| Arthritis is a common disease that inflicts about 10% of people in the world. Synovial membranes in arthritis patient joints are found to show higher activity of hexosaminidase than those obtained from normal joints. Inhibition of the catalytic activity of hexosaminidase appears to be one possible way to treat the human arthritis disease.; In our work, several inhibitors towards the hexosaminidase have been chemo-enzymatically synthesized with FDP aldolase, and their inhibition activities have been tested with the enzyme from human placenta. Compound 1.2 was found to strongly inhibit hexosaminidase (Ki = 24 nM), and the cartilage tissue shows a remarkable GAG accumulation after incubation with 1.2. The different activities of 6-sulfated inhibitor 1.7 to Hex A and HexB were also investigated.; In chapter 2, a new method to prepare 2-hydroxy- and 2-aminoglycals from glycosyl sulfoxides was introduced. The utility of 2-deoxyribose-5-phosphate aldolase (DERA, EC 4.1.2.4) in organic synthesis was investigated in chapters 3 and 4.; In order to synthesize useful 1,3-polyol synthons, two strategies were used, which allowed the preparation of a number of heterocyclic synthons. A switch of the substrate's stereoselectively in DERA catalysis was observed, which was elucidated based on the available crystal structure of DERA. In an effort to engineer the enzyme to improve its catalytic activity, Ser238 in DERA was mutated to Asp238. The new DERA Ser238Asp was more effective than the wild type, and the “sequential one-pot aldol condensation” catalyzed by the mutant DERA was used to synthesize ‘liptor-like’ synthons.; Involving DERA catalysis and chiral induction through the chelation-controlled alkylation, a concise and highly enantioselective chemo-enzymatic synthesis of epothilones A and C was described in chapter 4. Due to the wide substrate tolerance of DERA, analogs of epothilones could be synthesized following a similar pathway. The protecting groups (PMP, TBS) in 4.50 can be easily differentiated, which allowed selective incorporation of substituents, such as carbohydrates, to the epothilones in order to improve their solubility and bioactivity.; New utilities of Selecfluor™ were described in chapter 5. Selecfluor™ was used to remove PMP, THP and 1,3-dithiane protecting groups. Allylstannation of aldehydes can also be mediated with Selecfluor™. In a one-pot fashion, Selecfluor™ can promote the allylation of imines directly from aldehydes, amines, and allyltributyltin. |
