Design, synthesis and biological assessment of erlotinib-1,2,3-triazole derivatives for anticancer applications

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Hepatocellular carcinoma (HCC) treatment faces challenges with current therapies like erlotinib, necessitating novel approaches.
• Limited efficacy of existing monotherapy and combination regimens highlights an unmet clinical need for new HCC drugs.

Purpose of the Study:

• To design and synthesize novel erlotinib derivatives with 1,2,3-triazole moieties for potential HCC treatment.
• To evaluate the in vitro and in vivo antitumor efficacy and safety of these novel compounds.

Main Methods:

• Synthesis of 14 erlotinib derivatives via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC).
• In vitro evaluation using MTT assays, proliferation, colony formation, and migration assays on HepG2 and Huh7 cell lines.
• Apoptosis induction analysis by Western blotting for Bcl-2, cleaved-caspase 3, and cleaved-PARP.
• In vivo antitumor activity and toxicity assessment of lead compounds.

Main Results:

• Compounds 3c and 3d displayed significant antitumor efficacy against HepG2 and Huh7 HCC cell lines.
• Compounds 3c and 3d inhibited proliferation, colony formation, and migration in HepG2 cells concentration-dependently.
• Antitumor activity was linked to apoptosis induction, evidenced by Bcl-2 downregulation and cleaved-caspase 3/PARP upregulation.
• Compound 3d showed in vivo antitumor efficacy with low toxicity to normal tissues.

Conclusions:

• Novel erlotinib derivatives incorporating 1,2,3-triazole moieties possess potent antitumor activity against HCC.
• Compound 3d is a promising candidate for further development as a therapeutic agent for hepatocellular carcinoma.
• The observed activity is mediated by apoptosis induction, offering a potential mechanism for HCC treatment.