Glioblastoma multiforme (GBM), the most common brain tumors which are very hard to prognosis, with high proliferative activity, and highly resistive to chemotherapeutic agents. Apart from that, the survival rate of GBM patients are very poor, there are about 3.3% of average 2-years survival, 1.2% of average 3-years survival and the mean survival time are approximately 12 months. Therefore, a significant unmet medical need is urgent to develop new drug which fulfill the effective requirement for GBM treatment. <br/>Glioblastoma cells proliferation is associated with HADC6. Histone deacetylases (HDACs) are involved in different physiological function, and also found involved in tumorigenesis. HDAC6, a class IIb HDACs family which observed overexpression in different cancer cell lines, including lymphoma, leukemia, breast cancer, lung cancer and brain cancer.<br/>Herein, this poster reports the design and synthesis of a tricyclic napthalimide, a well-known pro-fluorophore, as the HDAC6 selective inhibitors for the potential GBM treatment.<br/>To design and synthesize HDAC6 inhibitors, we employed naphthalimide as the core structure which connected with hydroxamate group through p-toyl linker, and several target compounds were synthesized for SAR study. Compound with methoxy derivative (HDAC6 IC50 = 0.1 nM, HDAC1 IC50 = 108 nM) showed sub-nM inhibition activity against HDAC6 and 1080 times of selectivity against HDAC6 over HDAC1, and U87MG IC50 = 0.92 μM. From SAR analysis, O-substitution or N-substitution at para-position provided far better activities. However, substitutions at meta-position lost inhibition against HDAC and cancer cell lines.<br/>To sum up, the napthalimide scaffolds of HDAC6 inhibitors were developed for the potential therapeutic agents against glioblastoma in this study. Further studies on the improvement of pharmacokinetic properties are undergoing.

Design and synthesis of selective HADC6 inhibitors as potential agents against glioblastoma

253rd National Meeting (2017)

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