Exploration of 2‑((Pyridin-4-ylmethyl)­amino)­nicotinamide Derivatives as Potent Reversal Agents against P‑Glycoprotein-Mediated Multidrug Resistance

Overexpression
of the ATP-binding cassette (ABC) transport proteins, like ABCB1,
commonly referred to as P-glycoprotein (P-gp), initiates active efflux
of a broad spectrum of unrelated chemotherapeutic drugs in structure
and function, leading to chemotherapy failure. A series of 2-((pyridin-4-ylmethyl)­amino)­nicotinamide
derivatives as potent reversal agents against P-glycoprotein-mediated
multidrug resistance (MDR) were designed and synthesized. The majority
of target compounds displayed great reversal potency, especially 9n. In-depth studies demonstrated 9n has high
potency (EC50 = 119.6 ± 6.9 nM), low cytotoxicity,
and long duration (>24 h) in reversing adriamycin (ADM) resistance
in K562/A02 cells. 9n also improved the effects of other
cytotoxic agents related to MDR, increased accumulation of ADM, interrupted
P-gp-mediated Rh123 efflux function, and suppressed P-gp ATPase activity
in K562/A02 MDR cells. The Western blot analysis indicated that the
MDR reversal by 9n was not due to a decrease in protein
expression. Besides, the effect of CYP3A4 was not influenced by 9n, avoiding the toxicity caused by drug interactions. The
study yielded 9n with superior properties compared to
the classical inhibitor verapamil (VRP) and leading compound apatinib.