Synthesis of Fluorescent Probes Targeting Tumor-Suppressor Protein FHIT and Identification of Apoptosis-Inducing FHIT Inhibitors.

For the early diagnosis of cancer, leading to a better chance of full recovery, marker genes whose expression is already altered in precancerous lesions are desirable, and the tumor-suppressor gene FHIT is one candidate. The gene product, FHIT protein, has a unique dinucleoside triphosphate hydrolase (AP3Aase) activity, and in this study, we designed and synthesized a series of FHIT fluorescent probes utilizing this activity. We optimized the probe structure for high and specific reactivity with FHIT and applied the optimized probe in a screening assay for FHIT inhibitors. Screening of a compound library with this assay identified several hits. Structural development of a hit compound afforded potent FHIT inhibitors. These inhibitors induce apoptosis in FHIT-expressing cancers via caspase activation. Our results support the idea that FHIT binders, no matter whether inhibitors or agonists of AP3Aase activity, might be promising anticancer agents.

A solvent-dependent chirality-switchable thia-Michael addition to α,ß-unsaturated carboxylic acids using a chiral multifunctional thiourea catalyst.

An asymmetric thia-Michael addition of arylthiols to α,ß-unsaturated carboxylic acids using a thiourea catalyst that bears arylboronic acid and tertiary amine moieties is reported. Both enantiomers of the Michael adducts can be obtained in high enantioselectivity and good yield merely by changing the solvent. The origin of the chirality switch in the products was examined in each solvent via spectroscopic analyses.