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 <b>1d</b>, <b>1g</b>, and <b>1m</b> showed significantly enhanced antiproliferative activities on a broad scope of cancer cell lines. Further studies indicated that both <b>1d</b> and <b>1m</b> 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 <i>in vitro</i>. The biodistribution of compounds <b>1d</b> and <b>1m</b> 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.