Synthesis and biological evaluation of enantiomeric rhamnose analogues of the antitumour agent spicamycin - is the mode of action by modification of N-linked glycoproteins?

The synthesis of both enantiomers of dodecyl rhamnospicamycin 2a and 2b, a rhamnose analogue of the naturally occurring combinatorial library spicamyc in 1, are derived from L-rhamnose and methyl alpha-D-mannopyranoside, respe ctively. The L-(+)-enantiomer 2a containing an L-rhamnose fragment is shown to be highly cytotoxic towards human myeloma cells with an IC50=120 nM, wh ereas the D-(-)-enantiomer 2b, based on a D-mannose structure, shows no sig nificant cytotoxicity. The analogue 16, in which the nucleotide base fragme nt has been replaced by a simple methoxy group, has no cytotoxicity. Initia l studies towards clarifying the mechanism of anti-cancer action of spicamy cin analogues are reported. (C) 1999 Elsevier Science Ltd. All rights reser ved.