Ansamycins are a class of macrocyclic compounds in which non-adjacent positions on an aromatic ring system are spanned by the long aliphatic bridge (Latin: ansa = handle). The aromatic portion may be a substituted naphthalene or naphthaquinone, or alternatively a substituted benzene ring. The macrocycle in the ansamycins is closed by an amide rather than an ester linkage, i.e. ansamycins are lactams. The only ansamycins currently used therapeutically are semi-synthetic naphthalene-based macrocycles produced from rifamycin B.
The rifamycins are ansamycin antibiotics produced by cultures of Amycolatopsis mediterranei (formerly Nocardia mediterranei or Streptomyces mediterranei). The crude antibiotic mixture was found to contain five closely related substances rifamycins A-E, but if the organism was cultured in the presence of sodium diethyl barbiturate (barbitone or barbital), the product was almost entirely rifamycin B (Figure 3.71). Rifamycin B has essentially no antibacterial activity, but on standing in aqueous solution in the presence of air, it is readily transformed by oxidation and intramolecular nucleophilic addition into rifamycin O, which
under acidic conditions then hydrolyses and gives rifamycin S, a highly active antibacterial agent (Figure 3.73). Chemical reduction of rifamycin S using ascorbic acid (vitamin C) converts the quinone into a quinol and provides a further antibacterial, rifamycin SV. Rifamycins O, S, and SV can all be obtained by fermentation using appropriate strains of A. mediterranei. Rifamycin SV is actually the immediate biosynthetic precursor of rifamycin B under normal conditions, so this conversion can be genetically blocked and lead to accumulation of rifamycin SV. Several other rifamycin analogues have also been characterized. Rifamycin O is usually produced by chemical or electrochemical oxidation of rifamycin B, and converted into rifamycin SV as in Figure 3.73.
The most useful rifamycin employed clinically is rifampicin (Figure 3.73), a semisynthetic derivative produced from rifamycin SV via a Mannich reaction (see page 18) using formaldehyde and N-amino-N-methylpiperazine. Rifampicin has a wide antibacterial spectrum, with high activity towards Gram-positive bacteria and a lower activity towards Gram-negative organisms. Its most valuable activity is towards Mycobacterium tuberculosis and rifampicin is a key agent in the treatment of tuberculosis, usually in combination with at least one other drug to reduce the chances for development of resistant bacterial strains. It is also useful in control of meningococcal meningitis and leprosy. Rifampicin's antibacterial activity arises from inhibition of RNA synthesis by binding to DNA-dependent RNA polymerase. RNA polymerase from mammalian cells does not contain the peptide sequence to which rifampicin binds, so RNA synthesis is not affected. In contrast to the natural rifamycins which tend to have poor absorption properties, rifampicin is absorbed satisfactorily after oral administration, and is also relatively free of toxic side-effects. The most serious side-effect is disturbance of liver function. A trivial, but to the patient potentially worrying, side-effect is discoloration of body fluids, including urine, saliva, sweat, and tears, to a red-orange colour, a consequence of the naphthalene/naphthoquinone chromophore in the rifamycins. Rifamycin, the sodium salt of rifamycin SV (Figure 3.73), has also been used clinically in the treatment of Gram-positive infections, and particularly against tuberculosis. Rifabutin (Figure 3.73) is a newly introduced derivative, synthesized via 3-amino-rifamycin SV, which also has good activity against the Mycobacterium avium complex frequently encountered in patients with AIDS.
and controlling coccidiae and also having the ability to improve the efficiency of food conversion in ruminants. The polyether antibiotics are characterized by the presence of a number of tetrahydrofuran and/or tetrahydropyran rings along the basic chain. The polyether acts as an ionophore, increasing influx of sodium ions into the parasite, causing a resultant and fatal increase in osmotic pressure. Current thinking is that these ring systems arise via a cascade cycliza-tion mechanism, probably involving epoxide intermediates. Thus, in the biosynthesis of monensin A (Figure 3.75), chain assembly from acetate, mal-onate, methylmalonate, and ethylmalonate precursors could produce the triene shown. If the triepox-ide is then formed, a concerted stereospecific cyclization sequence initiated by a hydroxyl and involving carbonyls and epoxides could proceed as indicated.
Even more remarkable polyether structures are found in some toxins produced by marine dinoflag-ellates, which are in turn taken up by shellfish and pass on their toxicity to the shellfish. Okadaic acid (Figure 3.76) and related polyether structures from Dinophysis species are responsible for
I concerted I cyclization | sequence
I concerted I cyclization | sequence
diarrhoeic shellfish poisoning in mussels, causing severe diarrhoea in consumers of contaminated shellfish in many parts of the world. Brevetoxin A (Figure 3.77) is an example of the toxins associated with 'red tide' blooms of dinoflagellates, which affect fishing and also tourism especially in Florida and the Gulf of Mexico. The red tide toxins are derived from Gymnodimium breve and are the causative agents of neurotoxic shellfish poisoning, leading to neurological disorders as well as gastrointestinal troubles. The toxins are known to bind to sodium channels, keeping them in an open state. Fatalities among marine life, e.g. fish, dolphins, whales, and in humans, are associated with these toxins synthesized by organisms at the base of the marine food chain. These compounds are postulated to be produced from a polyunsaturated fatty acid by epoxidation of the double bonds, and then a concerted sequence of epoxide ring openings leads to the extended polyether structure (Figure 3.77). The carbon skeleton does not conform to a simple polyketide chain, and biosynthetic studies have shown that fragments from the citric acid cycle and a four-carbon starter unit from mevalonate are also involved, and that some of the methyls originate from methionine. Ciguatoxin (Figure 3.78) is one of the most complex examples of a polyether structure found in nature. This is found in the moray eel (Gymnothorax javanicus) and in a variety of coral reef fish, such as red snapper (Lutjanus bohar). Ciguatoxin is remarkably toxic even at microgram levels, causing widespread food poisoning (ciguatera) in tropical and subtropical regions, characterized by vomiting, diarrhoea, and neurological problems. Most sufferers slowly recover, and few cases are fatal, due principally to the very low
levels of toxin actually present in the fish. A dinoflagellate Gambierdiscus toxicus is ultimately responsible for polyether production, synthesizing a less toxic analogue, which is passed through the food chain and eventually modified into the very toxic ciguatoxin by the fish.
The zaragozic acids (squalestatins) are not macrolides, but they are primarily acetate derived, and the central ring system is suggested to be formed by an epoxide-initiated process resembling the polyether derivatives just described. Thus, zaragozic acid A (Figure 3.79) is known to be constructed from two acetate-derived chains and a C4 unit such as the Krebs cycle intermediate oxaloacetate (see Figure 2.1). One chain has a benzoyl-CoA starter (from the shikimate pathway, see page 141), and both contain two methionine-derived side-chain substituents (Figure 3.79). The
O OAc ho2c' ho2c.
co2h succinic acid zaragozic acid A (squalestatin S1)
succinic acid zaragozic acid A (squalestatin S1)
H » O CO2H oxaloacetic acid aldol reaction aldol reaction
heterocyclic ring system can be envisaged as arising via nucleophilic attack on to oxaloacetic acid, formation of a diepoxide, then a concerted sequence of reactions as indicated (Figure 3.80). The zaragozic acids are produced by a number of fungi, including Sporomiella intermedia and Leptodontium elatius, and are attracting considerable interest since they are capable of reducing blood cholesterol levels in animals by acting as potent inhibitors of the enzyme squalene synthase (see page 212). This is achieved by mimicking the steroid precursor presqualene PP (Figure 3.79) and irreversibly inactivating the enzyme. They thus have considerable medical potential for reducing the incidence of coronary-related deaths (compare the statins, below).
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