Podophyllum

Podophyllum consists of the dried rhizome and roots of Podophyllum hexandrum (P. emodi) or P. peltatum (Berberidaceae). Podophyllum hexandrum is found in India, China, and the Himalayas and yields Indian podophyllum, whilst P. peltatum (May apple or American mandrake) comes from North America and is the source of American podophyllum. Plants are collected from the wild. Both plants are large-leafed perennial herbs with edible fruits, though other parts of the plant are toxic. The roots contain cytotoxic lignans and their glucosides, P. hexandrum containing about 5%, and P. peltatum about 1%. A concentrated form of the active principles is obtained by pouring an ethanolic extract of the root into water, and drying the precipitated podophyllum resin or 'podophyllin'. Indian podophyllum yields about 6-12% of resin containing 50-60% lignans, and American podophyllum 2-8% of resin containing 14-18% lignans.

MeO'

MeO'

R = Me, podophyllotoxin R = H, 4'-demethylpodophyllotoxin

R = Me, podophyllotoxin R = H, 4'-demethylpodophyllotoxin

MeO y OMe OR

MeO y OMe OMe desoxypodophyllotoxin

OMe podophyllotoxone

OMe podophyllotoxone

O O

MeO y OMe OH

4'-demethylepipodophyllotoxin

MeO y OMe OR

MeO y OMe OMe desoxypodophyllotoxin

Podophyllin Resin

Figure 4.21

MeO y OMe OH teniposide

Figure 4.21

The lignan constituents of the two roots are the same, but the proportions are markedly different. The Indian root contains chiefly podophyllotoxin (Figure 4.21) (about 4%) and 4 -demethylpodophyllotoxin (about 0.45%). The main components in the American root are podophyllotoxin (about 0.25%), g>-peltatin (about 0.33%) and a-peltatin (about 0.25%). Desoxypodophyllotoxin and podophyllotoxone are also present in both plants, as are the glucosides of podophyllotoxin, 4-demethylpodophyllotoxin, and the peltatins, though preparation of the resin results in considerable losses of the water-soluble glucosides.

Podophyllum resin has long been used as a purgative, but the discovery of the cytotoxic properties of podophyllotoxin and related compounds has now made podophyllum a commercially important drug plant. Preparations of podophyllum resin (the Indian resin is preferred) are effective treatments for warts, and pure podophyllotoxin is available as a paint for venereal warts, a condition which can be sexually transmitted. The antimitotic effect of podophyllotoxin and the other lignans is by binding to the protein tubulin in the mitotic spindle, preventing polymerization and assembly into microtubules (compare vincristine, page 356, and colchicine, page 343). During mitosis, the chromosomes separate with the assistance of these microtubules, and after cell division the microtubules are transformed back to tubulin. Podophyllotoxin and other Podophyllum lignans were found to be unsuitable for clinical use as anticancer agents due to toxic side-effects, but the semi-synthetic derivatives etoposide and teniposide (Figure 4.21), which are manufactured from natural podophyllotoxin, have proved excellent antitumour agents. They were developed as modified forms (acetals) of the natural

base removes acidic proton a to carbonyl and OH generates enolate anion

NaOAc O

OMe OMe podophyllotoxin

reformation of keto form results OH in change of stereochemistry OH

Figure 4.22

Figure 4.22

MeO y OMe OMe picropodophyllin

MeO y OMe OMe picropodophyllin

4-demethylpodophyllotoxin glucoside. Attempted synthesis of the glucoside inverted the stereochemistry at the sugar-aglycone linkage, and these agents are thus derivatives of 4 -demethylepipodophyllotoxin (Figure 4.21). Etoposide is a very effective anticancer agent, and is used in the treatment of small cell lung cancer, testicular cancer and lymphomas, usually in combination therapies with other anticancer drugs. It may be given orally or intravenously. The water-soluble pro-drug etopophos (etoposide 4 -phosphate) is also available. Teniposide has similar anticancer properties, and, though not as widely used as etoposide, has value in paediatric neuroblastoma.

Remarkably, the 4 -demethylepipodophyllotoxin series of lignans do not act via a tubulin-binding mechanism as does podophyllotoxin. Instead, these drugs inhibit the enzyme topoisomerase II, thus preventing DNA synthesis and replication. Topoisomerases are responsible for cleavage and resealing of the DNA strands during the replication process, and are classified as type I or II according to their ability to cleave one or both strands. Camptothecin (see page 365) is an inhibitor of topoisomerase I. Etoposide is believed to inhibit strand-rejoining ability by stabilizing the topoisomerase II-DNA complex in a cleavage state, leading to double-strand breaks and cell death. Development of other topoisomerase inhibitors based on podophyllotoxin-related lignans is an active area of research. Biological activity in this series of compounds is very dependent on the presence of the trans-fused five-membered lactone ring, this type of fusion producing a highly-strained system. Ring strain is markedly reduced in the corresponding cis-fused system, and the natural compounds are easily and rapidly converted into these cis-fused lactones by treatment with very mild bases, via enol tautomers or enolate anions (Figure 4.22). Picropodophyllin is almost devoid of cytotoxic properties.

Podophyllotoxin is also found in significant amounts in the roots of other Podophyllum species, and in closely related genera such as Diphylleia (Berberidaceae).

oil from the bark of cinnamon (Cinnamomum zeylanicum; Lauraceae), widely used as a spice and flavouring. Fresh bark is known to contain high levels of cinnamyl acetate, and cinnamalde-hyde is released from this by fermentation processes which are part of commercial preparation of the bark, presumably by enzymic hydrolysis and participation of the reversible aldehyde - alcohol oxidoreductase. Cinnamon leaf, on the other hand, contains large amounts of eugenol (Figure 4.23) and much smaller amounts of cinnamaldehyde. Eugenol is also the principal constituent in oil from cloves (Syzygium aromaticum; Myrtaceae), used for many years as a dental anaesthetic, as well as for flavouring. The side-chain of eugenol is derived from that of the cinnamyl alcohols by reduction, but differs in the location of the double bond. This change is accounted for by resonance

OCOCH3

cinnamaldehyde cinnamyl acetate

OH eugenol

myristicin

OMe OMe anethole estragole

(methylchavicol)

OH eugenol

myristicin

O MeO y OMe OMe elemicin

Figure 4.23

Ar' ^ "OH cinnamyl alcohol loss of hydroxyl as © leaving group

Ar resonance-stabilized allylic cation

NADPH

Ar ^ propenylphenol

etc OMe

OMe OH

NADPH

allylphenol etc OMe

OMe OH

Figure 4.24

forms of the allylic cation (Figure 4.24), and addition of hydride (from NADPH) can generate either allylphenols, e.g. eugenol, or propenylphenols, e.g. anethole (Figure 4.23). Loss of hydroxyl from a cinnamyl alcohol may be facilitated by protonation, or perhaps even phosphorylation, though there is no evidence for the latter. Myristicin (Figure 4.23) from nutmeg (Myristica fragrans; Myristicaceae) is a further example of an allylphe-nol found in flavouring materials. Myristicin also has a history of being employed as a mild hallucinogen via ingestion of ground nutmeg. Myris-ticin is probably metabolized in the body via an amination reaction to give an amfetamine-like derivative (see page 385). Anethole is the main component in oils from aniseed (Pimpinella anisum; Umbelliferae/Apiaceae), star anise (Illi-cium verum; Illiciaceae), and fennel (Foeniculum vulgare; Umbelliferae/Apiaceae). The propenyl components of flavouring materials such as cinnamon, star anise, nutmeg, and sassafras (Sassafras albidum; Lauraceae) have reduced their commercial use somewhat since these constituents have been shown to be weak carcinogens in laboratory tests on animals. In the case of saf-role (Figure 4.25), the main component of sassafras oil, this has been shown to arise from hydroxylation in the side-chain followed by sul-phation, giving an agent which binds to cellular macromolecules. Further data on volatile oils containing aromatic constituents isolated from these and other plant materials are given in Table 4.1. Volatile oils in which the main components are terpenoid in nature are listed in Table 5.1, page 177.

ho3so

A

HO;i

A?

-A

safrole

Table 4.1 Volatile oils containing principally aromatic compounds

Volatile or essential oils are usually obtained from the appropriate plant material by steam distillation, though if certain components are unstable at these temperatures, other less harsh techniques such as expression or solvent extraction may be employed. These oils, which typically contain a complex mixture of low boiling components, are widely used in flavouring, perfumery, and aromatherapy. Only a small number of oils have useful therapeutic properties, e.g. clove and dill, though a wide range of oils is now exploited for aromatherapy. Most of those employed in medicines are simply added for flavouring purposes. Some of the materials are commercially important as sources of chemicals used industrially, e.g. turpentine.

For convenience, the major oils listed are divided into two groups. Those which contain principally chemicals which are aromatic in nature and which are derived by the shikimate pathway are given in Table 4.1 below. Those oils which are composed predominantly of terpenoid compounds are listed in Table 5.1 on page 177, since they are derived via the deoxyxylulose phosphate pathway. It must be appreciated that many oils may contain aromatic and terpenoid components, but usually one group predominates. The oil yields, and the exact composition of any sample of oil will be variable, depending on the particular plant material used in its preparation. The quality of an oil and its commercial value is dependent on the proportion of the various components.

Oil

Plant source

Plant part used

Oil content (%)

Major constituents with typical (%) composition

Uses, notes

Aniseed

Pimpinella anisum

ripe fruit

2-3

anethole (80-90)

flavour, carminative,

(Anise)

(Umbelliferae/ Apiaceae)

estragóle (1-6)

aromatherapy

Star anise

Illicium verum (Illiciaceae)

ripe fruit

5-8

anethole (80-90) estragóle (1-6)

flavour, carminative fruits contain substantial amounts of shikimic and quinic acids

Cassia

Cinnamomum cassia (Lauraceae)

dried bark, or leaves and twigs

1-2

cinnamaldehyde (70-90) 2-methoxycinnamal-dehyde (12)

flavour, carminative known as cinnamon oil in USA

Cinnamon bark

Cinnamomum zeylanicum

(Lauraceae)

dried bark

1-2

cinnamaldehyde (70-80) eugenol (1-13) cinnamyl acetate (3-4)

flavour, carminative, aromatherapy

Cinnamon leaf

Cinnamomum zeylanicum

(Lauraceae)

leaf

0.5-0.7

eugenol (70-95)

flavour

('Continued overleaf )

('Continued overleaf )

Table 4.1 (Continued)

Oil Plant source Plant part Oil Major constituents with Uses, notes used content typical (%) composition

Clove

Fennel

Nutmeg

Wintergreen

Syzygium aromaticum (Eugenia caryophyllus) (Myrtaceae)

Foeniculum vulgare

(Umbelliferae/

Apiaceae)

Myristica fragrans (Myristicaceae)

dried flower buds ripe fruit seed

Gaultheria procumbens (Ericacae) or Betula lenta (Betulaceae)

leaves bark

15-20

5-16

eugenol (75-90) eugenyl acetate (10-15) ß-caryophyllene (3)

anethole (50-70) fenchone (10-20) estragole (3-20)

sabinene (17-28) a-pinene (14-22) ß-pinene (9-15) terpinen-4-ol (6-9) myristicin (4-8) elemicin (2)

methyl salicylate (98%)

flavour, aromatherapy, antiseptic flavour, carminative, aromatherapy flavour, carminative, aromatherapy although the main constituents are terpenoids, most of the flavour comes from the minor aromatic constituents, myristicin, elemicin, etc myristicin is hallucinogenic (see page 385)

flavour, antiseptic, antirheumatic prior to distillation, plant material is macerated with water to allow enzymic hydrolysis of glycosides methyl salicylate is now produced synthetically

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