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 against Hela (cervix), MCF-7 (breast), A549 (lung), HepG2 (liver), and HUVEC (umbilical vein) cells by MTT assay. The toxicity of - (IC = 5.92- >100 μM) was lower than (1.27 μM) and DOX (4.40 μM) in every case. Compound had higher anti-HepG2 0.66 μM), anti-MCF-7 (5.33 μM), and anti-A549 (2.11 μM) and compound 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 IC values of 0.66 and 5.98 μM, 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 had no significant toxicity but high anti-HepG2 activity . Thus, it may be a potential antiproliferation drug with nontoxic side effects.