Design, synthesis, and evaluation of novel coumarin-dithiocarbamate derivatives (IDs) as anti-colorectal cancer agents

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 36; no. 1; pp. 593 - 604
• Main Authors: Zhu, Heping, Ying, Shilong, Zhou, Bingluo, Hu, Xinyang, Liang, Xiao, Li, Wangyu, Wang, Dungai, Jin, Hongchuan, Pan, Yuanjiang
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2021; Taylor & Francis Group
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor activities; Apoptosis - drug effects; Biochemistry & Molecular Biology; bromodomain-containing protein 4; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chemistry, Medicinal; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; coumarin-dithiocarbamate derivatives; Coumarins - chemistry; Coumarins - pharmacology; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; Research Paper; Science & Technology; Structure-Activity Relationship; Thiocarbamates - chemistry; Thiocarbamates - pharmacology; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; POTENT; NATURAL-PRODUCTS; Colorectal cancer; coumarin-dithiocarbamate derivatives; bromodomain-containing protein 4; antitumor activities; INHIBITORS; DISCOVERY; BRD4; SCAFFOLD
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.1875458

Colorectal cancer (CRC) is a common malignant tumour of human digestive tract. The high mortality rate of CRC is closely related to the limitations of existing treatments. Thus, there is an urgent need to search for new anti-CRC agents. In this work, twenty novel coumarin-dithiocarbamate derivatives (IDs) were designed, synthesized and evaluated in vitro. The results suggest that the most active compound ID-11 effectively inhibited the proliferation of CRC cell lines while shown little impact on normal colon epithelial cells. Mechanism studies revealed that ID-11 displayed bromodomain-containing protein 4 inhibitory activity, and induced G2/M phase arrest, apoptosis as well as decreased the expression levels of the key genes such as c-Myc and Bcl-2 in CRC cell lines. Moreover, the ADMET properties prediction results shown that ID-11 possess well metabolic characteristics without obvious toxicities. Our data demonstrated that compound ID-11 may be a promising anti-CRC agent and deserved for further development.