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

Abstract

The synthesis of both enantiomers of dodecyl rhamnospicamycin 2a and 2b, a rhamnose analogue of the naturally occurring combinatorial library spicamycin 1, are derived from l-rhamnose and methyl α- d-mannopyranoside, respectively. The l-(+)-enantiomer 2a containing an l-rhamnose fragment is shown to be highly cytotoxic towards human myeloma cells with an IC 50=120 nM, whereas the d-(−)-enantiomer 2b, based on a d-mannose structure, shows no significant cytotoxicity. The analogue 16, in which the nucleotide base fragment has been replaced by a simple methoxy group, has no cytotoxicity. Initial studies towards clarifying the mechanism of anti-cancer action of spicamycin analogues are reported.