Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P‑Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance

Natural
macrocycles have shown impressive activity to
overcome
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). However,
the total synthesis and structural modification of natural macrocycles
are challenging, which would hamper the deeper investigations of their
structure–activity relationship (SAR) and drug likeness. Herein,
we describe a modular biomimetic strategy to expeditiously achieve
a new class of macrocycles featuring polysubstituted 1,3-diene, which
efficiently inhibited P-gp and reversed MDR in cancer cells. The SAR
analysis revealed that the size and linker of the macrocycles are
important structural characteristics to restore activity. Particularly, 32 containing a naphthyl group and (d)-Phe moiety
has higher potency with an excellent reversal fold than verapamil
at a concentration of 5 μM, which induces conformational change
of P-gp and inhibits its function instead of altering P-gp expression.
Furthermore, 23 and 32 were identified to
be attractive leads, which possess a good pharmacokinetic profile
and antitumor activity in a KBV200 xenograft mouse model.