Synthesis of Structurally Simplified Analogs of Pancratistatin: Truncation of the Cyclitol Ring

摘要

Pancratistatin is a phenanthridone-type natural product isolated from several plants of the Amaryllidaceae family. Its potent antiproliferative, antivascular, antiviral and antiparasitic properties have attracted the attention of synthetic, biological and medicinal chemists. Pancratistatin's low natural availability and complex structure have steered many of these research projects toward the preparation of its simplified synthetic analogs with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogs with a truncated cyclitol portion of the molecule. The described synthetic pathways are based on a highly anti-diastereoselective arylcuprate conjugate addition to γ-alkoxy-α,β-enoates and syn-selective azidation at the α-position of ester enolates. Analogs with the formally cleaved C3-C4 bond, and thus containing an open ring C, as well as a compound containing a truncated lactol moiety in lieu of the cyclitol, were prepared. Several of the analogs exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analog. From these results implications for the design of future pancratistatin analogs are discussed. Furthermore, the synthetic pathways can be used to construct pancratistatin-mimetic libraries, in which the cyclitol moiety is replaced by other cyclic motifs.