Biology-oriented synthesis of a withanolide-inspired compound collection reveals novel modulators of hedgehog signaling.
Biology-oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans-hydrindane dehydro-δ-lactone motif defines the characteristic scaffold of the steroid-like withanolides, a plant-derived natural product class with a diverse pattern of bioactivity. A withanolide-inspired compound collection was synthesized by making use of three key intermediates that contain this characteristic framework derivatized with different reactive functional groups. Biological evaluation of the compound collection in cell-based assays that monitored biological signal-transduction processes revealed a novel class of Hedgehog signaling inhibitors that target the protein Smoothened.
Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany).
Jakub
J
Švenda
Michael
M
Sheremet
Lea
L
Kremer
Lukáš
L
Maier
Jonathan O
JO
Bauer
Carsten
C
Strohmann
Slava
S
Ziegler
Kamal
K
Kumar
Herbert
H
Waldmann
D000818:Animals; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006364:Hedgehogs / Q000378:metabolism*; D008968:Molecular Conformation; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D054358:Withanolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D001688:Biological Products; D054358:Withanolides
biology-oriented synthesis; chemical biology; hedgehog pathway; natural products; total synthesis