•Fifteen novel emodin derivatives were designed and synthesized.•Compound 4a showed significant antiproliferative activity in vitro.•Compound 4a induced apoptosis through caspase-3 and P53 activation.•Compound 4a directly effected on mitochondrial by generating ROS and decreasing ΔΨm.Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been demonstrated to exhibit good anti-cancer effect. In this study, a series of novel quaternary ammonium salts of emodin, anthraquinone and anthrone were synthesized and their anticancer activities were tested in vitro. The effects of emodin quaternary ammonium salts on cell viability, apoptosis, intracellular ROS, and mitochondrial membrane potential were investigated in A375, BGC-823, HepG2 and HELF cells. The results demonstrated that compound 4a induced morphological changes and decreased cell viability. Apoptosis triggered by compound 4a was visualized using DAPI staining and Annexin V-FITC/PI staining. Compound 4a-induced apoptosis of A375 cells were showed to be associated with the dissipation of mitochondrial membrane potential (ΔΨm) as a result of the up-regulation of P53 and Caspase-3. When cancer cells were treated with emodin derivative, their ability to generate reactive oxygen species (ROS) rose significantly and the mitochondrial membrane potential decreased. Additionally, confocal microscopy assay confirmed that compound 4a was primarily located in the mitochondria of A375 cells. These results suggested that compound 4a has the potential for use in cancer therapy.Fifteen new emodin derivatives were synthesized and investigated for their anticancer activities. Compound 4a was shown to induce apoptosis in cancer cells in vitro.

•A tautomerization of mono-esterified product of 1,8-dihydroxyanthraquinone exits.•Tautomerizations of bis-esterified products of dihydroxyanthraquinone hardly exit.•Nucleophilicity plays a key role in tautomerization of ester of hydroxyanthraquinone.Three dichloroacetate derivatives of hydroxyanthraquinone were synthesized. NMR studies showed that only monoesterified derivative compound 1 had a tautomerization. Since monoetherified derivative of hydroxyanthraquinone did not show tautomerization, a hypothesis that nucleophilicity played an important role in the tautomerization was proposed. The molecular structures of monoesterified derivative compound 1 and diesterified derivative compound 2 were calculated by using DFT method, and the result showed that the electronic density of carbonyl at 9-position of compound 1 was much larger than that of compound 2, which indicated that the hypothesis mentioned above was reasonable.

A series of new emodin derivatives modified at the C-3 and the C-6 positions were synthesized, and evaluated for their anticancer activities in vitro and in vivo. Among them, Compounds 5g and 5h had more significant antiproliferative ability against HepG2, BGC-823, AGS cancer cell lines and low cytotoxicity to HELF normal cell line, respectively. Compounds 5g and 5h induced AGS cell cycle arrest at G0/G1 phase and induce apoptosis via activation of caspase-3 and caspase-9 enzyme. In vivo studies using H22 xenografts in Kunming mice were conducted with 5g and 5h. The results revealed that the medium dosage group (10 mg/kg) of 5g and the high dosage group (25 mg/kg) of 5h showed significant antitumor activity compared to the control group.Graphical abstractTwenty new emodin derivatives were synthesized and investigated their anticancer activities. Compounds 5g and 5h showed significant antiproliferative and apoptosis abilities in vitro and exerted preferable proliferation inhibition effect in vivo.Highlights► Twenty novel emodin derivatives were synthesized. ► Compounds 5g and 5h showed significant anticancer activity in vitro and in vivo. ► Compounds 5g and 5h induced apoptosis through caspase-9 and caspase-3 activation. ► Compounds 5g and 5h arrested cell cycle progression at the G0/G1 phase in AGS cells.