Anthraquinone derivatives induce G2/M cell cycle arrest and apoptosis in NTUB1 cells.

Thirteen anthraquinone derivatives 5-17 including two 3-(3-alkylaminopropoxy)-9,10-anthraquinone (NHA) derivatives 5 and 6, and 11 1-hydroxy-3-(3-alkylaminopropoxy)-9,10-anthraquinone (MHA) derivatives 7-17 were synthesized, evaluated for cytotoxicities against two cancer cell lines, and assayed the generation of reactive oxygen species (ROS) in NTUB1 cells (a human bladder carcinoma cell line). Compound 9 bearing a pyrrolidinyl group induced the stronger cytotoxic effect than those of other synthesized NHA and MHA derivatives. Exposure of NTUB1 cells to 9, 13, and 17 for 24h significantly increased the production of ROS, respectively. Flow cytometric analysis exhibited that the exposure of NTUB1 cells to the selective 9 led to the G2/M phase arrest accompanied by an increase of apoptotic cell death after the incubation for 24h. Compound 9 induced up-regulation of cyclinB1 and p21 expressions. Biological results suggested that the induction of G2/M arrest, apoptosis, and cell death by 9 may associate with increased expression of p21 and cyclin B1, elevation of Bax and p53 levels, and generation of ROS in the cell. In conclusion, these series of compounds may be used as anticancer agents.

Synthetic 2',5'-dimethoxychalcones as G(2)/M arrest-mediated apoptosis-inducing agents and inhibitors of nitric oxide production in rat macrophages.

In an effort to develop novel antitumor or chemopreventive agents, a series of 2',5'-dimethoxychalcone derivatives were prepared by Claisen-Schmidt condensation of appropriate acetophenones with suitable aromatic aldehyde. In vitro screening revealed low micromolar activity (IC(50)) against several human cancer lines. Activity in MCF-7 cells correlated with the ability to induce G(2)/M arrest-mediated apoptosis following drug treatment by the most potent agent, 8, an observation further reinforced by fluorescence microscopy. Compounds 3, 8, and 10 showed potent inhibitory effect on NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophage-like cells. The present results demonstrated that 3, 8, and 10 are potential anti-inflammatory and cancer chemopreventive agents.

Identification, SAR studies, and X-ray co-crystallographic analysis of a novel furanopyrimidine aurora kinase A inhibitor.

Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in-house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in-house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC(50) values ranging from approximately 300 nM to approximately 15 microM, by testing only 133 compounds from a database of approximately 125,000 compounds. Structure-activity relationship studies and X-ray co-crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC(50) value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.

Antiplatelet effect and selective binding to cyclooxygenase by molecular docking analysis of 3-alkylaminopropoxy-9,10-anthraquinone derivatives.

In an effort to develop potent cytotoxic inhibitors of cyclooxygenase (COX), a series of cytotoxic 3-alkylaminopropoxy-9,10-anthraquinone derivatives was screened to evaluate their antiplatelet effect on washed rabbit platelets and human platelet-rich plasma (PRP). Thrombin, arachidonic acid (AA), collagen, and platelet-activating factor (PAF) induced platelet aggregations were potently inhibited by compounds 1, 2, and 3 (each at 300 microM). Of the compounds tested in human PRP, compounds 1, 8, and 10 showed significant inhibition of primary and secondary aggregation induced by epinephrine and had a weak inhibitory effect on cyclooxygenase-1 (COX-1). Molecular docking studies revealed that compounds, 1, 8, and 10 were bound in the active sites of COX-1. This indicated that the antiplatelet effect of these three compounds was partially mediated through the suppression of COX-1 activity and reduced thromboxane formation. It is concluded that the cytotoxic compounds 1, 8, and 10 may interfere the conversion of arachidonic acid to prostaglandin (PG)H(2) in the active site of COX-1.

Design, synthesis and cytotoxic effect of hydroxy- and 3-alkylaminopropoxy-9,10-anthraquinone derivatives.

In previous paper, we have reported the synthesis and the cytotoxic effect of 1,3-dihydroxy-9,10-anthraquinone derivatives. For further design of more potent compounds, a new series of 1-hydroxy-3-(3-alkylaminopropoxy)-9,10-anthraquinones and 3-(3-alkylaminopropoxy)-9,10-anthraquinones have been synthesized. The cytotoxicity of synthetic compounds were evaluated against human Hep G2, Hep 3B and HT-29 cells. Almost all compounds indicated significant inhibitory activity against Hep G2, Hep 3B and HT-29 cell lines in vitro. Compound 5 exhibited selective cytotoxicity against Hep G2 in a concentration-dependent manner with ED50 value of 1.23 +/- 0.05 microM. Structure-activity analysis revealed that most of the 1-hydroxy-3-(3-alkylamino-2-hydroxypropoxy)-9,10-anthraquinone showed stronger cytotoxic effects than those of 1-hydroxy-3- or 3-(3-alkylaminopropoxy)-9,10-anthraquinones against Hep 3B cell line in vitro. A sub-G1 cell stage and DNA fragmentation in MCF-7 cells were significantly observed after 72 h incubation with selective compound 16. The results show that 16 causes cell death by apoptosis.