ABSTRACT
With evolutionary drug resistance impacting efforts to treat disease, the need for small molecules that exhibit novel molecular mechanisms of action is paramount. In this study, we combined scaffold-directed synthesis with a hybrid experimental and transcriptome analysis to identify bis-spirooxindole cyclopropanes that inhibit cancer cell proliferation through disruption of ribosomal function. These findings demonstrate the value of an integrated, biologically inspired synthesis and assay strategy for the accelerated identification of first-in-class cancer therapeutic candidates.
Subject(s)
Antineoplastic Agents/pharmacology , Cyclopropanes/pharmacology , Oxindoles/pharmacology , RNA, Neoplasm/drug effects , Ribosomes/drug effects , Spiro Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cyclopropanes/chemical synthesis , Cyclopropanes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Oxindoles/chemical synthesis , Oxindoles/chemistry , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Ribosomes/genetics , Ribosomes/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity Relationship , Transcriptome , Tumor Cells, CulturedABSTRACT
A RhII -catalyzed, formal [4+1]-cycloaddition between diazooxindoles as electrophilic C1 synthons and 1,3-heterodienes for the construction of spirooxindole pyrrolones is described. Employing vinyl isocyanates as 1,4-dipoles, the cycloannulation occurs under relatively mild conditions and provides the corresponding pyrrolones in good to excellent yields.