Methyleneoxy-bridged lignans as cytotoxic candidates and intermediates in synthesis

Podophyllotoxin (PT) is well known for its antitumor activity and use as the starting material for the manufacture of Etoposide. alpha-Conidendrin (ACON) can be isolated in quantity as a by-product arising from wood pulping process. ACON can also be isolated from different species of plants. Sikkimotoxin (SK) is an A-ring opened PT derivative and isolated from P. sikkimensis . All PT, SK and ACON are cyclolignans and have remarkable structural similarities and differences. The aim of this research was to explore whether ACON could be adapted to make cytotoxic derivatives using PT and SK as models. Four types of methyleneoxy-bridged derivatives were synthesized from natural PT and ACON in this research, namely: oxabicyclooctane, dioxatricyclodecane, benzodihydropyran and oxolane derivatives. Three different oxidizing agents (DDQ, CuSO4/K2S2O8 oxidant couple, and NaIO4) and dehydration were involved in these syntheses. Their possible mechanisms are proposed. A new method for the preparation of the most cytotoxic compound (PT-dioxatncyclodecane) previously discovered in this research was developed. Fremy's salt [(KSO3)2NO] oxidation of ACON showed excellent selectivity between the fused and the pendant aromatic rings, and this reagent was used to prepare the SK-methyleneoxy-bridged compound from ACON. Also, the inversion of configuration at C-4 in ACON was achieved by DDQ oxidation and Lewis acid induced LiAlH4 reduction. Selective silylations of ACON derivatives have been used to prepare mono-methyl-ACON derivatives. The cytotoxicity of the synthesized targets was evaluated. Structure-activity relationships (SAR) concerning these new lignans was also discussed.