Synthesis and Anticancer Activity Evaluation of Novel Carborane-Containing Isoflavonoid Analogues

Isoflavonoids represent a privileged structure derived from natural products with diverse bioactivities. Carborane has been utilized as a three-dimensional mimetic of phenyl rings in medicinal chemistry. Herein, we replaced the phenyl group of isoflavonoids with carborane and prepared a series of carborane-containing isoflavonoid analogues. Compounds 1d, 1g, and 1m showed significantly enhanced antiproliferative activities on a broad scope of cancer cell lines. Further studies indicated that both 1d and 1m inhibited JAK/STAT5, PI3K/AKT, and p38 MAPK pathways, leading to G1 cell cycle phase arrest. Additionally, both compounds reduced the expression of P-glycoprotein (P-gp), a key mediator in multidrug resistance, and reversed the resistance of chemotherapeutic agents in multidrug-resistant cells in vitro. The biodistribution of compounds 1d and 1m was evaluated through ICP-mass and positron emission tomography imaging studies. Taken together, these results suggested promising pharmaceutical properties for the carborane-containing isoflavonoid analogues.