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Published on: June 26, 2018
Design, synthesis, and bioactivity evaluation of antitumor sorafenib analogues
Shiyang Zhou1,2, Guangying Chen1,2
1College of Chemistry and Chemical Engineering, Hainan Normal University Haikou 571158 China chgying123@163.com.
Abstract:
Malignant tumors are a serious threat to human health and are generally treated with chemical therapy. This chemical therapy uses agents that act on signal transduction pathway mechanism of tumor with good selectivity and low toxicity. Sorafenib is a multikinase target inhibitor with good tumor inhibitory activity and a protein kinase inhibitor. In this research, a novel series of sorafenib analogues and derivatives were designed, synthesized, and evaluated as tumor inhibitors. These compounds used sorafenib as the lead compound and achieved modifications using bioisosteres and the alkyl principle. The in vitro the results showed that compounds 3c, 3d, 3h, 3n, 3r, and 3z had good inhibitory effects on human cervical cancer cells (Hela), while compounds 3t and 3v had good inhibitory effects on human lung cancer cells (H1975 and A549). Among these, compound 3d had an inhibitory activity (IC50) of 0.56 ± 0.04 μmol L-1 against Hela cells (human cervical cancer), the compound 3t had an IC50 of 2.34 ± 0.07 μmol L-1 against H1975 cells (human lung cancer), and compound 3v had an IC50 of 1.35 ± 0.03 μmol L-1 against A549 cells (human lung cancer). The in vivo results showed that these compounds had good antitumor effects and low acute toxicity.
Insights
Researchers developed novel sorafenib derivatives as potential cancer therapies. These compounds show significant tumor inhibitory activity against human cervical and lung cancer cells, with low toxicity in preclinical studies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Malignant tumors pose a significant global health challenge, necessitating advanced therapeutic strategies.
- Current chemical therapies often target tumor signal transduction pathways, aiming for selectivity and reduced toxicity.
- Sorafenib, a known multikinase inhibitor, serves as a foundation for developing new anticancer agents.
Purpose of the Study:
- To design, synthesize, and evaluate novel sorafenib analogues and derivatives as potential tumor inhibitors.
- To explore modifications using bioisosteres and the alkyl principle based on the sorafenib lead compound.
- To assess the in vitro and in vivo antitumor efficacy and toxicity of the synthesized compounds.
Main Methods:
- Synthesis of a novel series of sorafenib analogues and derivatives.
- In vitro evaluation of compound efficacy against human cervical cancer (Hela) and human lung cancer (H1975, A549) cell lines.
- Determination of inhibitory activity (IC50) for promising compounds.
- In vivo assessment of antitumor effects and acute toxicity.
Main Results:
- Compounds 3c, 3d, 3h, 3n, 3r, and 3z demonstrated significant inhibitory effects on Hela cells.
- Compounds 3t and 3v exhibited potent inhibition against H1975 and A549 lung cancer cells, respectively.
- Compound 3d showed an IC50 of 0.56 ± 0.04 μmol L-1 against Hela cells.
- Compound 3t achieved an IC50 of 2.34 ± 0.07 μmol L-1 against H1975 cells, and compound 3v had an IC50 of 1.35 ± 0.03 μmol L-1 against A549 cells.
- In vivo studies confirmed good antitumor activity and low acute toxicity for the evaluated compounds.
Conclusions:
- The novel sorafenib analogues and derivatives exhibit promising in vitro and in vivo antitumor activities.
- Specific compounds demonstrate potent and selective inhibition against distinct human cancer cell lines.
- These findings suggest the potential of these novel compounds as effective anticancer agents with favorable safety profiles.
