RESUMO
A short, high-yielding protocol involving the enantioselective α-chlorination of aldehydes has been developed for the enantioselective synthesis of C2-functionalized aziridines and N-alkyl terminal azetidines from a common intermediate. This methodology allows for the rapid preparation of functionalized aziridines in 50-73% overall yields and 88-94% ee, and azetidines in 22-32% overall yields and 84-92% ee. Moreover, we developed a scalable and cost-effective route to the key organocatalyst (54% overall yield, >95% dr).
RESUMO
Apoptolidinâ A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidinâ A consists of a 20-membered macrolide with mono- and disaccharide moieties. In contrast to apoptolidinâ A, the aglycone (apoptolidinone) shows no cytotoxicity (>10â µM) when evaluated against several tumor cell lines. Apoptolidinâ H, the C27 deglycosylated analogue of apoptolidinâ A, displayed sub-micromolar activity against H292 lung carcinoma cells. Selective esterification of apoptolidinsâ A and H with 5-azidopentanoic acid afforded azido-functionalized derivatives of potency equal to that of the parent macrolide. They also underwent strain-promoted alkyne-azido cycloaddition reactions to provide access to fluorescent and biotin-functionalized probes. Microscopy studies demonstrate apoptolidinsâ A and H localize in the mitochondria of H292 human lung carcinoma cells.
Assuntos
Antineoplásicos/química , Corantes Fluorescentes/química , Macrolídeos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Macrolídeos/toxicidade , Microscopia Confocal , Pironas/química , Pironas/toxicidadeRESUMO
Small molecules active in the pathogenic bacterium Staphylococcus aureus are valuable tools for the study of its basic biology and pathogenesis, and many molecules may provide leads for novel therapeutics. We have previously reported a small molecule, 1, which activates endogenous heme biosynthesis in S. aureus, leading to an accumulation of intracellular heme. In addition to this novel activity, 1 also exhibits toxicity towards S. aureus growing under fermentative conditions. To determine if these activities are linked and establish what features of the molecule are required for activity, we synthesized a library of analogs around the structure of 1 and screened them for activation of heme biosynthesis and anaerobic toxicity to investigate structure-activity relationships. The results of this analysis suggest that these activities are not linked. Furthermore, we have identified the structural features that promote each activity and have established two classes of molecules: activators of heme biosynthesis and inhibitors of anaerobic growth. These molecules will serve as useful probes for their respective activities without concern for the off target effects of the parent compound.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Heme/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Bactérias Anaeróbias/efeitos dos fármacos , Bactérias Anaeróbias/crescimento & desenvolvimento , Bactérias Anaeróbias/metabolismo , Humanos , Ferro/metabolismo , Oxigênio/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/metabolismo , Relação Estrutura-AtividadeRESUMO
The apoptolidins are glycomacrolide microbial metabolites reported to be selectively cytotoxic against tumor cells. Using fluorescently tagged active derivatives we demonstrate selective uptake of these four tagged glycomacrolides in cancer cells over healthy human blood cells. We also demonstrate the utility of these five fluorescently tagged glycomacrolides in fluorescent flow cytometry to monitor cellular uptake of the six glycomacrolides and cellular response.