Novel Dimer Derivatives of PF-543 as Potential Antitumor Agents for the Treatment of Non-Small Cell Lung Cancer.

Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer, and the incidence and mortality rate are continuously increasing. In many cases, lung cancer cannot be completely treated with surgery, so chemotherapy is used in parallel; however, the treatment often fails due to drug resistance. Therefore, it is necessary to develop a new therapeutic agent with a new target. The expression of sphingosine kinase promotes cancer cell growth and survival and induces resistance to chemotherapeutic agents. Sphingosine-1-phosphate (S1P), produced by sphingosine kinase (SK), has been shown to regulate cancer cell death and proliferation. PF-543, currently known as an SK inhibitor, has been reported to demonstrate low anticancer activity in several cancers. Therefore, in this study, a derivative of PF-543 capable of increasing anticancer activity was synthesized and its efficacy was evaluated by using an NSCLC cell line and xenograft animal model. Based on the cytotoxic activity of the synthesized compound on lung cancer cells, the piperidine forms (Compounds 2 and 4) were observed to exhibit superior anticancer activity than the pyrrolidine forms of the head group (Compounds 1 and 3). Compounds 2 and 4 showed inhibitory effects on SK1 and SK2 activity, and S1P produced by SK was reduced by both compounds. Compounds 2 and 4 demonstrated an increase in the cytotoxicity in the NSCLC cells through increased apoptosis. As a result of using an SK1 and SK2 siRNA model to determine whether the cytotoxic effects of Compounds 2 and 4 were due to SK1 and SK2 inhibition, it was found that the cytotoxic effect of the derivative was SK1 and SK2 dependent. The metabolic stability of Compounds 2 and 4 was superior compared to PF-543, and the xenograft experiment was performed using Compound 4, which had more excellent MS. Compound 4 demonstrated the inhibition of tumor formation. The results of this experiment suggest that the bulky tail structure of PF-543 derivatives is effective for mediating anticancer activity, and the results are expected to be applied to the treatment of NSCLC.

Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells.

Sphingosine kinase (SK) is involved in the growth of cells, including cancer cells. However, which of its two isotypes-SK1 and SK2-is more favorable for cancer growth remains unclear. Although PF-543 strongly and selectively inhibits SK1, its anticancer effect is not high, and the underlying reason remains difficult to explain. We previously determined that the tail group of PF-543 is responsible for its low metabolic stability (MS). In this study, compounds containing aromatic or aliphatic tails in the triazole group were synthesized, and changes in the SK-inhibitory effect and anticancer activity of PF-543 were assessed using pancreatic cancer cells. The compounds with aliphatic tails showed high inhibitory effects on pancreatic cancer cells but slightly lower selectivity for SK1. A compound with an introduced aliphatic tail activated protein phosphatase 2A (PP2A), showing an effect similar to that of FTY720. Molecular docking analysis revealed that the PP2A-binding form of this newly synthesized compound was different from that noted in the case of FTY720. This compound also improved the MS of PF-543. These results indicate that the tail structure of PF-543 influences MS.

Water quality impacts of irrigation return flow on stream and groundwater in an intensive agricultural watershed.

Irrigation return flow can include contaminants derived from agricultural practices, and then deteriorate the quality of surface and subsurface water within the watershed. Thus, it is important to estimate the effect of irrigation return flow on water chemistry/quality. To do that water samples were collected between November 2004 and December 2005 from stream and groundwater in a small watershed that contains extensive rice paddy fields. The water isotopic compositions represented seasonal variation, particularly in downstream of main channel and the tributary. In April and May, water samples in the downstream and tributary could not be explained by three-component (soil water, groundwater and rainfall) hydrograph separation models (THSM). These results indicated that the stream water was affected by high evaporation and that another water body (e.g. quick return flow) impacted on THSM. Plot of Cl/NO3 and NO3/HCO3 showed that the water chemistry of all water samples was mainly regulated by soil water and groundwater. In addition, the water chemistry was related to water derived from rice paddy fields (WR) and manure. Manure impacted the water chemistry in tributary, one of the shallow groundwaters and the deep groundwaters, whereas that water in downstream was affected by WR. On a plot of δ15NNO3 and δ18ONO3 values, many samples were in a cluster indicative of manure and on a denitrification line. These imply that irrigation return flow characterized by denitrification processes was involved in determining the water chemistry. We suggest that chemical and multi-isotopes approach combined with the THSM is useful to elucidate the sources and processes controlling water chemistry in stream associated with rice paddy fields.