Gossypol

Gossypol occurs in the seeds of cotton (Gossypium species, e.g. G. hirsutum, G. herbaceum, G. arboreum, G. barbadense; Malvaceae) in amounts of 0.1-0.6%. Its contraceptive effects were discovered when subnormal fertility in some Chinese rural communities was traced back to the presence of gossypol in dietary cottonseed oil. Gossypol acts as a male contraceptive, altering sperm maturation, spermatozoid motility, and inactivation of sperm enzymes necessary for fertilization. Extensive clinical trials in China have shown the antifertility effect is reversible after stopping the treatment provided consumption has not been too prolonged. Cases of irreversible infertility have resulted from longer periods of drug use. The molecule is chiral due to restricted rotation, and can thus exist as two atropisomers which do not easily racemize (Figure 5.38). Only the (-)-isomer is pharmacologically active as a contraceptive, whereas most of the toxic symptoms appear to be associated with the (+)-isomer, which also displays antitumour and antiviral activities. Most species of Gossypium (except G. barbadense) produce gossypol where the (+)-isomer predominates over the (-)-isomer, with amounts varying according to species and cultivar. Racemic (±)-gossypol (but neither of the enantiomers) complexes with acetic acid, so that suitable treatment of cotton seed extracts actually separates the racemate from the excess of (+)-isomer. The racemic form can then be resolved. Other plants in the Gossypieae tribe of the Malvaceae also produce gossypol, with the barks of Thespia populnea (3.3%) and Montezuma speciosissima (6.1%) being particularly rich sources. Unfortunately, gossypol from these is almost entirely the inactive (+)-form.

(+)-gossypol (-)-gossypol a single example will be used as illustration. The trichothecenes* are a group of fungal toxins found typically in infected grain foodstuffs. Their name comes from the fungal genus Tri-chothecium, but most of the known structures are derived from cultures of Fusarium species. A particularly prominent trichothecene contaminant is deoxynivalenol (vomitoxin), which is produced from the less substituted trichothecene isotricho-dermol by a sequence of oxygenation reactions (Figure 5.39). The trichothecenes have their origins in nerolidyl diphosphate, and ring closure of the bisabolyl cation derived from it generates a new carbocation with a five-membered ring (Figure 5.39). At this stage, a series of one hydride and two methyl migrations occur to give a cation, which loses a proton to produce the specific tri-chothecene precursor trichodiene. These migrations are fully backed up by experimental data, and although not immediately predictable, can be rationalized satisfactorily by consideration of the cation suitably bound to the enzyme surface as shown in Figure 5.39. The sequence is initiated by a 1,4-hydride shift which is spatially allowed by the relative proximity of the centres. Two

1,2-methyl shifts then follow, and it is important to note that each migrating group attacks the opposite side of the centre from which the previous group is departing, i.e. inverting the configuration at these centres. Accordingly, a concerted sequence of migrations is feasible, such a process being seen more vividly in the formation of triterpenoids and steroids (see page 216). Loss of a proton and generation of a double bond terminates the process giving trichodiene. Oxygenation of trichodi-ene gives, in several steps, isotrichotriol. Two of the hydroxylations are at activated allylic positions; hydroxylation on the five-membered ring will therefore occur before the epoxidation. Ether formation, involving perhaps protonation, loss of water and generation of an allylic cation, completes the pathway to the basic trichothecene structure as in isotrichodermol.

Finally, it is worth noting how many of the sesquiterpene derivatives described above are found in plants belonging to the daisy family, the Compositae/Asteraceae. Whilst sesquiterpenes are by no means restricted to this family, the Composi-tae/Asteraceae undoubtedly provides a very rich source.

electrophilic addition leads to five-membered ring and secondary | cation

Wagner-Meerwein rearrangements: 1,4-hydride shift; two 1,2-methyl shifts h r©

bisabolyl cation trichodiene trichodiene nucleophilic attack of hydroxyl on to allylic cation sequence of epoxidation and three |

nucleophilic attack of hydroxyl on to allylic cation

deoxynivalenol (DON)

isotrichodermol allylic cation hydroxylations

HO OH

HO V

deoxynivalenol (DON)

HO OH

isotrichotriol

isotrichodermol allylic cation isotrichotriol

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Pregnancy Guide

Pregnancy Guide

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