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Since the first reports on the photoreactions of 1-phenyl-2-(pentamethyldisilanyl)ethyne 1 and phenylpentamethyldisilane 2 by Ishikawa et al., the intermolecular photolysis of these compounds and their derivatives has been extensively investigated. It is well known that the photolysis of 1-phenyl-2-(pentamethyldisilanyl)ethyne afforded silacyclopropene 3-10 and 1-sila-1,2-propadiene 11-13 intermediate and the photoreaction of phenylpentamethyldisilane gave silatriene 14-20 intermediate. However, relatively little is known about the intramolecular photoreactions of ortho-substituted 1-phenyl-2-(pentamethyldisilanyl)ethynes and ortho-substituted phenylpentamethyldisilanes.Recently, we have found that the photolysis of orthosubstituted 1-phenyl-2-(pentamethyldisilanyl)ethynes 21 and ortho-substituted phenylpenta methyldisilanes 22,23 afforded the novel intramolecular photoproducts via silacyclopropene, 1-sila-1,2-propadiene, and silatriene intermediates.Very recently, we have found that the photoreaction of (2-hydroxymethylphenyl)pentamethyldisilane 24 and (2-hydroxyethoxyphenyl)pentamethyldisilane 25 afforded the novel intramolecular photoproducts via silatriene intermediates.In connection with our ongoing studies for the utility of silacyclopropenes, 1-sila-1,2-propadiene, and silatriene as reaction intermediates in organic synthesis of silicon-containing heterocyclic compounds, we were now interested in the synthesis of silicon-containing large ring compounds via the photolysis of ortho-substituted phenylpentamethyldisilanes. And, we have investigated the photoreactions of (2-hydroxypropoxyphenyl)pentamethyldisilane 2, since novel photoproducts from the intramolecular reaction of orthosubstituted group with the silatriene intermediate are expected and we would like to report the detailed photochemical study of 2.The starting material 2 was prepared by the reaction of (2-hydroxyphenyl)pentamethyldisilane 25 (1) with 3-chloro-1-propanol in the presence of sodium hydroxide and tetra-nbutyl ammonium iodide using microwave reactor, Micro-SYNTH in water as a solvent as shown in Scheme 1.To investigate whether or not the hydroxypropoxy group as ortho-substituent in 2 reacts intramolecularly with silatriene moiety in the reaction intermediate 3 formed in the photoexcited state of 2, the photoreaction of 2 in benzene was studied.Photolysis of 2 in deaerated benzene with 254 nm UV light gave a novel photoproduct 6 (32% yield) along with some decomposition products of unknown structure as shown in Scheme 2, when 95% of 2 was photolyzed but the expected intramolecular photoproduct was not obtained. The formation of a novel photoproduct 6 can best be explained in terms of the initial formation of silatriene intermediate 3 arising from1,3-migration of trimethylsilyl radical, which is formed via the homolytic cleavage of silicon-silicon bond of pentamethyldisilanyl group in the photoexcited state of 2 to the C6 position of benzene ring as shown in Scheme 2. The intramolecular reaction to form a oxirane ring in this silatriene ...

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.

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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.