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

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 L¹-L¹⁰ (IC₅₀ = 5.92- >100 μM) was lower than L⁰ (1.27 μM) and DOX (4.40 μM) in every case. Compound L¹ had higher anti-HepG2 (0.66 μM), anti-MCF-7 (5.33 μM), and anti-A549 (2.11 μM) and compound L³ 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 IC₅₀ values of 0.66 and 5.98 μM, L¹ 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 L¹ had no significant toxicity but high anti-HepG2 activity in vivo. Thus, it may be a potential antiproliferation drug with nontoxic side effects.