Development of Natural-Product-Inspired ABCB1 Inhibitors Through Regioselective Tryptophan C3-Benzylation

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Cancer Biology

Background:

• Cancer drug resistance, often mediated by ATP-dependent binding cassette (ABC) transporters like ABCB1 (P-glycoprotein), leads to treatment failure and relapse.
• Existing P-glycoprotein inhibitors face challenges in balancing efficacy with toxicity to normal human cells.
• Natural products offer a rich source of scaffolds for developing novel therapeutic agents.

Purpose of the Study:

• To design and synthesize novel indole-C3-benzyl cyclo-L-Trp-L-Trp diketopiperazines (DKPs) as potent inhibitors of the ABCB1 efflux pump.
• To evaluate the efficacy of these DKPs in restoring sensitivity to chemotherapy in drug-resistant cancer cells.
• To establish structure-activity relationships and identify key interactions for improved ABCB1 inhibitor design.

Main Methods:

• Regioselective synthesis of unique indole-C3-benzyl diketopiperazine derivatives.
• In vitro evaluation of ABCB1 inhibition using bat cells as a model for human P-gp.
• Assessment of chemotherapy sensitivity restoration in drug-resistant human cancer cells.
• Molecular docking studies to predict inhibitor-ABCB1 interactions.
• Fluorescence-based assays to determine inhibitor efficacy.

Main Results:

• Identified exo-C3-N-Dbn-Trp2 (13) as a lead ABCB1 inhibitor, outperforming Verapamil in inhibiting ABCB1.
• Demonstrated that C3-N-Dbn-Trp2 restored chemotherapy sensitivity in resistant cancer cells with no observed toxicity to cell proliferation.
• C3-benzylated derivatives showed superior performance compared to isoprenylated analogues, with p-cyano- and p-nitro-substituted analogues being most efficacious.
• Molecular docking studies correlated inhibitor interactions within the ABCB1 access tunnel with observed efficacy.

Conclusions:

• Novel diketopiperazine derivatives effectively inhibit ABCB1-mediated drug resistance in cancer.
• The C3-benzylated scaffold provides a promising basis for developing new generations of ABCB1 inhibitors with improved efficacy and reduced toxicity.
• Understanding inhibitor interactions at the ABCB1 access tunnel is crucial for rational drug design.