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

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 analogues with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogues 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. Analogues 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 analogues exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analogue. From these results implications for the design of future pancratistatin analogues 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

Synthesis and biological evaluation of aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F structurally related to the amaryllidaceae anticancer constituents

Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds

Synthesis and biological evaluation of aromatic analogues of comduritol F, L-chiro-inositol, and dihydroconduritol F structurally related to the Amaryllidaceae anticancer constituents

Pancratistatin is a potent anticancer natural product, whose biol. evaluation is hampered by the limited natural abundance and the stereochem. complex structure undermining practical chem. prepn. Fifteen arom. analogs of conduritol F, L-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereo-centers have been synthesized and evaluated for anticancer activity. These compds. serve as truncated pancratistatin analogs lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochem. The lack of activity of these compds. provides further insight into pancratistatin's min. structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple arom. conduritol and inositol analogs and, therefore, this study expands the chem. and biol. of these important classes of compds