Studies On Design,Synthesis And Activity Of Hydroxamate Acids Derivatives As Histone Deacetylases Inhibitors

Transcriptional modulation by histone acetylation and deacetylation is mediated by histone acetyltransferases(HATs) and histone deacetylases(HDACs),which are critical components in balancing many physiological and pathological processes. The aberrant transcriptional repression caused by abnormal expression of HDAC is believed to be able to act as key regulators of many diseases, including cancers,acute promyelocytic leukemia, viral and flammation. Studies on HADC inhibitors are important in treatment of the above diseases.In this thesis, three total synthetic routes of hydroxamate acids derivatives as HDAC inhibitors were explored and twenty-one compounds were synthesized. The structures of these compounds were identified by ¹HNMR and MS (FAB, EI). 11 compounds which had good activity at the dosages of 10μM were selected and determined by HPLC, and the results showed that the purities of the compounds were above 90%.HDAC inhibition ratio of 21 compounds were evaluated by HDAC colorimetric activity in vitro, the results indicated that the IC₅₀ of the 21 compounds were higher than SAHA. Based on the results of preliminary screens, the structure-activity relationship of the compounds is as follows: l)when the substituent is at the 2-position of hydroxamate acid, the HDAC inhibition activity decreases remarkably. 2)When the substituent at the benzene ring and the N atom of aniline, the HDAC inhibition activity is different from that of SAHA. 3)When the substituent at the enzyme binding is ring alkyl, the HDAC inhibition activity is decreased. The results are helpful to further study and design new class of histone deacetylases...