Design, synthesis and biological evaluation of nitrogen-containing macrocyclic bisbibenzyl derivatives as potent anticancer agents by targeting the lysosome.

A series of novel nitrogen-containing macrocyclic bisbibenzyl derivatives was designed, synthesized, and evaluated for antiproliferative activity against three anthropic cancer cell lines. Among these novel molecules, the tri-O-alkylated compound 18a displayed the most potent anticancer activity against the A549, MCF-7, and k562 cancer cell lines, with IC50 values of 0.51, 0.23, and 0.19 μM, respectively, which were obviously superior to those of the parent compound riccardin D, and were 3-10-fold better than those of the clinical used drug ADR. The bis-Mannich derivative 11b also exhibited significantly enhanced antiproliferative potency, with submicromolar IC50 values. Structure-activity relationship analyses of these newly synthesized compounds were also performed. Mechanistic studies indicated that these compounds could target the lysosome to induce lysosomal membrane permeabilization, and could also induce cell death that displayed features characteristic of both apoptosis and necrosis.