The attraction of leukocytes to tissues is essential in order for inflammation and the host response to infection to occur. The process is controlled by chemokines, a term which refer to chemotactic cytokines. 1,2) In their monomeric forms, chemokines are 8-to 10-kD proteins with 20 to 70% homology in amino acid sequences, and are characteristically basic heparin-binding proteins, which facilitate binding to cells and matrix components. There are at least four chemokine families, but only two have been extensively characterized. These two subfamilies, which contain four cyteines, appear to be the largest groups. They can be distinguished according to the position of first two cysteines, which either are separated by one amino acid (CXC chemokine) or are adjacent to each other (CC chemokines). The CXC chemokines can be further subdivided into those that contain the sequence glutamic acid-leucine-arginine (ERL) near the N-terminal, and those that do not.3) The CXC chemokines that contain the sequence are chemotactic for neutrophils, whereas those that do not contain in the sequence act on lymphocytes.Airway inflammation is a very common cause of illness with a substantial impact on health care. Neutrophils play an essential role in the host defense and in inflammation, but the latter may trigger and sustain the pathogenesis of a range of acute and chronic diseases. Infiltration of neutrophils occurs as a response to chemoattractant molecules by resident tissue cells. The recruitment of neutrophils in airway inflammation may account for the generation of interleukin 8 (IL-8), the prototypic CXC chemokine. IL-8 was identified as an agonist for neutrophils on the basis of two in vitro effects chemotaxis and the release of granule enzymes. As a result, the biological activities of IL-8 on neutrophils and the mechanism of signal transduction have been studied in great detail, and their effects have been compared with those of well-characterized neutrophil attractants such as C5a, fMet-Leu-Phe, platelet activating factor (PAF), and leukotriene (LT) B4. 4,5) The observation that IL-8 is a product of monocytes and macrophages and is also generated by tissue cells, was very important to understanding of the numerous potential implications of this chemokine in inflammatory conditions. IL-8 is associated with rhinitis, 6) bronchitis, 7) pulmonary fibrosis, 8) psoriasis, 9) inflammatory bowel disease, 10) and other disorders. Several other chemokines, such as growth-related oncogene (GRO)-a and ENA-78, are also potent neutrophil chemoattractants; this property depends on the presence of ERL motifs.2)The promoter of the IL-8 gene contains a binding site for the redox-responsive transcription factors, NF-kB, which have been shown to be important for IL-8 expression. 11,12) Activation of nuclear factor-kB (NF-kB) acts as a master switch or control point for the expression of a large number of proinflammatory genes.13) NF-kB, a member of the Rel family of transcription factors, is usually present in the cytoplasm of the cell in a...

To develop new anticancer agents, 3-allylthio-6-aminopyridazine derivatives were synthesized from maleic anhydrides or phthalic anhydrides by formation of a pyridazine nucleus, dichlorination, allylthiolation and amination. The pyridazine nuclei were obtained by condensing a hydrazine monohydrate with maleic anhydride. An allylthio group as a pharmacologically active group was introduced into one side of a pyridazine ring. Arylalkylamines with benzene or pyridine moieties or heterocycloalkylamines with heterocycle moieties such as morpholine, piperidine, or pyrrolidine were also introduced into the para-position of allylthio pyridazine. These new compounds showed antiproliferative activities against SK-Hep-1 human liver cancer cells in MTT assays. These compounds are thus promising candidates for chemotherapy of hepatocellular carcinomas. Two compounds, 20c and 22a, showed higher potencies for inhibiting growth of hepatocellular carcinoma cells than did K6 (ID50=1.08 mM). This suggests the potential anticancer activity of these two compounds.