CDR-007

β-Carboline is a crucial compound in medicinal chemistry known for its versatile pharmacological activities. Recent research has focused on hybrid molecules incorporating a β-carboline scaffold linked to other pharmacophore moieties. These hybrid compounds have demonstrated diverse therapeutic properties, including anticancer, antianxiety, antimalarial, antidepressant, anti-inflammatory, antileishmanial, and antioxidant effects. This review highlights studies conducted from 2014 to the present with a particular emphasis on the development of β-carboline hybrid compounds and their derivatives as potent anticancer agents. The structure-activity relationship (SAR) analysis reveals that these hybrids exhibit significant cytotoxicity against various cancer cell lines. This review aims to inspire further research into the novel synthesis and evolution of β-carboline hybrids and their derivatives, potentially leading to new therapeutic advancements.

The scarcity of ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp) inhibitors suitable for clinical application in improving multidrug resistance (MDR) promotes the development of drugs aimed at reversing MDR. In this work, we reported a comprehensive study for the first time about the reversal activity of β-carboline derivatives on ABCB1-mediated MDR. Among 48 synthesized derivatives, compound K27 significantly increased the sensitivity of ABCB1-mediated MDR SW620/AD300 cells to paclitaxel (PTX) (IC₅₀ = 15.33 ± 5.4 nM, RF = 171.2) and hardly showed toxicity even at a high concentration of 20 μM when used alone. The in vitro studies indicated that compound K27 distinctly enhanced the arresting effect of PTX on the SW620/AD300 cell cycle, thereby inhibiting their proliferation. Mechanistically, compound K27 was confirmed to directly bind to ABCB1 to inhibit efflux function, reducing cellular efflux and ensuring stable intracellular concentration of PTX without affecting ABCB1's normal expression. Importantly, the combination of compound K27 and PTX exhibited potent tumor suppression in vivo without generating toxicity. These results demonstrated that β-carboline compounds represented by compound K27 may be potent ABCB1 inhibitors with considerable potential in effectively reversing ABCB1-mediated MDR, showing promising prospects.