A subgroup of patients with chronic schizophrenia may substantially benefit from sulpiride addition to clozapine.

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SummaryThe discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC 50 value of 9.3 µM. In contrast, the IC 50 against normal peripheral blood mononuclear cells was 276.0 µM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC 50 =8.7 μM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppresses signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors. KeywordsGypsogenin, Abelson tyrosine-protein kinase 1, chronic myelogenous leukemia Biological and Pharmaceutical Bulletin Advance PublicationCancer is a worldwide health problem, and despite intensive research efforts over the last several decades, an effective cure has not been identified. 1)However, the recent discovery of molecular targeted drugs against cancer at the end of the 20 th century has led to promising results. 1,2) Imatinib (Fig. 1), which targets the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL), [3][4][5][6] was discovered based on the findings that chronic myelogenous leukemia (CML) is caused by a chromosomal translocation that results in the constitutively expressed and active BCR-ABL. 7,8) While imatinib can be initially effective in treating CML, some patients have shown drug resistance to imatinib. [9][10][11] Several new generation drugs with a different binding mode to Abelson kinase (ABL) have thus been developed. 6,[12][13][14][15][16] These drugs are artificial heterocyclic compounds, however, if widely distributed natural products and/or their derivatives show the inhibitory activity against BCR-ABL, it would be more convenient to get.Pentacyclic triterpenoids, a category of natural compounds, can be extracted from a variety of plants and show various activities. 17,18) Some of these triterpenoids were reported to exhibit anti-tyrosine kinase activity. 19,20) Here we focused on a pentacyclic triterpenoid gypsogenin, 21,22) extracted from Gypsophila species, 23,24) which is widely distributed in the Eu...

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SynopsisSerum concentrations of the third and fourth components of the complement system and total complement haemolytic activity were measured in 167 psychiatric patients. Total complement haemolytic activity was decreased in chronic schizophrenic patients as compared to healthy controls and bipolar patients. The relatively diminished total haemolytic activity was not attributable to drug treatment. It is not clear if the reduced total haemolytic activity is an epiphenomenon or related to the involvement of an autoimmune process in the pathophysiology of schizophrenia.

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In an attempt to develop potent antitumor agents, new 1,3,4-thiadiazole derivatives were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the K562 chronic myelogenous leukemia cell line that expresses the Bcr-Abl tyrosine kinase. N-(5-Nitrothiazol-2-yl)-2-((5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (2) inhibited the Abl protein kinase with an IC50 value of 7.4 µM and showed selective activity against the Bcr-Abl positive K562 cell line. Furthermore, a Bcr-Abl-compound 2 molecular modelling simulation highlighted the anchoring role of the nitrothiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. These results provide promising starting points for further development of novel kinase inhibitors.

Two series of amino‐1,4‐benzoquinones (AQ1–18) based on the structural analogs of plastoquinones were synthesized and the structure–activity relationship against chronic myelogenous leukemia activity was examined. All of the synthesized compounds were tested for their cytotoxic effects on different leukemic cell lines. Of interest, AQ15 exhibited a better selectivity than the reference drug imatinib on cancer cells. Owing to this, AQ15 was selected for a further apoptosis/necrosis evaluation where AQ15‐treated K562 cells demonstrated similar apoptotic effects like imatinib‐treated cells at their IC50 values. The inhibitory effects of AQ15 and the other three compounds with various activities against eight tyrosine kinases, including ABL1, were investigated. AQ15 showed weak activity against ABL1, and a correlation was observed between the anti‐K562 and anti‐ABL1 activities. The binding mode of AQ15 into the ATP binding pocket of ABL1 kinase was predicted in silico, showing the formation of some key interactions. In addition, AQ15 was shown to suppress the downstream signaling of BCR‐ABL in K562 cells. Finally, AQ15 obviously cleaved DNA in the presence of an iron(II) complex system, indicating that this can be the major mechanism of its antiproliferative action, whereas the mild inhibition of ABL kinase is just in‐part mechanism of its overall outstanding cellular activity.