Analogs incorporating trans-4-hydroxy-L-proline that reverse multidrug resistance better than hapalosin

摘要

Chemotherapy often fails over time due to multidrug resistance (MDR), one of whose principal mechanisms is expulsion of a wide spectrum of drugs from tumor cells by P-glycoprotein (P-gp). The cyclic depsipeptide hapal- osin, 1, reverses MDR presumably by inhibiting P-gp. Computation with the aid of H, H-NOESY data revealed That the major s-cis rotamer of hapalosin and the single s-trans rotamer of the non-N-Me analog 2 have very different conformations, whereas the minor s-trans rota- mer of hapalosin and analog 2 have very similar confor- mations.