The Design and Synthesis of Novel Phenothiazine Derivatives as Potential Cytotoxic Agents

Author(s): Yepeng Luan*, Jinyi Liu, Jianjun Gao, Jinhua Wang*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 1 , 2020

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Graphical 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.

Keywords: Phenothiazine, derivative, anti-cancer, design, synthesis, apoptosis.

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Article Details

Year: 2020
Published on: 31 December, 2019
Page: [57 - 67]
Pages: 11
DOI: 10.2174/1570180816666181115112236
Price: $65

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