Pleuromutilin Compound

Jacobs MR. (2007) Retapamulin A semisynthetic pleuromutilin compound for topical treatment of skin infections in adults and children. Future Microbiol 2 591-600. 

Pleuromutilin, a protein synthesis inhibitor, was first isolated from the genus Pleurotus and discovered as potent diterpene antibiotics in 1950. ° Later, several derivatives were discovered and have been used in veterinary and clinic environments. For example, tiamulin was the first pleuromutilin compound to be approved for veterinary use in 1979, followed by valnemulin in 1999. In 2007, retapamu-lin, a topical antibiotic developed by GlaxoSmithKline (London, U.K.), became the first pleuromutilin antibiotics approved for use in humans. It is marketed as an ointment under the brand names Altabax and Altargo. Retapamulin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of bacterial skin infections such as... 

Tiamulin, a pleuromutilin antimicrobial agent, is extensively metabolized (Fig. 7.10). With the exception of eggs, EU MRLs for tiamulin are defined as the sum of those metabolites that may be hydrolyzed to 8a-hydroxymutilin—this does not include the parent compound. Parent tiamulin forms a significant part of the residue profile only in eggs. 

In principle any except tetrasubstituted olefins could be labeled by catalytic exchange, but in practice it is difficult to find experimental conditions under which significant tritium incorporation can be catalyzed without reducing the double bond. However, if the olefinic starting material is separable from the reduced product, it is sometimes possible to find reaction conditions that disfavour complete reduction, then isolate the unreduced olefin which has become labeled. Two examples with which this has been accomplished are pleuromutilin (71) and cyclosporin A (72) " °. Treatment with a deficiency of tritium gas for 60-90 min in the presence of 10% Pd/C in ethyl acetate (71) or DMF (72 followed by removal of reduced product by HPLC, provided the compounds, labeled as indicated, at specific activities of 10 and 19Ci/mmol, respectively. Unfortunately, it proved to be difficult to separate the cis/trans mixture formed with 72, which stimulated the development of a tritide labeling approach (see Chapter 4, Section 4.3.1). 

In rare cases advantage has been taken of isotopic scrambling to introduce tritium at or adjacent to double bonds without (entirely) reducing them. This was exploited for the preparation of labeled pleuromutilin ([ H] 12) and cyclosporin A ([ H] 13). Treatment of the unlabeled drug substances 12 and 13 with a deficiency of tritium gas over 10% Pd/C, followed by HPLC separation of the unsaturated and the saturated reaction products, provided the two isotopomers with specific activities of lOCi/mmol and 19Ci/mmol, respectively. The label proved to be biologically stable for both compounds, so that they could be used for a variety of in vivo investigations. 

Bioconjugates of nucleosides and Pleuromutilin, a naturally occurring antibacterial agent, have also been prepared and found to display antibacterial activity (compounds 36-41) (Figure 10.9). Interestingly, some of these analogs showed improved affinity to the peptidyl transferase center in the ribosome compared to the natural Pleuromutilin [51]. 

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