Natural product-derived modulators of cell cycle progression and viral entry by enantioselective oxa Diels-Alder reactions on the solid phase.
The underlying frameworks of natural product classes with multiple biological activities can be regarded as biologically selected and prevalidated starting points in vast chemical structure space in the development of compound collections for chemical biology and medicinal chemistry research. For the synthesis of natural product-derived and -inspired compound collections, the development of enantioselective transformations in a format amenable to library synthesis, e.g., on the solid support, is a major and largely unexplored goal. We report on the enantioselective solid-phase synthesis of a natural product-inspired alpha,beta-unsaturated delta-lactone collection and its investigation in cell-based screens monitoring cell cycle progression and viral entry into cells. The screens identified modulators of both biological processes at a high hit rate. The screen for inhibition of viral entry opens up avenues of research for the identification of compounds with antiviral activity.
Lessmann
Torben
T
Abteilung Chemische Biologie, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Leuenberger
Michele G
MG
Menninger
Sascha
S
Lopez-Canet
Meritxell
M
Müller
Oliver
O
Hümmer
Stefan
S
Bormann
Jenny
J
Korn
Kerstin
K
Fava
Eugenio
E
Zerial
Marino
M
Mayer
Thomas U
TU
Waldmann
Herbert
H
D000818:Animals; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D002521:Cercopithecus; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008968:Molecular Conformation; D011485:Protein Binding; D013237:Stereoisomerism; D014721:Vesicular stomatitis Indiana virus; D053586:Virus Internalization / Q000187:drug effects*
D001688:Biological Products; D007783:Lactones