Design And Synthesis Of Carbamates As Focal Adhesion Kinase (FAK) Inhibitors And Study On Synthesis Of Taturolidine

This thesis contains two sections, one is design and synthesis of carbamates as focal adhesion kinase (FAK) Inhibitors, and the other one is study on synthesis of Taturolidine.FAK is a multifunctional non-receptor tyrosine kinase, and its over-expression and over-activation are found in the epithelial and hematological tumor cells and involved in the process of cancer development, such as initial, progress, metastasis, multi-drug resistance of cancer. FAK has become a new target of oncotherapy. In 2008, Dr. Krikor ((McGill University, Canada) found compound KB2 has efficient inhibition on FAK in the study of a pool of synthetic compounds' biological activities (unpublished). Therefore, a series of KB2 analogues have been synthesized based on KB2 as a leading compound in this thesis. The screening of their proliferation inhibition on human breast cancer cell MDA-231 has been completed and the study of FAK inhibitory ability is underway.1) Isocyanate and secondary alcohol were coupled and 16 KB2 analogues were obtained and characterized by NMR and MS. These compounds divided into three groups:(Ⅰ) methoxy substituted KB2 analogues; (Ⅱ) n-butyl as side chains KB2 analogues; (Ⅲ) glucose-conjugagted KB2 analogues.2) Human breast cancer cell MDA-231 inhibition of these compounds were screened and compound 5,15,18 and 22 showed an proliferation inhibitory rate of 40-50% at 25μM. The primary structure-activity relationships indicated that:allylic side chain is a pivotal part to the activities of the compounds and their bioactivity can be improved by carbohydrate conjugation.Taurolidine is an broad-spectrum antibiotic against gram-positive and gram-negative bacteria.It is used in clinics to treat infectious diseases and has a good market perspective. Recent studies have found that Taurolidine has excellent anti-tumor effects.Based on references, synthetic methods of Taurolidine from cysteamine hydrochloride had been studied in this thesis. The improvement of purification steps resulted in a simpler operation. The cost of production is reduced for the using TLC method instead of 1H-NMR in Taurolidine synthetic process.