Chloro and bromo-pyrazole curcumin Knoevenagel condensates augmented anticancer activity against human cervical cancer cells: design, synthesis, in silico docking and in vitro cytotoxicity analysis
Chloro and bromo-pyrazole curcumin Knoevenagel condensates augmented anticancer activity against human cervical cancer cells: design, synthesis, in silico docking and in vitro cytotoxicity analysis
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DOI：
10.1080/07391102.2019.1578264
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发表时间：
2020-01-02
影响因子：
4.4
通讯作者：
Madan, Jitender
中科院分区：
文献类型：
--
作者：
Chaudhary, Monika;Kumar, Neeraj;Madan, Jitender
为了开发新型的姜黄素类似物作为潜在的抗癌药物，我们设计并合成了一系列通过在姜黄素骨架的活性亚甲基碳原子上连接吡唑甲醛来合成Knovenagel缩合物。进行了分子对接研究，以靶向潜在的抗癌靶点人激酶β(Ikk Beta)上的拟议衍生物。氯代衍生物有5个氢键相互作用，对接分数为-11.874千卡/摩尔，高于姜黄素(对接分数为-7.434千卡/摩尔)。这一点得到了这样一个事实的支持，即推进剂形状的衍生品恰好适合装订口袋。对铅分子也进行了分子模拟研究，结果表明，稳定的络合物是在0.11-0.92埃的范围内形成的每蛋白残基的最小偏差。用标准细胞增殖实验对所筛选的化合物进行了合成、表征和体外杀伤宫颈癌细胞HeLa的活性评价。氯代衍生物和溴代类似物的半数抑制浓度(IC50值)分别为14.2mU/ml和18.6mU/ml，明显低于姜黄素的42.4mU/ml，高于紫杉醇的0.008 mU/ml。通过caspase-3酶的裂解来评价其对细胞的诱导作用，其诱导的细胞凋亡率分别为69.6%和65.4%，明显高于姜黄素诱导的19.9%。总之，氯和溴的衍生物必须在一套严格的体外和体内参数下进行评估，才能转化为临床可行的产品。拉马斯瓦米·H·萨尔马沟通
With an endeavor to develop novel curcumin analogs as potential anti-cancer agents, we designed and synthesized a series of Knoevenagel condensates by clubbing pyrazole carbaldehydes at the active methylene carbon atom of the curcumin backbone. Molecular docking studies were carried out to target the proposed derivatives on human kinase beta (IKK beta), a potential anti-cancer target. The chloro derivative displayed five hydrogen bond interactions with a docking score of -11.874 kcal/mol higher than curcumin (docking score = -7.434 kcal/mol). This was supported by the fact that the propellant shaped derivatives fitted aptly into the binding pocket. Molecular simulations studies were also conducted on the lead molecule and the results figured out that the stable complexes were developed as the minimal deviations per residue of protein within the range of 0.11-0.92 angstrom. The screened compounds were synthesized, characterized and evaluated in vitro for cytotoxicity against cervical cancer cell line, HeLa using standard cell proliferation assay. Chloro derivative and bromo analog demonstrated IC50 (half maximal inhibitory concentration) value of 14.2 and 18.6 mu g/ml, respectively, significantly lower than 42.4 mu g/ml of curcumin and higher than 0.008 mu g/ml of paclitaxel. Induction of apoptosis was evaluated in the terms of cleavage of caspase-3 enzyme and they also exhibited 69.6 and 65.4% of apoptosis significantly higher than 19.9% induced by curcumin. In conclusion, chloro and bromo derivatives must be evaluated under a set of stringent in vitro and in vivo parameters for translating in to a clinically viable product. Communicated by Ramaswamy H. Sarma