•Two Pt(II) complexes 7a,b with indolin-2-one derivatives were synthesized.•7a,b exhibited stronger cytotoxicity against three cell lines than the corresponding ligands.•Treatment of HCT-116 cells with 7a,b increased sub-G1 population in cell cycle profiles.•Treatment with 7a,b led to the cleavage of PARP1, caspases 3, 7 and 9 in HCT-116 cells.•The new complexes induced apoptosis in cancer cells possibly through non-covalently binding to DNA.Two new platinum(II) complexes 7a and 7b with methyl hydrazinecarbodithioate derivatives of indolin-2-one have been prepared and characterized by single-crystal X-ray diffraction, NMR spectroscopy and mass spectrometry. Antiproliferative activity of the two complexes and their ligands 6a and 6b against HCT-116, MCF-7 and MDA-MB-231 cell lines was determined by the MTS assay. Complexes 7a and 7b exhibited stronger antiproliferative activity against three cell lines than compounds 6a and 6b (IC50, 1.89–5.60 versus 6.52–35.13 μM). Moreover, treatment of HCT-116 cells with the complexes resulted in an obvious sub-G1 peak by cell cycle profile analysis, and an increase of cleaved PARP1 and caspases 3, 7, and 9 by immunoblotting analysis. Live cell imaging showed that nucleus shrinkage and condensation started to appear when MCF-7 cells were treated with 7a for 8 h. Fluorescent spectrophotometric analysis revealed that the complexes physically associated with calf thymus DNA. Competitive DNA binding assays uncovered that the complexes non-covalently bind to DNA. Taken together, our results indicated that the two new platinum(II) complexes 7a and 7b non-covalently bind to DNA with high affinity and exhibit cytotoxicity against cancer cells by inducing apoptosis.Coordination of 6a,b with Pt(II) resulted in complexes 7a,b with enhanced cytotoxicity. The complexes exerted cytotoxic effects towards cancer cells by inducing apoptosis, possibly through non-covalently binding to DNA.Download high-res image (120KB)Download full-size image

•Twenty dithiocarbamate derivatives of quinazolin-4(3H)-one were synthesized.•Antiproliferative activities of 5a−t against five cancer cell lines were evaluated.•Compound 5c induced a G2/M arrest in HT29 cells.•5c promoted tubulin polymerization and activated the spindle assembly checkpoint.A series of quinazolin-4(3H)-one derivatives bearing dithiocarbamate side chain at the C2-position were synthesized and evaluated for their antiproliferative activities against A549, MCF-7, HeLa, HT29 and HCT-116 cell lines. Most of the synthesized compounds exhibited broad spectrum antitproliferative activity against five cell lines, of which 5c was the most potent against HT29 cell line with an IC50 value of 5.53 μM, inducing a G2/M phase arrest in HT29 cells. Treatment of HT29 cells with 5c resulted in BubR1 phosphorylation and an increase of mitotic index in a time-dependent manner. Furthermore, 5c promoted tubulin polymerization in vitro. These results demonstrate that quinazolin-4(3H)-one derivatives bearing dithiocarbamate side chain at C2-position may be potentially novel antitumor agents targeting tubulin to activate the spindle assembly checkpoint.Compounds 5a−t were synthesized and evaluated as antitumor agents. Among them, 5c inhibited the proliferation of HT29 cells by interfering with tubulin, leading to a cell cycle arrest at G2/M phase.

A series of quinazoline derivatives bearing piperazine-1-carbodithioate moiety at the C4-position were synthesized using piperidine and 1-bromo-3-chloropropane as starting materials via eight steps. Final compounds 8a–q and 9a–i were evaluated for their antiproliferative activity against human lung cancer A549, breast adenocarcinoma MCF-7, and colorectal cancer HCT-116 cell lines. The results showed that fourteen of twenty-six final compounds inhibited the proliferation of three cancer cell lines with IC50 values less than 10 μM. When treated with a representative compound 8n, HCT-116 cells were arrested at G0/G1 phase of the cell cycle. This provided a clue to further investigation of the mechanism of action.4-Quinazolinylpiperazine-1-carbodithioates 8a–q and 9a–i were synthesized. Most of them exhibited promising cytotoxicity, and 8n induced a dose-dependent G0/G1 phase arrest in HCT-116 cells.

•A novel series of 2,4-diaminoquinazoline derivatives were synthesized.•Most compounds showed broad spectrum antitumour activity against five cell lines.•Compounds 8f, 8m and 8q exhibited weak inhibition against DHFR and no activity against TS.•They induced DNA damage in HCT-116 cells, leading to G2/M checkpoint activation and G2/M arrest.A novel series of 4-substituted-piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline were synthesized and tested for their antiproliferative activities against five human cancer cell lines including A549 (lung cancer), MCF-7 (breast adenocarcinoma), HeLa (cervical carcinoma), HT29 and HCT-116 (colorectal cancer). Most of the synthesized compounds showed broad spectrum antiproliferative activity (IC50 1.47–11.83 μM), of which 8f, 8m and 8q were the most active members with IC50 values in the range of 1.58–2.27, 1.84–3.27 and 1.47–4.68 μM against five cancer cell lines examined, respectively. Further investigations revealed that compounds 8f, 8m and 8q exhibited weak inhibition against dihydrofolate reductase and no activity against thymidylate synthase, while induced DNA damage and activated the G2/M checkpoint in HCT-116 cells.Compounds 8a–u were synthesized. 8f, 8m and 8q showed broad spectrum antiproliferative activity and induced DNA damage in HCT-116 cells, leading to the G2/M checkpoint activation and G2/M arrest.

By varying the substituents (R1) at the indolin-2-one scaffold, a series of indolin-2-one derivatives bearing 4-phenylpiperazine-1-carbothiohydrazide moiety at the C3-position were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines. We further selected the 5-chloroindolin-2-one moiety for the extension to another series of compounds by varying the substituents (R2) at the phenyl group connected with the piperazine ring. Among all the compounds synthesized, 6d and 6l were most potent with IC50 values of 3.59 and 5.58 μM, respectively against A549 lung cancer cells, while 5f and 6l possessed IC50 values of 3.49 and 4.57 μM, respectively against HCT-116 colon cancer cells which were comparable to that of Sunitinib, an indolin-2-one derivative in cancer therapy.Indolin-2-one derivatives 5a–l and 6a–l were synthesized and evaluated for their antiproliferative activity. The effects of R1, R2 and piperazine moiety on the antiproliferative activity were examined.