Related Experiment Video
Updated: Jan 11, 2026
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
1,2,3-Triazole-modified sorafenib derivatives induce DNA damage, apoptosis, and PI3K/AKT pathway suppression in
Longfei Mao1, Junfei Wu1, Yimian Wang1
1College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan 471023, PR China.
Abstract:
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and remains one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, has been widely used in the systemic treatment of advanced HCC, but its clinical efficacy is limited due to acquired resistance, poor selectivity, and adverse effects. To address these limitations, a series of novel sorafenib derivatives incorporating a 1,2,3-triazole moiety were rationally designed and synthesized via a molecular hybridization strategy. The N,N-diphenylurea fragment of sorafenib was retained, while the C-ring pyridine was replaced by various substituted 1,2,3-triazoles to improve antitumor potency and induce DNA damage. Biological evaluation revealed that compounds 12e, 12 g and 12j exhibited potent anti-proliferative activity against HepG2 cells, with IC₅₀ values of 6.49 ± 0.17 μM, 6.53 ± 1.27 μM, and 7.21 ± 0.30 μM, respectively. These compounds significantly inhibited colony formation and cell migration, elevated intracellular ROS levels, and induced mitochondrial-mediated apoptosis and DNA damage, as evidenced by DAPI staining, Annexin V/PI flow cytometry, TUNEL assays, and upregulation of pro-apoptotic proteins (Bax, cleaved-caspase-3/9, cleaved-PARP) along with downregulation of Bcl-2. Moreover, western blot analysis showed marked activation of DNA damage markers (p-H2AX) and suppression of the PI3K/AKT signaling pathway. In vivo, compounds 12e and 12 g effectively inhibited tumor growth in a HepG2 xenograft mouse model without significant systemic toxicity, as confirmed by tumor volume/weight analysis, organ index, serum transaminase levels, and histological evaluation. These findings demonstrate that 1,2,3-triazole-modified sorafenib derivatives possess promising antitumor activity and favorable safety profiles. Compounds 12e, 12 g and 12j represent promising lead candidates for further development of targeted therapeutics against liver cancer.
Insights
Novel sorafenib derivatives with 1,2,3-triazole moieties show potent anti-cancer effects against liver cancer cells. These compounds effectively inhibit tumor growth in vivo with a favorable safety profile, offering promising therapeutic candidates.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer death, with limited treatment options for advanced stages.
- Sorafenib, a multi-kinase inhibitor, faces challenges like resistance, poor selectivity, and side effects in HCC treatment.
Purpose of the Study:
- To design and synthesize novel sorafenib derivatives by incorporating 1,2,3-triazole moieties.
- To evaluate the in vitro and in vivo anti-cancer activity and safety profiles of these new compounds against HCC.
Main Methods:
- Molecular hybridization strategy to synthesize sorafenib derivatives with 1,2,3-triazole replacements.
- In vitro assays including cell proliferation (IC50), colony formation, cell migration, ROS levels, apoptosis (Annexin V/PI, TUNEL), and western blotting for protein expression (Bax, Bcl-2, Caspase, PARP, p-H2AX, PI3K/AKT pathway).
- In vivo studies using a HepG2 xenograft mouse model to assess tumor growth inhibition and systemic toxicity (organ index, serum analysis, histology).
Main Results:
- Compounds 12e, 12g, and 12j demonstrated potent anti-proliferative activity against HepG2 cells (IC50 values ~6-7 μM).
- These derivatives inhibited colony formation and migration, increased ROS, induced apoptosis, and caused DNA damage.
- In vivo, compounds 12e and 12g significantly inhibited tumor growth in mice with no major systemic toxicity.
Conclusions:
- 1,2,3-triazole-modified sorafenib derivatives exhibit significant anti-tumor efficacy and improved safety profiles.
- Compounds 12e, 12g, and 12j are promising lead candidates for developing novel targeted therapies for liver cancer.
