Tacrolimus and Sirolimus

Tacrolimus (FK-506) (Figure 3.69) is a macrolide immunosuppressant isolated from cultures of Streptomyces tsukubaensis. It is used in liver and kidney transplant surgery. Despite the significant structural differences between tacrolimus and the cyclic peptide cyclosporin A (ciclosporin; see page 429), these two agents have a similar mode of action. They both inhibit T-cell activation in the immunosuppressive mechanism by binding first to a receptor protein giving a complex, which then inhibits a phosphatase enzyme called calcineurin. The resultant aberrant phosphorylation reactions prevent appropriate gene transcription and subsequent T-cell activation. Structural similarities between the region C-17 to C-22 and fragments of the cyclosporin A peptide chain have been postulated to account for this binding. Tacrolimus is 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 hygroscop-icus 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.

SCoA HN^COiH N" ^CO2H

L-Cys

SCoA HN^COiH N" ^CO2H

L-Cys

CO2H CO2H

Malonyl Coa Methylmalonyl Coa Groups

Figure 3.70

of the substituent at C-12, which is hydrogen in epothilone A but a methyl group in epothilone B. Genetic evidence shows that the polyketide synthase enzyme can accept either malonyl-CoA or methylmalonyl-CoA extender units for this position. Thus, epothilone B is constructed from three malonate and five methylmalonate extender units as shown in Figure 3.70, whilst epothiolone A requires four units of each type. The epothilones display marked antitumour properties with a mode of action paralleling that of the highly successful anticancer drug taxol (see page 205). However, the epothilones have a much higher potency (2000-5000 times) and are active against cell lines which are resistant to taxol and other drugs. There appears to be considerable potential for developing the epothilones or analogues into valuable anticancer drugs.

A further group of macrolides in which non-adjacent positions on an aromatic ring are bridged by the long aliphatic chain is termed ansa macrolides*. These are actually lactams rather than lactones, and the nitrogen atom originates from 3-amino-5-hydroxybenzoic acid, which acts as the starter unit for chain extension with malonyl-CoA or methylmalonyl-CoA. 3-Amino-5-hydroxybenzoic acid (Figure 3.71) is a simple phenolic acid derivative produced by an unusual variant of the shikimate pathway (see Chapter 4), in which aminoDAHP is formed in the initial step, and then the pathway continues with amino analogues. This proceeds through to aminodehydroshikimic acid which yields 3-amino-5-hydroxybenzoic acid on dehydration. In the biosynthesis of rifamycin B (Figure 3.71) in Amycolatopsis mediterranei, this starter unit, plus two malonyl-CoA and eight methylmalonyl-CoA extenders, are employed to fabricate proansamycin X as the first product released from the enzyme. The enzyme-bound intermediate shown in Figure 3.71 is not strictly correct, in that the naphthoquinone ring system is now

PEP CO2H

PEP CO2H

D-erythrose 4-P

D-erythrose 4-P

HO HO

PO^O

CO2H

CO2H

_ NH2 OH aminoDAHP

_ NH2 OH aminoDAHP

proansamycin X

aminodehydroshikimic 3-amino-5-hydroxy-

acid benzoic acid

HO HO

carbon lost proansamycin X

HSCoA,

CO2H CO2H

NH2 T I

carbon lost

rifamycin W Figure 3.71

rifamycin W Figure 3.71

Maytansine Structural Group

rifamycin B

rifamycin B

known to be constructed during, not after, chain assembly. Rifamycin W and then the antibiotic rifamycin B are the result of further modifications including cleavage of the double bond, loss of one carbon, then formation of the ketal. Maytansine (Figure 3.72) is a plant-derived ansa macrolide from Maytenus serrata (Celastraceae), though other esters of the parent alcohol, maytansinol, are produced by species of the fungus Nocardia. Maytansine has been extensively investigated for its potential antitumour activity.

The macrolide systems described above are produced by formation of an intramolecular ester or amide linkage, utilizing appropriate functionalities in the growing polyketide chain. Macrolide formation does not always occur, and similar acetate - propionate precursors might also be expected to yield molecules which are essentially linear in nature. Good examples of such molecules

O Me

O Me

Goodexamples Vitaamins

maytansine

Figure 3.72

maytansine

Figure 3.72

are lasalocid A (Figure 3.74) from Streptomyces lasaliensis and monensin A (Figure 3.75) from Streptomyces cinnamonensis, representatives of a large group of compounds called polyether antibiotics. These, and other examples, are of value in veterinary medicine, being effective in preventing

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  • Kasey
    Is sirolimus better than tacrolimus?
    8 years ago

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