Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Cancer Biology

Background:

• Cancer's multifactorial nature necessitates innovative therapeutic strategies beyond traditional cytotoxic agents.
• Multitarget drugs are emerging as a promising alternative to polypharmacy for complex diseases.
• Developing novel antiproliferative agents with improved efficacy and selectivity is a critical unmet need.

Purpose of the Study:

• To synthesize and characterize novel organochalcogen derivatives of phenolic compounds.
• To evaluate the antioxidant and antiproliferative properties of these novel compounds against various cancer cell lines.
• To assess the potential of these compounds to overcome P-glycoprotein-mediated chemoresistance.

Main Methods:

• Synthesis of phenolic derivatives conjugated with organochalcogen motifs (selenium and sulfur).
• In vitro evaluation of antioxidant and antiproliferative activity against six tumor and one non-tumor cell line.
• P-glycoprotein assay to determine substrate potential and predict chemoresistance evasion.

Main Results:

• Selenium-containing compounds exhibited significantly stronger antiproliferative effects than their sulfur counterparts.
• The length and nature of the tether, along with the organoselenium scaffold, influenced bioactivity.
• A lead compound with a methylenedioxyphenyl moiety and diselenide functionality showed potent activity (GI50 = 0.88–2.0 µM) and selectivity (SI = 14–32).
• The tested compounds were not substrates for the P-gp efflux pump, suggesting they can avoid P-gp-mediated chemoresistance.

Conclusions:

• Novel organochalcogen compounds, particularly selenium derivatives, possess significant antiproliferative and anticancer potential.
• Structural modifications, including the tether and organoselenium scaffold, are key determinants of efficacy and selectivity.
• These compounds represent promising candidates for developing new chemotherapeutic agents that circumvent P-gp-mediated drug resistance.