O

OH

COOCH3

CH3H3C

OH

Dibenzofuran

Pd(OAc)2

TFA/Acetic acid

O

CH3

HO OH

CO2H

CH3

Hypostrepsilic acid

Formal synthesis of pannaric acid derivatives

CO2H

O

CH3CH3

HO OH

CO2RCO2CH3

O

CH3

HO

CH3

OH

CO2CH31) NaOH/MeOH

Diphenyl ether 1Diphenyl ether 2R = -CH2CH(OH)CH(OH)CH2OH

O

CH3

CO2CH3

OCH3H3C

OCH3

CO2CH3

O

OCH3

CO2CH3

CH3H3C

OCH3

CO2CH3

3-5'3-3'

Dibenzofuran 2Dibenzofuran 1

3

3'

55'

2) K2CO3/MeI

Some natural analogues of dibenzofuran

CO2CH3

O

OCH3

H3C

CH3

CO2H

OCH3

CO2H

O

OH

H3C

CH3

CO2H

OH

CO2H

O

OH

H3C

CH3

CO2CH3

OH

Iso-schizopeltic acid

Pannaric acid 9-Methylpannarate

B

CO2H

O

OCH3

H3C

CH3

CO2CH3

OCH3

Schizopeltic acid

Conclusion

This study reveals the possibility of conversion of major lichen specific secondary metabolites into new compounds through biotransformation and semi-synthesis.

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