CHAPTER – I

Introduction to bioactive natural compounds

Introduction to bioactive natural compounds

The term macrocycle refers to medium- and large-ring compounds,

with respectively, 8-11 and 12 or more atoms in the ring. Macrocyclic

structures that have one or more ester linkages are generally referred

to as macrolides or macrocyclic ring lactones.1-4 In some cases,

macrocyclic lactams have also been described as macrolides.

Originally macrolides denoted a class of antibiotics derived from

species of Streptomyces and containing a highly substituted

macrocyclic lactone ring aglycone with few double bonds and one or

more sugars, which may be amino sugars, non-nitrogen sugars or

both.5 To our knowledge the largest naturally occurring macrolides are

the 60-membered quinolidomycins6 and the largest constructed

macrolide is the 44-membered swinholide.7 Isolation and biological

activities of some of these natural products are discussed below.

In 1927 Kerchbaum8 isolated the first macrocyclic lactone,

exaltolide 1 and ambrettolide 2, from Angelica root and Ambrette seed

oil, respectively. The discovery of these vegetable musk oils aroused

interest in finding synthetic routes to these and related macrolides

owing to commercial importance in the fragrance industry.2 Even

today exaltolide 1, is one of the most widely produced macrocyclic

musk lactones (Figure 1.1). The production was estimated at 200

tons in 1996. The importance of macrocyclic musks is increasing due

to their ready biodegradability.

O

O

O

O

1 2

Figure 1.1

The interest in macrolides has grown enormously since the 1950’s.

Chemical Abstracts (CA) (August 2001) gave over 7500 references to

macrolides, of which 965 are classified as reviews. In 1990 CA cited

241 publications about macrolides in one year, while ten years later

the number was 670. The tremendous interest in macrolide chemistry

can be understood if one takes a look at the diversity of the structures

and physiological effects of macrolides. Natural products containing a

macrolactone framework are found in plants, insects, and bacteria

and they may be of terrestrial or marine origin. The great importance

of macrolides is showing wide range of biological activity. Few of those

(Figure 1.2) such as erythromycin9 3, is widely used to treat bacterial

infections, and because of their safety and efficacy, they are still the

preferred therapeutic agents for treatment of respiratory infections

and the biopesticide spinosad, a mixture of spinosyn A and D,10 4 is

currently marketed for use against a wide variety of insects.

Epothilones11 5, with a mode of action similar to that of Taxol and the

potential to overcome known mechanisms of drug resistance, are

considered to be promising anticancer drug.

O

O

O

R

H

H

H

H

OOMe

OMe

ON

4 Spinosyn A (R= H) and D (R=Me) insecticidal

O

O OH O

OH

OS

N

5 Epothilone A anticancer

O

O

O

OO

HOOH

OO

N

OHOMe

HO

3 Erythromycin A antibiotic

OMeOH

OO

Figure 1.2

Owing to their immense biological and pharmacological

importance, macrolides have attracted a great attention of organic

chemists worldwide. Recent findings in the field of macrolides revealed

that most of pharmacologically active macrolides have highly

substituted structures as can be seen from the few examples above.

However, complexity of the structure is not essential for biological

activity. Interestingly then, even very simple macrolides possess

properties that make them worth studying.

Verbalactone 6, a macrocyclic dimer lactone with C2- symmetry,

was isolated by Mitaku et al, from the roots of Verbascum undulatum,

Lam.12 a biennial plant widely spread in the Balkan peninsula. The

genus Verbascum, belongs to the family Scrophulariaceae, comprises

more than 300 species. This macrocycle is a symmetrical dimeric

lactone of (+) (3R-5R)-3-dihydroxy-5-decanolide 7 (Fig. 1.3), which is a

potent inhibitor of the enzyme HMG-CoA reductase.13

O

O

O

OHH

HOHO

H

H

6

1

2 4 6

81012

14

1517

18 22

O O

OH

7

1

3

5

Figure 1.3

6-Substituted-5,6-dihydro-2H-pyran-2-one (,-unsaturated--

lactone) 814 (Fig. 1.4) is an important structural subunit in many

biologically promising natural products. This unit is valuable for a

wide variety of biological activities, such as insect growth inhibition

and insect antifeedent, antifungal, and antitumor properties. The

pyrone units are widely distributed in all parts of plants (Lamiaceae,

Piperaceae, Lauraceae, and Annonaceae families) including leaves,

stems, flowers, and fruits. Various kinds of substitutions have been

found at the C-6 position of the ring such as polyacetoxy alkane,

polyhydroxy alkane, a combination of both, or even a simple alkane.

Biological activity of these types of molecules, their structural

complexities, and the challenge to synthesize them in optically pure

form made them an attractive target for many total syntheses.

1. 5,6-dihydropyran-2-one

R

O

O

12

3

4

56

8

Figure 1.4

(+)-Boronolide (9)

The (+)-boronolide 9 (Fig. 1.5) was isolated from the bark and

branches of Tetradenia fruticosa and from the leaves of Tetradenia

barbera,15 which have been used as local folk medicine in Madagascar

and southern Africa. (+)-Deacetylboronolide and (+)-

dideacetylboronolide were obtained from Tetradenia riparia,16 a cental

African species widely used as a tribal medicine. Medicinal properties

of boronolides have been exploited for a long time in crude form. Zulu

was used roots of these plants as an emetic, and infusion of leaves

has been reported to be effective against malaria.17

Figure 1.5

Tarchonanthuslactone (10)

R = R1 = Ac (+)-Boronolide

R = R1 = H (+)-Deacetylboronolide

R = H, R1 = Ac (+)-Dideacetylboronolide9

O

O

OR

OR

OR1

The simplest compound isolated with the syn-1,3-diol/5,6-

dihydropyran-2-one motif is the dihydrocaffeic ester,

tarchonanthuslactone 10.18 Some more complex examples of these

structures are cryptocarya diacetate 11 and cryptocarya triacetate 12.

Tarchonanthuslactone 10 was isolated by Bohlmann et al from

Tarchonanthustrilobus compositae (Fig. 1.6). Hsu et al., have reported

that tarchonanthuslactone lowers plasma glucose in diabetic rats.19

Figure 1.6

Passifloricin A (13)

Polyketide-type -pyrone passifloricin A20 13 (Fig. 1.7), was

isolated from the resin of Passiflora foetida var, hispida, a species from

the family Passifloraceae that grows in tropical zones of America and

was found to be active in the Artemia salina test. Passifloricin was

found to be active in the Artemia salina test.

O

OO

O

10. Tarchonanthus lactone

O

OOAcOAc

11. Cryptocarya diacetate

O

OOAcOAcOAc

12. Cryptocarya triacetate

13. Passifloricin A

OOHOHOH

n

n = 14

O

Figure 1.7

Kurzilactone (14)

Kurzilactone 14,21 (Fig. 1.8) a new ,-unsaturated--lactone, has

been isolated from the leaves of Cryptocarya kurzii. The structure of

kurzilactone was determined by spectroscopic methods. Kurzilactone

exhibits marked cytotoxicity against KB cells with IC50 = 1 g ml-1.

Figure 1.8

Massoialactone (15) and Argentilactone (16)

In 1977, Ruveda and co-workers reported the isolation of

argentilactone 1622 from Aristolochia argentina (Aristolochiaceae).

Later, this natural pyranone was also isolated from Chorisia crispflora

and Annona haematantha. Argentilactone 16 was shown to have

antileishmanial and cytotoxic activities. Massoialactone 1523 (Fig.

1.9) was first isolated from the bark oil of Cryptocarya massoia by Abe

in 1937. This lactone has been used for many centuries as a

constituent of native medicines.

O OH O

O

14. Kurzilactone

Figure 1.9

Strictifolione (17)

Strictifolione 1724 (Fig. 1.10) was isolated from Criptocarya

stricifolia and has shown to display antifungal activity.

Figure 1.10

(-)-Ratjadone (18)

In 1994, the polyketide ratjadone 18 (Fig. 1.11) was isolated from

cultures of Sorangium cellulosum strain Soce360.25 Ratjadone displays

potent in vitro antifungal activity with MIC values in the range from

0.004 to 0.6 g/mL for Mucor hiemalis, Phythophthora drechsleri,

Ceratocystis ulmi, and Monilia brunnea. Additionally, significant

cytotoxicity in mammalian L929 cell lines (IC50 = 0.05 ng/mL) and

HeLa cell line KB3.1 (IC50 = 0.04 ng/mL) has been demonstrated.26

O

O

16. (R)-Argentilactone

O

O

15. (R)-Massoialactone

O OOH

O

OH

18. (+)-Ratjadone

O

OHOH O

17. (+)-Strictifoline

Figure 1.11

Fostriecin (19)

Fostriecin 19 (Fig. 1.12) was isolated in 1983 from Streptomyces

pulveraceus.27 This compound displayed potent in vitro activiy against

a broad range of cancer cell lines and its inhibitory activity against

protein serine/threonine phosphatases.

Figure 1.12

(-)-Callystatin A (20)

(-)-Callystatin A 20 (Fig. 1.13) is a polyketide-based natural

product isolated in 1997 by Kobayashi et al from the marine sponge

Callyspongia truncata. It exhibits remarkable cytotoxicity with an IC50

value of 10pg/mL against KB cell lines and 20 pg/mL against L1210

cells.28

O

O

OOH

20. Callystatin A

Figure 1.13

Spicigerolide and related lactones

O

O

OHOH

HO

HO

19. Fostriecin

,-Unsaturated -lactones (+)-spicigerolide 21,29 (+)-hyptolide

22,30 (-)-synrotolide 2331 and (+)-anamarine 2432 (Fig. 1.14) have been

isolated from several Hyptis species and other botanically related

genera. These compounds contain a polyoxygenated chain connected

with an ,-unsaturated six memberted lactone and have been found

to show a range of pharmacological properties, such as cytotoxicity

against human tumor cells, antimicrobial and antifungal activity, etc.

(+)-Spicigerolide, for instance, has been found to exhibit cytotoxicity

with ED50 =1.5 g/mL in the human nasopharyngeal carcinoma (KB)

assay system. Other structurally similar lactones ‘synrolide’,

‘hypotolide’ and ‘anamarine’ from Hyptis and taxonomically related

species have been found to be antimicrobial.33

Figure 1.14

(6S)-5,6-dihydro-6-[(2R)-2-hdroxy-6-phenylhexyl]-2H-pyran-2-one

(25):

Hostettman et al isolated an α,β-unsaturated lactone in 2001 from

Ravensara crassifolia DANGUY (Lauraceae) (syn. Cryptocarya

OAc

OAc

OAc

OAc O

21. (-)-Spicigerolide

OOAc

OAc

OH

OH

23. (-)-Synrotolide

O

OAc

OAcOAc

22. Hypotolide

OOAc

OAc

OAc

OAc

24. (+)-Anamarine

O

OO

O

crassifolia Baker), tree growing up to 18-20m long in the eastern

region of Madagascar. The genus Ravensara is considered as endemic

to Madagascar. In a series of preliminary screenings, (6S)-5,6-

dihydro-6-[(2R)-2-hdroxy-6-phenylhexyl]-2H-pyran-2-one (25)34, was

isolated from above natural source displayed antifungal activity

against the phytopathogenic fungus Cladosporium cucumerinum in a

bioautographic TLC assay.

The minimum amount of compound 25 (Fig. 1.15) required to

inhibit Cladosporium cucumerimum fungal growth on TLC plates was 1

g. This amount was comparable to the minimum quantities in the

same assays of miconazole (1 g) and propiconazole (0.1 g), two

commercially available reference antifungal compounds.

O

O

OH1 2

3

4

56

1'2'

3'4'

5'6'

1"

2"

3"

4"

5"

6"

25. (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-

phenylhexyl]-2H-pyran-2-one

Figure 1.15

Stagonolides:

Antonio Evidente35 and co-workers reported new phytotoxic

metabolites, stagonolides, from pycnidial fungal Stagonospora cirsii, a

fungal pathogen isolated from Cirsium arvense. Six new nonenolides,

named stagonolides A-F (26-31), with interesting phytotoxic

properties were isolated from liquid and solid culture and

characterized using spectroscopic methods. The members of this

macrolide family have varied skeleton with alkyl side chains, epoxide

centers (Fig. 1.16).

O

R5O

R1R2

R3

R4

A (26) R1=H, R2=R3=O, R4=-OH, R5=-CH2CH2CH3

B (27) R1=-OH, R2=-H, R3=-OH, R4=-OH, R5=-CH2CH2CH3

C (28) R1=-OH, R2=-H, R3=-OH, R4=H, R5=-Me

Figure 1.16

Jatropha species:

The species belonging to the genus Jatropha have created a

considerable amount of interest in recent years because of their

important medicinal activities. Some of the important Jatropha species

with their biological properties and bioactive constituents are

mentioned here. The latex of the plant employed to cure ulcers and

leprosy and the compound Jatrophone exhibits Cytotoxicity (Fig.

1.17).

O

OH

O

OMe

OH

O

OH

Me

MeH

H

OO

O

D (29) E (30) F (31)

O

O

O

32 Jatrophone

Figure 1.17

The toxicity of seeds of Jatropha curcas is ascribed mainly to a

group of diterpene esters termed the phorhol esters (33-37). They are

known to cause a wide range of biological effects including tumor

promotion and inflammation (Fig. 1.18).

O

O

O OHOH

O

O

O OHOH

O

O

O

O

33 34

OOH

O

O

O

O

O

OOH

O

O

35 36

OOH

O

O

O

O

37

Figure 1.18

A cyclic octapeptide, curcacycline-A 38 isolated from Jatropha

curcas showed immuno-suppressive activity. Curcacycline-B 39, also

isolated from Jatropha curcas enhanced rotamase activity of

cyclophilin B (Fig. 1.19).

N

HN

O

N

O

N

O

N

O

OH

O

N

NO

O

N

N

HH

H

H H

H

H

O

O

Curacacyclin-BCuracacyclin-A

N

O

N

O

O H

HN

O

H

NH

H

H

H

O

N

O

N

O

NO

N

H

38 39

Figure 1.19

Jatrogrossidion 40, the main diterpene of Jatropha grossidentata

was tested against Leshmania and Trypanosoma cruzi strains in vitro

as well as against Leishmania amazonensis in vivo (Fig. 1.20).

O

OH

O

40 Jatrogrossidion

Figure 1.20

A lactam namely jatropham 41 and a triterpane, acetylaleuritolic

acid 42 (Fig. 1.21) have shown tumour inhibitory properties against

the P-388 lymphocytic leukemia test system.

NOHO

H

AcO

H

COOH

41 Jatropham 42 Acetylaleuritolic acid

Figure 1.21

Jatrophatrione, a diterpene isolated from Jatropha macrorhiza was

found to be antitumor agent. The compounds chevalierin-A 43,

chevalierin-B 44 (Fig. 1.22) were isolated from Jatropha chevalieri

and the compound chevalierin-A36 was found to be antimalarial.

O

O

O

H

H

N

O

H

NO

H

N

H

O

O N

N

NO

O

N

O

ON

H

H

H

X

O

X = S Chevalierin-BX = S Chevalierin-A

43 Jatrophatrione 43 44

Figure 1.22

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