Probing the influence of an allylic methyl group in zearalenone analogues on binding to Hsp90.
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.
Rink
Christian
C
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany.
Sasse
Florenz
F
Zubrienė
Asta
A
Matulis
Daumantas
D
Maier
Martin E
ME
D000818:Animals; D005347:Fibroblasts / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism* / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D013237:Stereoisomerism; D015025:Zearalenone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D015025:Zearalenone