Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents

摘要

Several dehydroabietylamine derivatives containing heterocyclic moieties such as thiophene and pyrazine ring were successfully synthesized. The antiproliferative activities of these thiophene-based Schiff-bases, thiophene amides, and pyrazine amides were investigated in?vitro against Hela (cervix), MCF-7 (breast), A549 (lung), HepG2 (liver), and HUVEC (umbilical vein) cells by MTT assay. The toxicity of Lsup1/sup-Lsup10/sup (ICsub50/sub = 5.92-?100?μM) was lower than Lsup0/sup (1.27?μM) and DOX (4.40?μM) in every case. Compound Lsup1/sup had higher anti-HepG2 (0.66?μM), anti-MCF-7 (5.33?μM), and anti-A549 (2.11?μM) and compound Lsup3/sup had higher anti-HepG2 (1.63?μM) and anti-MCF-7 (2.65?μM) activities. Both of these compounds were recognized with high efficiency in apoptosis induction in HepG2 cells and intercalated binding modes with DNA. Moreover, with average ICsub50/sub values of 0.66 and 5.98?μM, Lsup1/sup was nine times more effective at suppressing cultured HepG2 cells viability than normal cells (SI = 9). The relative tumor proliferation rate (T/C) was 38.6%, the tumor inhibition rate was up to 61.2%, which indicated that Lsup1/sup had no significant toxicity but high anti-HepG2 activity in?vivo. Thus, it may be a potential antiproliferation drug with nontoxic side effects.