Seven target compounds coupled by rhein and furoxan were synthesized and their chemical structures were confirmed by 1H NMR, IR, and MS. All target compounds were evaluated for anti-proliferative activity against human hepatoma cells HepG2 and Bel-7402, human colon cancer cells HCT116, human osteosarcoma cells U2OS, drug-resistant cells Bel-7402/5-FU and normal hepatocytes cells LO2 in vitro by thiazolyl blue(MTT) colorimetry. The results indicated that all target compounds had more potent anti-proliferative activity than their parent compound rhein. Additionally, compound 4g had stronger proliferation inhibitory activity on HepG2, Bel-7402, U2OS and Bel-7402/5-FU,with little effect on the proliferation of normal cells, exhibiting selective inhibitory activity. Griess assay was used to measure the release of nitric oxide in vitro. Results showed that compound 4g could increase the releases NO in HepG2 cells, which may be associated with its antitumor effects. Furthermore, the antitumor activity of compound 4g was attenuated by NO scavenger (hemoglobin), which indicates that the antitumor activity of compound 4g may be partly related to the release of NO.

Abstract: In order to search for coumarin-based anti-platelet aggregation compounds with high efficacy and good druggability, twenty-five 3-acetyl-7-hydroxy-coumarin oxime derivatives (6a-6y) were synthesized via Vilsmeier-Haack reaction, Knoevenagel reaction, Williamson reaction, electrophilic substitution reaction and oximation reaction from resorcinol. Their structures were confirmed by HRMS and 1H NMR spectra. The anti-platelet aggregation activity of the target compounds was evaluated using Born’s turbidimetric method. The results revealed that most of them could significantly inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen, arachidonic acid (AA) and thrombin. Among them, the target compounds 6a and 6b not only had strong inhibitory activity on platelet aggregation induced by the four inducers, but also exhibited good water solubility (3.46 mg/mL and 3.85 mg/mL, respectively) and lipid-water partition coefficient (2.56 and 2.85, respectively) and were expected to become a preclinical candidate compound with multi-target action against platelet aggregation.