Anatoxins

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Aflatoxins are potent mycotoxins produced by the fungi Aspergillus flavus and A. parasiticus. Four main naturally occurring aflatoxins, aflatoxins B^ B2, Gi, and G2 (Figure 3.50), are recognized, but these can be metabolized by microorganisms and animals to other aflatoxin structures, which are also toxic. Aflatoxin B1 is the most commonly encountered member of the group, and is also the most acutely toxic and carcinogenic example. Aflatoxin B2 is a dihydro derivative of aflatoxin B1, whilst aflatoxins G1 and G2 are an analogous pair with a six-membered lactone rather than a five-membered cyclopentenone ring. These toxins are most commonly associated with peanuts (groundnuts), maize, rice, pistachio nuts, and Brazil nuts, though other crops can be affected, and, although found world-wide, they are particularly prevalent in tropical and subtropical regions. Aflatoxin M1 (Figure 3.50) is a hydroxy derivative of aflatoxin B1 and equally toxic. It may occur in cow's milk as a result of mammalian metabolism of aflatoxin B1 originally contaminating the animal's food. Because these compounds fluoresce strongly under UV light, they are relatively easily detected and monitored.

The aflatoxins primarily affect the liver, causing enlargement, fat deposition, and necrosis, at the same time causing cells of the bile duct to proliferate, with death resulting from irreversible loss of liver function. In the case of aflatoxin B1, this appears to be initiated by cytochrome P-450-dependent metabolism in the body to the epoxide (Figure 3.50). The epoxide intercalates with DNA, and in so doing becomes orientated towards nucleophilic attack from guanine residues. This leads to inhibition of DNA replication and of RNA synthesis, and initiates mutagenic activity. Aflatoxins are also known to cause hepatic carcinomas, this varying with the species of animal. The above normal incidence of liver cancer in parts of Africa and Asia has been suggested to be linked to the increased amounts of aflatoxins found in foodstuffs, and a tolerance level of 30 ppb has been recommended. Acute hepatitis may result from food containing aflatoxin B1 at levels of the order of 0.1 ppm, and levels of more than 1 ppm are frequently encountered.

The biosynthesis of aflatoxins proceeds through intermediates sterigmatocystin and versicolorin (see Figure 3.49). Toxins related to these structures but differing in aromatic substituents are also produced by various fungi. The sterigmatocystins are synthesized by species of Aspergillus and Bipolaris, and contain a reduced bifuran fused to a xanthone, whilst the versicolorins from Aspergillus versicolor contain the same type of reduced bisfuran system but fused to an anthraquinone. Like the aflatoxins, the sterigmatocystins are acutely toxic and carcinogenic. The versicolorins are less toxic though still carcinogenic.

Lactone Ring Aflatoxin And

carbonyl functionality. Aflatoxin G1 is derived by further modification of aflatoxin Bi, cleaving the cyclopentenone ring and forming a lactone, perhaps via a further Baeyer-Villiger reaction.

Hexanoate is also likely to feature as a starter unit in the formation of the cannabinoids, a group of terpenophenolics found in Indian hemp (Cannabis sativa; Cannabaceae). This plant, and preparations from it, known under a variety of names including hashish, marihuana, pot, bhang, charas, and dagga, have been used for centuries for the pleasurable sensations and mild euphoria experienced after its consumption, usually by smoking.

The principal psychoactive component is tetrahy-drocannabinol (THC) (Figure 3.51), whilst structurally similar compounds such as cannabinol (CBN) and cannabidiol (CBD), present in similar or larger amounts, are effectively inactive. In recent years, the beneficial effects of cannabis*, and especially THC, in alleviating nausea and vomiting in cancer patients undergoing chemotherapy, and in the treatment of glaucoma and multiple sclerosis, has led to a study of cannabinoid analogues for potentially useful medicinal activity. All the cannabinoid structures contain a monoter-pene C1o unit attached to a phenolic ring having a C5 alkyl chain. The aromatic ring/C5 chain

CoAS

3 x malonyl-CoA

SEnz aldol

CO2H

hexanoyl-CoA

SEnz aldol

geranyl PP

CO2H

olivetolic acid

olivetolic acid

Allyl Carbocation

electrophilic cyclization on to carbocation geranyl PP

oxidation to allylic cation; allows change in configuration around double bond (see Figure 3.52) OH

C-alkylation oxidation to allylic cation; allows change in configuration around double bond (see Figure 3.52) OH

CO2H

electrophilic cyclization on to carbocation

CO2H

b nucleophilic attack of hydroxyl on to carbocation

cannabigerolic acid

sequential oxidation of cyclohexene gives aromatic ring sequential oxidation of cyclohexene gives aromatic ring

cannabidiolic acid tetrahydrocannabinolic acid decarboxylations -CO2 facilitated by ortho hydroxyl

CO2H

cannabinolic acid -CO2

OH cannabidiol CBD

OH cannabidiol CBD

tetrahydrocannabinol THC

CO2H

cannabinolic acid -CO2

cannabinol CBN

tetrahydrocannabinol THC

cannabinol CBN

is likely to originate from hexanoate and mal-onate, cyclization to a polyketide giving olive-tolic acid, from which cannabigerolic acid can be obtained by C-alkylation with the monoterpene unit geranyl diphosphate (Figure 3.51). Cyclization in the monoterpene unit necessitates a change in configuration of the double bond, and this may be rationalized as involving the allylic cation, which will then also allow electrophilic cyclization to proceed (for further detail see Figure 3.52, and compare terpenoid cyclization mechanisms, page 173). Cannabidiolic acid is the result of proton loss, whilst tetrahydrocannabinolic acid is the product from heterocyclic ring formation. CBD and THC are then the respective decarboxylation products from these two compounds. The aromatic terpenoid derived ring in cannabinolic acid and cannabinol can arise via a dehydrogenation process (compare thymol, page 186).

Figure 3.52

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