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On the basis and continuation of our previous studies on anti-tubulin and anti-gastric cancer agents, novel tertiary amide derivatives incorporating benzothiazole moiety were synthesized and the antiproliferative activity was studied in vitro. Preliminary structure activity relationships (SARs) were explored according to the in vitro antiproliferative activity results. Some of compounds could significantly inhibit the proliferation of three cancer cells (HCT-116, MGC-803 and PC-3 cells) and compound F10 exhibited excellent antiproliferative activity against HCT-116 cells (IC 50 = 0.182 μM), MGC-803 cells (IC 50 = 0.035 μM), PC-3 cells(IC 50 = 2.11 μM) and SGC-7901 cells (IC 50 = 0.049 μM). Compound F10 effectively inhibited tubulin polymerization (IC 50 = 1.9 μM) and bound to colchicine binding site of tubulin. Molecular docking results suggested compound F10 could bind tightly into the colchicine binding site of β-tubulin. Moreover, compound F10 could regulate the Hippo/YAP signaling pathway. Compound F10 activated Hippo signaling pathway from its very beginning MST1/2, as the result of Hippo cascade activation YAP were inhibited. And then it led to a decrease of c-Myc and Bcl-2 expression. Further molecular experiments showed that compound F10 arrested at G2/M phase, inhibited cell colony formatting and induced extrinsic and intrinsic apoptosis in MGC-803 and SGC-7901 cells. Collectively, compound F10 was the first to be reported as a new anticancer agent in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway. Image 1 • Novel tertiary amide derivatives containing benzothiazole moiety were designed and prepared. • Compound F10 displayed excellent antiproliferative activity against gastric cancer cell lines. • Compound F10 acted as a novel colchicine site tubulin polymerization inhibitor with an IC 50 value of 1.9 μM. • Compound F10 activated Hippo signaling pathway. [ABSTRACT FROM AUTHOR]

With the expectation to find out new anti-gastric cancer agents with high efficacy and selectivity, a series of novel tertiary sulfonamide derivatives were synthesized and the anti-cancer activity was studied in three selected cancer cell lines (MGC-803, PC-3, MCF-7) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells and were more potent than the positive control (5-Fu). The structure-activity relationship of tertiary sulfonamide derivatives was explored in this report. Among the tested compounds, compound 13g containing benzimidazole moiety showed the best anti-proliferation activities against MGC-803 cells (IC 50 = 1.02 μM), HGC-27 cells (IC 50 = 1.61 μM), SGC-7901 (IC 50 = 2.30 μM) cells as well as the good selectivity between the cancer and normal cells. Cellular mechanism studies elucidated compound 13g inhibited the colony formation of gastric cancer cell lines. Meanwhile, compound 13g arrested cell cycle at G2/M phase and induced cell apoptosis. Mechanistically, compound 13g markedly decreased p-Akt and p- c -Raf expression, which revealed that compound 13g targeted gastric cancer cell lines via interfering with AKT/mTOR and RAS/Raf/MEK/ERK pathways. All the findings suggest that compound 13g might be a valuable lead compound for the anti-gastric cancer agents. Image 1 • Novel sulfonamide derivatives containing benzimidazole moiety were designed and prepared. • Compound 13g displayed excellent anti-proliferative activity and lower toxicity against the non-cancer cells. • Structure-activity relationship of sulfonamide derivatives was depicted. • Compound 13g caused cell cycle arrest at G2/M phase and induced cell apoptosis. • Compound 13g could down-regulate the p-Akt and p- c -Raf expression. [ABSTRACT FROM AUTHOR]