ArticleChemistry & biodiversity2026
Discovery of Bistratamides as Efficacious Reversers of P-Glycoprotein-Mediated Multidrug Resistance.
Article in Chemistry & biodiversity, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Although strategies combining multidrug resistance (MDR) reversal agents with chemotherapeutic drugs have demonstrated efficacy in clinical practice, their widespread application remains limited by potential toxicity. Natural thiazole-containing macrocycles have displayed promising MDR reversal potential. However, the 18-membered macrocycles bistratamides, despite their structural similarity to the known MDR reversal agent dendroamide A, remain unexplored regarding potential roles as MDR reversal agents and their molecular targets. In this study, we report the synthesis and initial discovery of bistratamides as potential MDR reversal agents. Structure-activity relationship analysis revealed that the oxazoline or oxazole motifs embedded within the macrocyclic framework are essential for MDR reversal activity in bistratamides. The oxazoline-containing bistratamide derivative 15 demonstrated the greatest synergistic anticancer effect among the examined compounds, exhibiting > three-fold greater activity than verapamil (VRP) with no observable toxicity in KBV cells and normal human podocytes. The MDR reversal effect of 15 in combination with paclitaxel was further validated through combination assays and flow cytometry. Subsequent rhodamine 123 (Rh123) accumulation assays and western blotting confirmed that 15 exerts its MDR reversal activity by inhibiting P-gp efflux function rather than affecting its expression. Our findings suggest that 15 represents a promising starting point for the development of novel chemosensitizing agents.
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