The Design and Synthesis of Novel Phenothiazine Derivatives as Potential
The Design and Synthesis of Novel Phenothiazine Derivatives as Potential
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具有潜力的新型吩噻嗪衍生物的设计与合成
DOI：
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发表时间：
2020
影响因子：
1
通讯作者：
Jinhua Wang
中科院分区：
文献类型：
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作者：
Yepeng Luan;Jinyi Liu;Jianjun Gao;Jinhua Wang
摘要：背景：癌症的发病率和死亡率一直呈上升趋势，癌症仍然是世界范围内的主要死亡原因。尽管癌症治疗取得了巨大的进步，但许多患者死于无效的化疗和耐药性。因此，设计和开发高效、低毒的抗肿瘤药物仍然是最具挑战性的课题之一。三环杂环化合物，如吩噻嗪，一直是抗癌药物发现的重要骨架来源。研究方法：本工作设计并合成了10个新的含脲吩噻嗪衍生物，它们通过一个三碳长的间隔基在末端偶联了不同种类的胺基序。化合物的结构经1H NMR和HRMS确证。对所合成的化合物进行了体外抗PC-3细胞增殖活性的测定，其中活性最好的化合物对其它22种人肿瘤细胞系进行了细胞毒活性评价。并对其机理进行了研究。结果：在10个目标化合物中，TTi-2对23株人癌细胞的增殖抑制作用最强，而TTi-2对正常细胞的增殖抑制作用不明显。effect.in TTi-2还能抑制MDA-MB-231细胞的迁移、侵袭和集落形成。TTi-2可通过激活caspase 3的活性，使细胞周期阻滞于G 0/G1期，诱导细胞凋亡。结论：TTi-2可能是一种有前途的抗癌药物先导化合物。A R T I C L E H I S T O R Y.投稿时间：2018 - 05 - 06修订日期：2018 - 10 - 23受理时间：2018 - 11 - 11 DOI：.10.2174/1570180816666181115112236.关键词：吩噻嗪，衍生物，抗癌，设计，合成，凋亡。
Abstract: Background: Cancer incidence and mortality have been increasing and cancer is still the.leading cause of death all over the world. Despite the enormous progress in cancer treatment, many.patients died of ineffective chemotherapy and drug resistance. Therefore, the design and development.of anti-cancer drugs with high efficiency and low toxicity is still one of the most challenging.tasks. Tricyclic heterocycles, such as phenothiazine, are always important sources of scaffolds for.anti-cancer drug discovery..Methods: In this work, ten new urea-containing derivatives of phenothiazine coupled with different.kinds of amine motifs at the endpoint through a three carbon long spacer were designed and synthesized..The structures of the synthesized compounds were elucidated and confirmed by 1H NMR and.HRMS. All the synthesized compounds were tested for their antitumor activity in vitro against the.proliferation of PC-3 cells, and the compounds with best potency entered further cytotoxicity evaluations.against other 22 human tumor cell lines. Mechanism was also studied..Results: From all data, it showed that among all 10 target compounds, TTi-2 showed the best effect.in inhibiting the proliferation of 23 human cancer cell lines while TTi-2 without obvious inhibitory.effect on normal cell. Furthermore, our results also showed that TTi-2 could inhibit migration, invasion and.colony formation of MDA-MB-231 cells. Finally, TTi-2 can induce arrest of cell cycle at G0/G1 phase and.cell apoptosis by activating the caspase 3 activity..Conclusion: All these results suggested that TTi-2 might be used as a promising lead compound for anticancer.drug development..A R T I C L E H I S T O R Y.Received: May 6, 2018.Revised: October 23, 2018.Accepted: November 11, 2018.DOI:.10.2174/1570180816666181115112236..Keywords: Phenothiazine, derivative, anti-cancer, design, synthesis, apoptosis.