Synthesis and evaluation of modified chalcone based p53 stabilizing agents
Synthesis and evaluation of modified chalcone based p53 stabilizing agents
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DOI：
10.1016/j.bmcl.2017.07.042
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发表时间：
2017-09-01
影响因子：
2.7
通讯作者：
Saleem, Rahman Shah Zaib
中科院分区：
文献类型：
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作者：
Iftikhar, Sunniya;Khan, Sardraz;Saleem, Rahman Shah Zaib
肿瘤抑制蛋白p53诱导细胞周期阻滞和凋亡细胞死亡，以应对各种细胞应激，从而防止癌症的发展。因此，通过小有机分子激活和稳定p53是治疗保留野生型p53的癌症的一种有吸引力的方法。在此背景下，采用Claisen-Schmidt缩合法制备了19种具有不同取代模式的查尔酮，包括氯、氟、甲氧基、硝基、苄氧基、4-甲基苄氧基。用NMR、HRMS、IR和熔点对化合物进行了表征。对合成的化合物对人结直肠癌（HCT116）和乳腺癌（CAL-51）细胞系的抗增殖活性进行了评价。9个化合物的GI（50）值在低微摩尔到亚微摩尔范围内；例如(E)-1-pheny1-3-（3,4,5-三甲氧基苯基）prop-2en-1-one （SSE14108）对HCT116细胞的GI（50）为0.473 +/- 0.043 mu M。对这些化合物的进一步分析表明，(E)-3-(4-chloropheny1)-1-phenylprop-2-en-1-one （SSE14105）和(E)-3-(4- methoxypheny1)-1-phenylprop-2-en-1-one （SSE14106）在HCT116细胞中引起p53的快速（处理后4和8小时）积累，与阳性对照Nutlin-3诱导相似。这些活性在3-（4-甲氧基苯基）丙烯酮（SSE14106H2）中不存在，这表明共轭酮对查尔酮的抗增殖和p53稳定活性具有重要作用。我们进一步评估了环己亚胺（CHX）存在下p53的水平，结果表明p53的稳定通过阻断其降解在翻译后水平受到调节。因此，这些查尔酮可以作为片段引线，进一步优化结构，以获得更有效的p53稳定剂，增强抗增殖活性。(C) 2017 Elsevier Ltd.版权所有。
Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (CAL-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI(50) values in the low micromolar to submicromolar range; for example (E)-1-pheny1-3-(3,4,5-trimethoxyphenyl)prop-2en-1-one (SSE14108) showed GI(50) of 0.473 +/- 0.043 mu M against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chloropheny1)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4methoxypheny1)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-h post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities. (C) 2017 Elsevier Ltd. All rights reserved.