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.

天然大环化合物已展现出优异的活性，可克服P-糖蛋白（P-glycoprotein，P-gp）介导的多药耐药（MDR）。然而，天然大环化合物的全合成与结构修饰极具挑战性，这阻碍了对其构效关系（structure–activity relationship，SAR）与成药性的深入研究。在此，我们报道一种模块化仿生合成策略，可快速构建一类全新的、带有多取代1,3-二烯结构的大环化合物，该类化合物可有效抑制P-gp活性并逆转癌细胞中的多药耐药。构效关系分析表明，大环的环大小与连接臂是影响其活性恢复的关键结构特征。其中，带有萘基与(d)-苯丙氨酸基团的化合物32活性更优，在5 μM浓度下的逆转倍数优于维拉帕米，其作用机制为诱导P-gp发生构象变化并抑制其功能，而非通过改变P-gp的表达水平。此外，化合物23与32被证实为极具潜力的先导化合物，在KBV200异种移植小鼠模型中展现出良好的药代动力学特征与抗肿瘤活性。