Thirty Cryptolepine and Aromathecin based mimics were designed and synthesized. Their cytotoxicity was evaluated in four human cancer cell lines (HepG-2, T24, NCI-H460 and MGC-803) and one normal human cell line (HL-7702). Most compounds exhibited potent anticancer activity with IC<sub>50</sub> values from 0.31 to 11.97 μM. 8-Fluoro-10-(N-3-dimethylaminopropyl)amino-11H-indeno[1,2-b]quinoline (5b) was identified as the most promising candidate in view of its anticancer activity. Molecular mechanism studies suggested that 5b not only could strongly bind to G-quadruplex, but intercalate into supercoil DNA and resulted in significant DNA double-strand break as well. Furthermore, 5b caused cell cycle arrest at S/G2 phase and induced apoptosis. After treatment with 5b, pro-apoptotic proteins Bak, Bax and Bim were up-regulated, anti-apoptotic proteins Bcl-2 and Bcl-xL were down-regulated, and the effector caspase-3/9 was activated to initiate apoptosis. The anticancer activity of 5b was finally validated in a MGC-803 xenograft tumor model with tumor growth inhibition (TGI) up to 53.2%, while displaying no obvious toxicity. Taken together, these results suggest that 5b may be a potential candidate of cytotoxic antineoplastic drugs for cancer therapy.