Yamali Cem, Gul Halise Inci, Ozgun Dilan Ozmen, Sakagam Hiroshi, Umemura Naoki, Kazaz Cavit, Gul Mustafa
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum 25240. Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Agri Ibrahim Cecen University, Agri 04100. Turkey.
Anticancer Agents Med Chem. 2017;17(10):1426-1433. doi: 10.2174/1871520617666170327123909.
Although anticancer chemotherapeutics are available in markets, side effects related to the drugs in clinical use lead to researchers to investigate new drug candidates which are more safe, potent and selective than others. Chalcones are popular with their anticancer activities with the several reported mechanisms including inhibition of angiogenesis, inhibition of tubulin polymerization, and induction of apoptosis etc.
This study was focused on to synthesize of 1-(2,4/2,6-difluorophenyl)-3-(2,3/2,4/2,5/3,4- dimethoxyphenyl)-2-propen-1-ones (1-8) and investigate their cytotoxic properties with possible mechanism of action.
The compounds were synthesized by Claisen-Schmidt condensation. The chemical structures were confirmed by 1H NMR, 13C NMR, DEPT, COSY, HMQC, HMBC, 19F NMR and HRMS. In vitro cytotoxic effects of the compounds against human tumour cell lines [gingival carcinoma (Ca9-22), oral squamous cell carcinoma (HSC-2)] and human normal oral cells [gingival fibroblasts (HGF), periodontal ligament fibroblasts (HPLF)] were evaluated via MTT test.
All compounds had higher cytotoxicity than reference compound 5-Fluorouracil (5-FU). The compounds 3-7 had higher potency selectivity expression values (PSE) than 5-FU and PSE values of the compounds were over 100. All chalcone derivatives seem good candidates for further studies according to very remarkable and high PSE values.
It was clearly demonstrated that compound 7 can induce early apoptosis at a concentration of 10 µM and dose-dependent late apoptosis starting at 10 µM. Compound 7 induced cleavage of the apoptosis marker PARP. The results indicate that new chalcones reported here can promote apoptosis in human tumour cell lines.
尽管市场上已有抗癌化疗药物，但临床使用的药物所产生的副作用促使研究人员去探寻比其他药物更安全、有效且具选择性的新候选药物。查耳酮因其抗癌活性而备受关注，其抗癌机制有多种报道，包括抑制血管生成、抑制微管蛋白聚合以及诱导细胞凋亡等。
本研究聚焦于合成1-(2,4/2,6 - 二氟苯基)-3-(2,3/2,4/2,5/3,4 - 二甲氧基苯基)-2 - 丙烯 - 1 - 酮（1 - 8），并探究其细胞毒性特性及可能的作用机制。
通过克莱森 - 施密特缩合反应合成化合物。化学结构经1H NMR、13C NMR、DEPT、COSY、HMQC、HMBC、19F NMR和HRMS确证。采用MTT法评估化合物对人肿瘤细胞系[牙龈癌（Ca9 - 22）、口腔鳞状细胞癌（HSC - 2）]和人正常口腔细胞[牙龈成纤维细胞（HGF）、牙周膜成纤维细胞（HPLF）]的体外细胞毒性作用。
所有化合物的细胞毒性均高于参考化合物5 - 氟尿嘧啶（5 - FU）。化合物3 - 7的效价比选择性表达值（PSE）高于5 - FU，且化合物的PSE值超过100。鉴于非常显著且高的PSE值，所有查耳酮衍生物似乎都是进一步研究的良好候选物。
已明确证明化合物7在浓度为10 μM时可诱导早期凋亡，并在10 μM时开始诱导剂量依赖性晚期凋亡。化合物7诱导凋亡标志物PARP的裂解。结果表明，此处报道的新型查耳酮可促进人肿瘤细胞系的凋亡。
