Molecular diversity of phenothiazines: design and synthesis of phenothiazine-dithiocarbamate hybrids as potential cell cycle blockers

Dong-Jun Fu; Ruo-Han Zhao; Jia-Huan Li; Jia-Jia Yang; Ruo-Wang Mao; Bo-Wen Wu; Ping Li; Xiao-Lin Zi; Qing-Qing Zhang; Hui-Jie Cai; Sai-Yang Zhang; Yan-Bing Zhang; Hong-Min Liu

doi:10.1007/s11030-017-9773-4

Molecular diversity of phenothiazines: design and synthesis of phenothiazine-dithiocarbamate hybrids as potential cell cycle blockers

Mol Divers. 2017 Nov;21(4):933-942. doi: 10.1007/s11030-017-9773-4. Epub 2017 Aug 7.

Authors

Dong-Jun Fu^{1

2

3

4}, Ruo-Han Zhao^{1

2

3

4}, Jia-Huan Li^{1

2

3

4}, Jia-Jia Yang^{1

2

3

4}, Ruo-Wang Mao^{1

2

3

4}, Bo-Wen Wu^{1

2

3

4}, Ping Li^{1

2

3

4}, Xiao-Lin Zi⁵, Qing-Qing Zhang^{1

2

3

4}, Hui-Jie Cai^{1

2

3

4}, Sai-Yang Zhang⁶, Yan-Bing Zhang^{7

8

9

10}, Hong-Min Liu^{11

12

13

14}

Affiliations

¹ New Drug Research and Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
² Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China.
³ Key Laboratory of Technology of Drug Preparation (Zhengzhou University) Ministry of Education, Zhengzhou, China.
⁴ Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province, China.
⁵ Pathology and Laboratory Medicine, University of California, Irvine, Orange, CA, 92868, USA.
⁶ School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. celeron16@163.com.
⁷ New Drug Research and Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. zhangyb@zzu.edu.cn.
⁸ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China. zhangyb@zzu.edu.cn.
⁹ Key Laboratory of Technology of Drug Preparation (Zhengzhou University) Ministry of Education, Zhengzhou, China. zhangyb@zzu.edu.cn.
¹⁰ Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province, China. zhangyb@zzu.edu.cn.
¹¹ New Drug Research and Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. liuhm@zzu.edu.cn.
¹² Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China. liuhm@zzu.edu.cn.
¹³ Key Laboratory of Technology of Drug Preparation (Zhengzhou University) Ministry of Education, Zhengzhou, China. liuhm@zzu.edu.cn.
¹⁴ Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province, China. liuhm@zzu.edu.cn.

Abstract

Novel phenothiazine-dithiocarbamate analogues were designed by molecular hybridization strategy and synthesized and evaluated for their anticancer activity in vitro against three selected cancer cell lines (EC-109, MGC-803, and PC-3). The preliminary structure-activity relationship (SAR) for this phenothiazine-dithiocarbamate hybrids is explored. Among all analogues, 2-oxo-2-(10H-phenothiazin-10-yl)ethyl 4-ethylpiperazine-1-carbodithioate (8a) showed the most potent inhibitory activity with an [Formula: see text] value of [Formula: see text] against PC-3 cells. In addition, compound 8a could arrest the cell cycle at the G1 phase and regulate the expression of G1 checkpoint-related proteins, suggesting that phenothiazine-dithiocarbamate hybrids might be useful as cell cycle blockers.

Keywords: Antiproliferative activity; Dithiocarbamate; G1 checkpoint-related protein; G1 phase; Phenothiazine.

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Drug Design*
Drug Screening Assays, Antitumor
Humans
Phenothiazines / chemical synthesis*
Phenothiazines / chemistry
Phenothiazines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Phenothiazines

Abstract

MeSH terms

Substances

Grants and funding