The mixture of GX (guttiferone E and xanthochymol), an inseparable polycyclic polyprenylated acylphloroglucinol (PPAP), showed moderate cytotoxic activities. The chemical transformation of GX yielded three different types of PPAPs (1, 2, and 3/4). A series of analogs were prepared, and the structures of the 40 newly synthesized compounds were elucidated by 1D and 2D NMR and HR-ESI-MS. The derivatives were screened in vitro for antiproliferative activity against five human cancer cell lines: human leukemic cell lines (HEL and K562), cervical cancer cell line (Hela), human breast adenocarcinoma cell line (MCF-7), and human non-small cell lung cancer cell line (A549), using the MTT assay, and most of the derivatives showed good cytotoxic activities. Noticeably, compound 2, a novel tautomer with a hemiketal, exhibited selective cytotoxic activities against HEL (IC<sub>50</sub> = 4.79 ± 0.23 μM) and K562 (IC<sub>50</sub> = 7.69 ± 0.34 μM) leukemia cells. The mechanism studies indicated that compound 2 induced apoptosis and arrested the cell cycle at the G0/G1 phase in the HEL cell line. Furthermore, compound 2 activated the intrinsic pathway by reducing the expression of anti-apoptotic protein Bcl-2 and cell cycle-specific cyclin D1 and by enhancing the pro-apoptotic protein Bax. Moreover, the caspase-3 and PPRP1 levels were also upregulated. Our present results suggest that compound 2 is a potential candidate for developing novel anti-leukemia agents in the future.