Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products.
In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3'-pyrrolidinyl spirooxindoles--which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1-3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF(6)(CH(3)CN)(4). Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity.
Antonchick
Andrey P
AP
Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Gerding-Reimers
Claas
C
Catarinella
Mario
M
Schürmann
Markus
M
Preut
Hans
H
Ziegler
Slava
S
Rauh
Daniel
D
Waldmann
Herbert
H
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D007211:Indoles; D011759:Pyrrolidines; D013141:Spiro Compounds