Design Synthesis and BiologicalEvaluations of Tumor-TargetingDual-Warhead Conjugates for a Taxoid–Camptothecin CombinationChemotherapy

摘要

Novel tumor-targeting dual-warhead conjugates, >2 (DW-1) and >3 (DW-2), which consist of a next-generation taxoid, >1 (SB-T-1214), and camptothecin as two warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of >2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR–, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, >2 exhibited IC50 values of 3.22–9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid–camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-warhead conjugate.