Dewick P.M. Medicinal natural products VCH-Wiley, Weinheim, 2002 / booktext@id88013689placeboie

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up to 100 times more potent than cyclosporin A, but produces similar side-effects including neurotoxicity and nephrotoxicity.

Rapamycin (sirolimus) (Figure 3.69) is produced by cultures of Streptomyces hygroscopicus and is also being investigated as an immunosuppressant drug. Although tacrolimus and rapamycin possess a common structural unit, and both inhibit T-cell activation, they appear to achieve this by somewhat different mechanisms. The first-formed rapamycin–receptor protein binds not to calcineurin, but to a different protein. Rapamycin suppresses lymphocyte production. Rapamycin also possesses pronounced antifungal activity, but is not active against bacteria.

Figure 3.70

Figure 3.71

Ansa Macrolides

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

Figure 3.73

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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.