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 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

Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis

Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on β-tubulin, provided a theoretical understanding of these successful experimental findings. © 2011 American Chemical Society.Articl