Differences in Antiproliferative Activity Between Salinomycin-AZT Conjugates Obtained via 'Click' and Esterification...

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Cancer Research

Background:

• Pharmacophore hybridization via bioconjugation is a key strategy in drug discovery.
• Synthesized novel hybrids of 3'-azido-3'-deoxythymidine (AZT) and salinomycin (SAL) to enhance anti-cancer efficacy.
• Investigated derivatives that can penetrate cancer cell membranes and undergo intracellular hydrolysis.

Purpose of the Study:

• To synthesize and evaluate novel AZT-SAL conjugates for anti-cancer properties.
• To assess the in vitro anti-proliferative activity and toxicity of the synthesized hybrids.
• To determine if these hybrids can overcome drug resistance in cancer cell lines.

Main Methods:

• Synthesized two AZT-SAL conjugates using 'click' chemistry (copper(I) catalyzed Huisgen cycloaddition) and ester bond formation.
• Evaluated in vitro anti-proliferative activity against drug-sensitive and drug-resistant cancer cell lines.
• Assessed toxicity against normal murine embryonic fibroblasts to determine selectivity indexes.

Main Results:

• The ester-linked hybrid (SAL-OAZT) showed significant anti-cancer activity against drug-resistant cell lines at low micromolar concentrations.
• SAL-OAZT exhibited high selectivity indexes, indicating low toxicity to normal cells.
• The 'click' chemistry conjugate (SAL-AZT) was largely inactive against drug-resistant cells and weakly active against drug-sensitive cells, with no observed synergistic effects.

Conclusions:

• The SAL-OAZT hybrid is a promising candidate for cancer therapy, particularly for overcoming drug resistance.
• SAL-OAZT offers improved selectivity and efficacy compared to SAL alone.
• Findings support combining SAL-O-AZT with reduced doxorubicin concentrations to mitigate toxicity.