Synthesis of sparsomycin derivatives, addressing its binding to the large ribosomal subunit
article
The syntheses of compounds 14-19, 6-methyluracilacryloyl derivatives, and 27-29, photoreactive aryl azide analogs of the antitumor antibiotic sparsomycin (1) are described. All of the modifications in the 6-methyluracilacryloyl part of 1 were achieved by selective reduction or by selective N- and O-methylation of 6 (Scheme 2). The key step in the synthetic scheme to the photo-affinity analogs is the reaction of the chloromethyl sulfoxides 20 and 21 with the properly protected cystamine 22 in liquid ammonia, to give the sparsomycin N-protected amines 23 and 24, respectively (Scheme 4). Subsequently, the photoreactive groups, viz. a p-azidosalicylyl and a 4-azido-2-nitrophenyl group, were coupled with these amines. For an evaluation of the biological activity of the compounds prepared, inhibition of protein biosynthesis in two cell-free assays, cell-growth inhibition of E. coli in liquid medium and inhibition of murine leukemia L1210 colony formation in soft agar were studied. All variations introduced in the "western A" fragment of 1 render the drug biologically inactive. Apparently, the uracil ring plays an important role in the interaction of sparsomycin with the ribosomal peptidyl transferase and its unmodified presence is crucial for displaying activity. The photoprobes, carrying modifications in the "eastern C" fragment of 1, do interact with the ribosome, but less effectively than sparsomycin itself. © 1992.
TNO Identifier
231860
ISSN
01650513
Source
Recueil des Travaux Chimiques des Pays-Bas, 111(4), pp. 163-169.
Pages
163-169
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