Design, Synthesis, and Anticancer Evaluation of Novel MGBs with Alkyne-Linked Thiazole Moieties

Minor groove binders (MGBs) are promising DNA-targeting agents for cancer therapy. Using a structure-based drug design approach, we developed a novel class of MGBs featuring alkyne-linked thiazole moieties to enhance DNA-binding affinity, lipophilicity, and cytotoxic efficacy. The synthesized compounds were evaluated using the NCI-60 panel and SRB assay, identifying MGB1Y, MGB2Y, and MGB6Y as potent inhibitors of cancer cell proliferation. Isothermal titration calorimetry, molecular docking, and molecular dynamics simulations confirmed their strong and reversible binding to the DNA minor groove, particularly at the 5′-ACTAGT-3′ and 5′-AGTACT-3′ binding sites. Transcriptomic analysis revealed downregulation of genes involved in cell cycle progression and chromatin organization alongside upregulation of lipid metabolism genes, suggesting the disruption of lipid homeostasis. Additionally, these compounds inhibit topoisomerase I, further supporting their DNA-targeting mechanism. Their strong anticancer activity, reversible noncovalent DNA interaction, and favorable binding properties highlight their potential for further development as anticancer therapeutics.