Natural product-like phenanthroquinolizidines: asymmetric synthesis and anti-glioblastoma activity evaluation.

Phenanthroquinolizidine alkaloids exhibit exceptional potency and broad-spectrum antitumor activities against various human malignancies. Here, utilizing a ring-expansion strategy based on phenanthroindolizidines, we report the substrate-controlled asymmetric synthesis of a pair of novel enantiomeric natural product-like phenanthroquinolizidines, S-CAT6 and R-CAT6. The synthesis employs (L)- or (D)-2-aminoadipic acid dimethyl ester as the chiral pool source, streamlining the sequence through a one-pot iodination/nucleophilic substitution, followed by E-ring cyclization, Friedel-Crafts acylation for D-ring annulation, and terminal deoxygenation. In vitro evaluations revealed that both compounds exhibited potent cytotoxicity against normal and temozolomide-resistant glioblastoma cell lines (IC50 = 3 - 43 nM). The S-isomer consistently outperformed the R-isomer in potency and displayed lower gastrointestinal toxicity, indicating that the S-configuration at the C-14a bridgehead is preferred for optimal target interaction and mitigating gastrointestinal toxicity. Mechanistic evaluation suggested that S-CAT6 could reverse TMZ resistance by modulating the Hedgehog signaling pathway and MGMT expression. In vivo studies in T98G xenograft models validated the superior antitumor efficacy and safety of S-CAT6. Structural scaffold expansion combined with precise stereochemical control thus provides a viable strategy for developing next-generation therapeutics for refractory glioblastoma.