Design, synthesis and evaluation of novel 1,3-benzodioxole derivatives for their anti-tumor activity

This study designed novel 1,3-benzodioxole derivatives (a core moiety of piperine essential for activity) by: 1) Retaining the 1,3-benzodioxole ring (critical for antitumor efficacy); 2) Introducing a vinyl linker (enhanced activity vs. direct amide attachment, per our prior work); 3) Incorporating trifluoromethylpiperazine (proven to boost antitumor effects). Target compounds were synthesized via bromination, nucleophilic substitution, reduction, and condensation, with structures confirmed by ¹H NMR, ¹³C NMR, and HR-MS. Target compounds were synthesized via bromination, nucleophilic substitution, reduction, and condensation, with structures confirmed by ¹H NMR, ¹³C NMR, and HR-MS. MTT assay showed most derivatives exhibited significant cytotoxicity against HeLa, A498, and MDA-MB-231 cells. Among them, (E)-3-(benzo[d][1,3]dioxol-5-yl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acrylamide (YL201) had the strongest activity against MDA-MB-231 cells (IC₅₀ = 4.92 ± 1.09 μM), outperforming 5-fluorouracil (5-Fu, IC₅₀ = 18.06 ± 2.33 μM). In vitro assays (colony formation, adhesion, Transwell invasion, wound healing) demonstrated YL201 concentration-dependently suppressed MDA-MB-231 cell proliferation, adhesion, invasion, and migration (e.g., 8 μM YL201 led to 23.30 ± 1.20 % proliferation rate vs. 69.63 ± 3.63 % for 5-Fu). In chick embryo chorioallantoic membrane (CAM) xenografts, YL201 inhibited tumor angiogenesis and reduced tumor weight (8.17 ± 1.17 mg at 8 μM vs. 14.40 ± 1.05 mg for 5-Fu) without affecting chick embryo weight, indicating good in vivo safety. SwissADME prediction showed YL201 complies with Lipinski's Rule of Five (MW = 461.48, logP = 3.94, HBA = 8, HBD = 1, rotatable bonds = 8), suggesting favorable druggability. In conclusion, YL201 is a promising candidate for breast cancer treatment worthy of further preclinical research.