ABSTRACT
Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetra-substituted naphthalene diimide (ND) derivatives with a phenyl substituent directly attached to the ND core. The lead compound (SOP1812) has 10 times superior cellular and in vivo activity compared with previous ND compounds and nanomolar binding to human quadruplexes. The pharmacological properties of SOP1812 indicate good bioavailability, which is consistent with the in vivo activity in xenograft and genetic models for pancreatic cancer. Transcriptome analysis shows that it down-regulates several cancer gene pathways, including Wnt/ß-catenin signaling.
ABSTRACT
Two routes are described for the synthesis of the sawaranospirolides, stereoisomeric spirolactone ascorbigenins isolated from Chamaecyparis pisifera. Trapping of the keto enal formed by oxidation of a functionalised 2-(4-hydroxybutyl)furan affords a potential butenolide spiroacetal precursor to sawaranospirolides A and C. Alternatively, epoxidation of protected 3-(dihydropyran-2-yl)-3-arylpropanoic acids results in spirolactonisation to generate ent-sawaranospirolide C; a related acid-mediated spirocyclisation gave access to ent-sawaranospirolide D.
Subject(s)
Chamaecyparis/chemistry , Spiro Compounds/chemical synthesis , Cyclization , Oxidation-Reduction , StereoisomerismABSTRACT
The synthesis is described of a range of 3-alkylidene-2-oxabicyclo[2.2.1]hept-5-ene and 3-alkylidene-2-oxabicyclo[2.2.2]oct-5-ene derivatives; Claisen rearrangement of these substrates either thermally or in the presence of an added Lewis acid results in the formation of bicyclic cyclobutanones with generally good conversions. These reactions may be performed in hydroxylic solvents, supporting a largely non-dissociative pathway for the rearrangement.