Synthesis, Antiproliferative Activity and In Silico Conformational Analysis of Triazole-Tethered Vindoline–Chalcone Hybrids Targeting the Vinblastine Site of Microtubules

Background/Objectives: Cancer is one of the leading causes of mortality worldwide. However, due to limitations in clinical treatment of malignancies, there is a continuous need for the development of more potent novel drugs with enhanced activity and selectivity towards tumours. Methods: In this context, we synthesised a focused library of chalcone–vindoline hybrids incorporating a 1,4-disubstituted 1,2,3-triazole linker using a modular strategy combining sequential Sonogashira coupling and CuAAC reactions. The same synthetic route afforded a zidovudine-derived vindoline hybrid, which served as a negative control to underscore the pivotal role of the chalcone moiety in mediating antiproliferative activity. To elucidate the contribution of the vindoline scaffold, two corresponding aryl-substituted chalcone analogues were also prepared. The synthesised hybrids and the reference compounds were evaluated against a panel of human adherent cancer cell lines (HeLa, SiHa, MCF-7, MDA-MB-231 and A2780) and non-malignant NIH/3T3 fibroblasts. Results: Vindoline hybrids incorporating trimethoxyphenyl chalcone moieties exhibited outstanding potency on all the cancer cell lines tested. By contrast, hybrids containing monomethoxy-substituted chalcone moieties with moderately reduced activity against malignant cells displayed a certain degree of cancer selectivity. A ferrocene-containing hybrid and the vindoline-free chalcones exhibited markedly lower antiproliferative activity, whereas another ferrocene hybrid featuring an alternative enone configuration and the zidovudine-derived vindoline hybrid were inactive. Molecular modelling results indicate that the vindoline hybrids might bind to the inter-dimer vinca crevice of tubulin oligomers and that the two segments exert a mutually stabilising effect on the binding of the other. Conclusion: Collectively, these findings provide a framework for future rational optimisation of this promising class of anticancer agents.