Probing the influence of an allylic methyl group in zearalenone analogues on binding to Hsp90

Chemistry. 2010 Dec 27;16(48):14469-78. doi: 10.1002/chem.201001752.

Abstract

By the replacement of an acetate with propionate by means of organic synthesis, a range of zearalenone analogues were prepared that feature an allylic methyl group. For the synthesis of the aliphatic region of the analogues, we used an asymmetric alkylation to yield pentenol derivatives 16 and ent-16. By means of hydroboration the corresponding aldehydes were secured. These were coupled with 2-pentynol derivate 23 by means of a Carreira acetylide addition. Further routine steps led to the sulfones 29 and 45, respectively. After merging them with 2-bromobenzaldehyde 9 in a Julia-Kocienski reaction, metalation, carboxylation, and protecting-group manipulations gave the seco acids 35 and 49. By means of lactonization under Mitsunobu (alcohol activation) or Trost-Kita conditions (carboxyl activation), all four possible macrocyclic ketone stereoisomers were accessible. In all, considering various protecting-group decorations, 16 analogues were obtained and tested for cytotoxicity (L929 mouse fibroblast cell line). Whereas most of the analogues were less active than zearalenone (IC(50)=9.4 μM), the resorcinol derivatives were comparable, with one stereoisomer (40 b) being slightly more active (IC(50)=6.6 μM). These results were also reflected in the binding assays to Hsp90 in which 40 b showed a dissociation constant (K(d)) value of 130 nM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fibroblasts / drug effects
  • HSP90 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / pharmacokinetics
  • Inhibitory Concentration 50
  • Lactones / chemistry
  • Mice
  • Molecular Structure
  • Stereoisomerism
  • Zearalenone* / analogs & derivatives
  • Zearalenone* / chemical synthesis
  • Zearalenone* / chemistry
  • Zearalenone* / metabolism

Substances

  • HSP90 Heat-Shock Proteins
  • Lactones
  • Zearalenone