Synthesis of compounds based on the active domain of cabotegravir and their application in inhibiting tumor cells activity

• Published in: ChemistryOpen (Weinheim) Vol. 13; no. 7; pp. e202300284 - n/a
• Main Authors: Yang, Ruyue, Yue, Wenhui, Hu, Dong, Wang, Guidan, Mao, Longfei, Huang, Jiahe, Wang, Huili, Liang, Gaofeng
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.07.2024; John Wiley and Sons Inc; Wiley-VCH
• Subjects: Alkynes; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cabotegravir; Cancer therapies; Catalytic Domain; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemical reactions; Chemical synthesis; Chemotherapy; Colorectal cancer; derivatives; Diketopiperazines; Drug dosages; Drug resistance; Drug Screening Assays, Antitumor; Drugs; ESCC; Esophageal cancer; HCT116 Cells; HIV; Human immunodeficiency virus; Humans; KYSE30; Medical prognosis; Mortality; Proteins; Pyridines - chemistry; Pyridines - pharmacology; Pyridones; R&D; Research & development; Smad2 Protein - metabolism; Smad3 Protein - metabolism; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Structure-Activity Relationship; Suppressors; Toxicity; Tumors; Cabotegravir; derivatives; apoptosis; KYSE30; ESCC
• ISSN: 2191-1363; 2191-1363
• DOI: 10.1002/open.202300284

Structural modification based on existing drugs, which ensures the safety of marketed drugs, is an essential approach in developing new drugs. In this study, we modified the structure of cabotegravir by introducing the front alkyne on the core structure through chemical reaction, resulting in the synthesis of 9 compounds resembling 1,2,3‐triazoles. The potential of these new cabotegravir derivatives as tumor suppressors in gastrointestinal tumors was investigated. Based on the MTT experiment, most compounds showed a reduction in the viability of KYSE30 and HCT116 cells. Notably, derivatives 5b and 5h exhibited the most significant inhibitory effects. To further explore the effects of derivatives 5b and 5h on gastrointestinal tumors, KYSE30 cells were chosen as a representative cell line. Both derivatives can effectively curtail the migration and invasion capabilities of KYSE30 cells and induce apoptosis in a dose‐dependent manner. We further demonstrated these derivatives induce cell apoptosis in KYSE30 cells by inhibiting the expression of Stat3 protein and Smad2/3 protein. Based on the above results, we suggest they show promise in developing drugs for esophageal squamous cell carcinoma. The objective of this study was to assess the inhibitory effect of modified cabotegravir derivatives on the activity of esophageal cancer KYSE30 cells. Results showed that compounds 5b and 5h effectively inhibited the migration and invasion of KYSE30 cells and induced apoptosis and may be involved in the stat3 and smad2/3 signal pathway. Based on these findings, we can consider these compounds as potential lead candidates for the treatment of esophageal squamous cell carcinoma.