Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the...

Area of Science:

• Medicinal Chemistry
• Oncology
• Drug Discovery

Background:

• Modern drug development increasingly focuses on multi-target therapies for complex diseases like cancer.
• Multi-targeted drugs offer a novel approach by simultaneously inhibiting multiple pathways involved in tumor progression, potentially overcoming limitations of traditional single-target therapies.

Purpose of the Study:

• To synthesize and evaluate novel ligustrazine-containing α, β-unsaturated carbonyl-based compounds and oximes for anticancer activity.
• To investigate the structure-activity relationships (SAR) of these compounds against various cancer cell types.
• To explore the mechanistic effects of potent compounds on key cancer targets and their ability to reverse multidrug resistance (MDR).

Main Methods:

• Synthesis of 34 novel ligustrazine-containing compounds, including oximes and α, β-unsaturated carbonyl derivatives.
• Biological evaluation of antiproliferative activity against five different cancer cell lines.
• Mechanistic studies involving tubulin polymerization, inhibition of EGFR TK, FAK, and BRAF^V600E kinases.
• In vitro assessment of multidrug resistance (MDR) reversal.
• Molecular docking studies to understand target-compound interactions.

Main Results:

• Ligustrazine-containing oximes demonstrated significant inhibition of cancer cell growth.
• Strong structure-activity relationships were observed for antiproliferative activity.
• Compounds 7e and 8o strongly inhibited EGFR.
• Compounds with a 1-isopropyl-piperidin-4-one linker showed the best FAK inhibition.
• Compound 5e exhibited potent BRAF^V600E inhibition (IC₅₀ = 0.7 μM).
• Analogs 5 and 7 (b,e,f) displayed dual anticancer and MDR reversal properties.

Conclusions:

• Novel ligustrazine-containing oximes are effective multi-targeted anticancer agents.
• These compounds target key pathways including EGFR, FAK, and BRAF^V600E.
• The identified compounds hold potential for developing new anticancer therapies, including those effective against resistant cancers.