In a search for novel therapeutic options for head and neck squamous cell carcinomas
(HNSCCs) generally treated with limited therapeutic success, we synthesized a series
of novel erlotinib–chalcone molecular hybrids with 1,2,3-triazole and alkyne linkers
and evaluated them for their anticancer activity on Fadu, Detroit 562 and SCC-25 HNSCC
cell lines. Time- and dose-dependent cell viability measurements disclosed a significantly
increased efficiency of the hybrids compared to the 1:1 combination of erlotinib and
a reference chalcone. The clonogenic assay demonstrated that hybrids eradicate HNSCC
cells in low micromolar concentrations. Experiments focusing on potential molecular
targets indicate that the hybrids trigger the anticancer effect by a complementary
mechanism of action that is independent of the canonical targets of their molecular
fragments. Confocal microscopic imaging and real-time apoptosis/necrosis detection
assay pointed to slightly different cell death mechanisms induced by the most prominent
triazole- and alkyne-tethered hybrids (6a and 13, respectively). While 6a featured
the lowest IC50 values on each of the three HNSCC cell lines, in Detroit 562 cells,
this hybrid induced necrosis more markedly compared to 13. The therapeutic potential
indicated by the observed anticancer efficacy of our selected hybrid molecules validates
the concept of development and justifies further investigation to reveal the underlying
mechanism of action.
