New 1,2,3-Triazole Hybrids as Anticancer Agents: Design, Synthesis, Characterization, and In Silico Studies

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• 1,2,3-triazole derivatives are a versatile scaffold in drug discovery.
• Targeting specific cancer cell vulnerabilities is crucial for effective therapy.

Purpose of the Study:

• To synthesize and evaluate novel 1,2,3-triazole-based molecules for anticancer activity.
• To identify compounds with selective cytotoxicity against various cancer cell lines.
• To elucidate the mechanism of action and identify potential drug targets.

Main Methods:

• Synthesis of two series of 1,2,3-triazole compounds.
• In vitro cytotoxicity assays against normal and cancer cell lines (lymphocytes, leukemias, adherent, non-tumor).
• Apoptosis induction analysis (caspase-3 activation).
• Spheroid-based drug testing.
• In vitro and computational binding affinity studies for protein kinase A.

Main Results:

• Compounds 18, 20, 12, 13, 14, 19, and 22 exhibited selective cytotoxicity against specific cancer cell lines.
• Compound 20 showed selectivity for T-cell leukemias, while compound 18 affected B-cell leukemia.
• Compound 14 was highly specific for T-cell leukemia.
• Compound 19 targeted A549 (lung cancer) cells.
• Compound 22 affected most tumor cell lines but spared A549.
• Active compounds induced apoptosis via caspase-3 activation.
• Compounds 13 and 22 were effective against HCT116 spheroids, and compound 19 against A549 spheroids.
• Compounds 11, 12, and 13 demonstrated high affinity for the A Cα subunit of protein kinase A.

Conclusions:

• Several 1,2,3-triazole derivatives possess significant and selective anticancer properties.
• The identified compounds represent promising lead candidates for targeted cancer therapy.
• The kinase-targeted mechanism, specifically involving protein kinase A, provides a basis for future optimization.