Propionate analogues of zearalenone bind to Hsp90.
By replacement of an acetate with propionate through organic synthesis a range of zearalenone analogues were prepared. As key steps in the synthesis of the analogues we used the Noyori hydrogenation of methyl acetoacetate followed by Frater alkylation of the enantiomeric 3-hydroxybutyrates. This converted the second acetate to a propionate. Through the derived alkyne, chain extension led to 3-methylundec-10-en-2-ol derivatives. These were condensed with 2,4-dimethoxy-6-vinylbenzoic acid. Ring-closing metathesis of the obtained esters led to macrolactones, which were deproteced to give the zearalenone analogues. Several of the analogues showed cytotoxicity against the L929 mouse fibroblast cell line comparable to zearalenone (9 microM) itself. In the thermal-shift assay, two analogues 35 and ent-35 displayed stronger binding than the natural product geldanamycin to the chaperone Hsp90.
Ugele
Markus
M
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany.
Sasse
Florenz
F
Knapp
Stefan
S
Fedorov
Oleg
O
Zubriene
Asta
A
Matulis
Daumantas
D
Maier
Martin E
ME
D000818:Animals; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006865:Hydrogenation; D008024:Ligands; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D011422:Propionates / Q000737:chemistry*; D011485:Protein Binding; D013237:Stereoisomerism; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity
D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D018942:Macrolides; D011422:Propionates; D015025:Zearalenone