Design and synthesis of substituted dihydropyrimidinone derivatives as cytotoxic and tubulin polymerization inhibitors
Design and synthesis of substituted dihydropyrimidinone derivatives as cytotoxic and tubulin polymerization inhibitors
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DOI：
10.1016/j.bioorg.2019.103317
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发表时间：
2019-12-01
影响因子：
5.1
通讯作者：
Shankaraiah, Nagula
中科院分区：
文献类型：
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作者：
Sana, Sravani;Tokala, Ramya;Shankaraiah, Nagula
采用操作简单的Biginelli方案合成了新的基于C6碳的芳基α-卤代丙烯酰胺连接的二氢嘧啶酮衍生物。将合成的化合物与正常肺成纤维细胞(HFL-1)进行体外抗增殖活性的比较，结果表明，所合成的化合物对人乳腺癌MCF-7、人乳腺癌MDA-MB-231、人结肠癌HCT-116、人结肠腺癌HCT-15、人结肠腺癌HT-29和人前列腺癌DU145的体外抗增殖活性较好。优选地，发现含有α-卤代丙烯酰胺(10a-g)官能团的化合物对所列出的癌细胞系表现出最显著的细胞毒性(IC50值0.54+/-0.12至8.35+/-0.82微米)，特别是对乳腺癌细胞系MCF-7和MDA-MB-231(IC50值0.54+/-0.12至3.70+/-0.24微米)。在所合成的化合物中，化合物10f对乳腺癌细胞株MCF-7(IC50值0.54+/-0.12mU M)和MDA-MB-231(IC50值1.18+/-0.32mU M)显示出较强的抗增殖活性。为了进一步了解细胞凋亡的潜在机制，采用了不同的染色技术，如AO/EB、DCFDA和DAPI染色。用Annexin V-FITC/PI和JC-1检测MCF-7细胞的凋亡程度和线粒体膜电位的丧失。细胞周期分析显示，化合物10f以剂量依赖的方式将细胞阻滞在G2/M期。化合物10f还表现出明显的抑制微管蛋白聚合的作用(IC50为6.91+/-0.43µM)，并具有微管的不稳定特性。分子对接研究还表明，化合物10f通过氢键与α/β-微管蛋白的关键催化活性残基Ser178、Val238和Val318有效地相互作用。
An operationally simple Biginelli protocol was employed for the synthesis of new C6-carbon based aryl alpha-haloacrylamide-linked dihydropyrimidinone derivatives. The synthesized compounds were appraised for their in vitro antiproliferative potential against a selected panel of human cancer cell lines especially MCF-7 (human breast cancer), MDA-MB-231 (human breast cancer), HCT-116 (human colon cancer), HCT-15 (human colorectal adenocarcinoma), HT-29 (human colon adenocarcinoma) and DU145 (human prostate cancer) along with normal lung fibroblasts (HFL-1). Preferably, compounds containing alpha-haloacrylamide (10a-g) functionality were found to exhibit most significant cytotoxicity (IC50 value 0.54 +/- 0.12 to 8.35 +/- 0.82 mu M) against the listed cancer cell lines, particularly towards breast cancer cell lines MCF-7 and MDA-MB-231 (IC50 value 0.54 +/- 0.12 to 3.70 +/- 0.24 mu M). In the seam of synthesized compounds, compound 10f exhibited potent antiproliferative activity against breast cancer cell lines namely MCF-7 (IC50 value 0.54 +/- 0.12 mu M) and MDA-MB-231 (IC50 value 1.18 +/- 0.32 mu M). Further to understand the underlying apoptosis mechanisms, different staining techniques such as AO/EB, DCFDA, and DAPI staining were performed. To know the extent of apoptosis and loss of mitochondrial membrane potential in MCF-7 cell lines, annexin V-FITC/PI and JC-1 were performed. Cell cycle analysis revealed that compound 10f arrested the cells at G2/M phase in a dose-dependent manner. The compound 10f also found to exhibit significant inhibition of tubulin polymerization (IC50 of 6.91 +/- 0.43 mu M) with microtubule destabilizing properties. Molecular docking studies also revealed that compound 10f efficiently interacted with critical catalytically active residues Ser178, Val238, and Val318 of the alpha/beta-tubulin by a hydrogen bond.