Synthesis And Anti-pancreatic Cancer Activity Of Polysubstituted 2-Pyridinone Derivatives

Pancreatic cancer is one of the most aggressive malignant cancers, and leads to more than 220,000 deaths per year worldwide. Due to the lack of specific symptoms, pancreatic cancer is difficult to diagnose during its formative stages. Because of the rapid progression and extremely high death rate, pancreatic cancer carries one of the most dismal prognoses in all of medicine, with a median survival of less than 6 months and a 5-year-survival rate of only 3%.Currently, there is no effective treatment for pancreatic cancer. Surgical resection offers the only possibility of cure, but only 15-20% of pancreatic cancer patients underwent potentially curative resection, and recurrence and metastasis may occur after operation. Chemotherapy and/or radiotherapy have become an important adjunct in the treatment of pancreatic cancer, for improving the quality of life and prolonging survival time. Gemcitabine (GEM) is the best chemotherapeutic drug for the treatment of pancreatic cancer. However, owning to the intense resistance of pancreatic cancer, GEM is less than 20% overall efficiency. Therefore, there is an urgent to identify new compounds which can effectively inhibit pancreatic cancer cells.In order to discover a kind of lead compounds which can selectively inhibit pancreatic cancer cells, we developed a new method for the synthesis of polysubstituted-2-pyridinone. MTT assay was used to evaluate the compounds to the inhibition of PANC-1 cells under nutrient-rich and nutrient-deprived conditions.1. Synthesis of polysubstituted-2-pyridinone derivatives.In our previous work, during the synthesis of a polycyclic polyprenylated acylphloroglucinols (PPAP) derivative, we discovered that the key intermediate bicycle[3.3.1]nonone(7a) reacted with 3-aminopropan-l-ol in the presence of TsOH afforded polysubstituted-2-pyridinone with a novel skeleton. After that, the optimized condition of this method of synthesis was established, using p-TsOH-H2O(0.3 eq) as catalyst, toluene as solvent, refluxing at 115℃ for 12 hours, and giving a 55-60% yield.Using 1,3-cyclohexanedione as a starting material with seven steps, prenyl-substituted /geranyl-substituted 2-pyridinone core(8/9) were synthesized. And starting from 8/9, we designed and synthesized 35 polysubstituted 2-pyridinone ether derivatives.2. Anti-pancreatic cancer activity of polysubstituted 2-pyridinone derivativesUsing MTT assay, the inhibition of synthesized compounds to PANC-1 cells was evaluated under the nutrient-rich and nutrient-deprived conditions respectively, and the structure-activity relationship (SAR) of the compounds was preliminarily discussed. The majority of compounds showed low inhibition rate under the nutrient-rich condition. Under the nutrient-deprived condition, the substituents of prenyl-substituted derivatives affected the inhibition significantly, in which compound 8b showed an inhibition rate of 75%, while the substituents of geranyl-substituted derivatives affected little. The inhibition rates of geranyl-substituted derivatives were slightly higher than those of prenyl-substituted derivatives under the nutrient-deprived condition, and both showed similar high cell survival rates under the nutrient-rich condition.In all 2-pyridinone derivatives, compounds 8b,8c and 9m showed the best activities to PANC-1 cells with an inhibition rate of 75.0%,73.6% and 73.6%, respectively, under the nutrient-deprived condition, and a cell survival rate of more than 80% under nutrient-rich condition,In summary,37 target compounds were synthesized, and compounds 8b,8c and 9m showed excellent selective inhibitory activities on PANC-1 cells. These compounds may become potential lead compounds with anti-pancreatic cancer activities.