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