Discovery of 1,2,3-triazole derivatives of phenanthroindolizidine to reverse temozolomide resistance in glioblastoma

Glioblastoma (GBM) is an aggressive brain tumor with extremely limited clinical treatment options. Highly efficacious and tolerable agents for the treatment of GBM are urgently needed. Herein, twenty-seven novel phenanthroindolizidine compounds were designed and synthesized using a "three birds, one stone" strategy, structurally featuring various novel 1,2,3-triazole moieties at the 3-position of phenanthroindolizidine. They were evaluated for antiproliferative activities in both standard and temozolomide (TMZ)-resistant GBM cell lines, and their structure-activity relationships (SAR) were determined. Among these, compound 10c2 exhibited high antiproliferative activity in both normal and TMZ-resistant GBM cell lines with decreased gastrointestinal cytotoxicity in vitro. Furthermore, 10c2 showed improved inhibition of cell migration and invasion, and induced cell Apoptosis in TMZ-resistant GBM cells. Mechanically, 10c2 could downregulate the expression of O6-methylguanine-DNA methyltransferase (MGMT) to impair the TMZ resistance by inhibiting the Hedgehog pathway. In the xenograft model, 10c2 exhibited a substantial inhibitory effect on GBM tumor growth and benefits for the combination therapy of TMZ without showing obvious toxicity. 10c2 also demonstrated significant potential for absorption and the blood-brain barrier (BBB) penetration following oral administration. Overall, these findings indicated that 10c2 might be a promising compound for the treatment of GBM, showing the potential to overcome resistance to TMZ.