Design of new isonitriles for the asymmetric Ugi reaction application to the synthesis of an unique vinyl fluoride peptide isostere and to the synthesis of small heterocyclic molecules

Glutathione S-Transferases (GST) are a multi-gene family of isoenzymes that catalyze the nucleophilic addition of glutathione to a variety of hydrophobic electrophilic species. The GST family of enzymes are found in nearly all forms of life. GST isoenzymes represent a major group of detoxification enzymes which provide protection for a diverse range of electrophilic xenobiotics. These enzymes can detoxify carcinogens, therapeutic drugs and environmental pollutants such as insecticides and herbicides. In addition, specific GST isozymes may play an important role in cancer treatment. Overexpression of GST in tumors has been associated with multi-drug resistant cancer cell lines. Although considerable information is available on the substrates for GST catalyzed glutathione conjugate addition, knowledge of the enzyme structure remains limited and a complete understanding of the catalytic mechanism is lacking. Vinyl fluoride peptide isosteres of conjugated glutathione are designed as potential inhibitors of GSTs. Inhibition studies of the isosteres, will allow to more clearly define the stereochernical factors responsible for the binding of an electrophilic substrate in the enzyme H-site as well as the binding of glutathione analogs in the G-site. There is a significant therapeutic benefit in finding a highly specific inhibitor of one of the GSTs class.; This study develops new chemistry in the asymmetric synthesis of functionalized vinyl fluoride isosteres of glutamic acid. Ugi 4-component coupling reaction is used to introduce the amino acid portion of the vinyl fluoride isostere; however, current methodology is not amenable to the application of this chemistry for the synthesis of vinyl fluoride containing amino acids. A new functionalized isonitrile is developed that will be applied to the synthesis of vinyl fluoride functionalized amino acids. Further applications of the new designed isonitriles to the synthesis of small heterocyclic molecules and to the Ugi solid phase reactions are presented. Complete total synthesis of a unique vinyl fluoride peptide isostere is described. The developed methodology can now be applied to the synthesis of various vinyl fluoride peptide isosteres of glutathione in the attempt to develop therapeutically useful inhibitors of alpha class GST isozymes for potential applications in cancer chemotherapy.