Synthesis and antiproliferative activity of 4-substituted-piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline

• Published in: European journal of medicinal chemistry 2013-06, Vol.64, p.401-409
• Main Authors: Cao, Sheng-Li, Han, Ying, Yuan, Chong-Zhen, Wang, Yao, Xiahou, Zhi-Kai, Liao, Ji, Gao, Rui-Ting, Mao, Bei-Bei, Zhao, Bao-Li, Li, Zhong-Feng, Xu, Xingzhi
• Format: Article
• Language: English
• Subjects: 2,4-Diaminoquinazoline; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Cell Line, Tumor; Cell Proliferation - drug effects; DNA damage; Dose-Response Relationship, Drug; HCT116 Cells; HeLa Cells; HT29 Cells; Humans; MCF-7 Cells; Molecular Structure; Piperazine-1-carbodithioate; Piperazines - chemistry; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Structure-Activity Relationship; Synthesis; Thiocarbamates - chemistry
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.04.017

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. [Display omitted] 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. •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.