Cp*Co(III)触媒特異的な反応性を利用した炭素－水素結合官能基化反応の開発

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 金井 求, 東京大学教授 大和田 智彦, 東京大学教授 井上 将行, 東京大学教授 浦野 泰照, 東京大学講師 宮本 和範University of Tokyo(東京大学

青色発光ダイオードはオプシン3を介し大腸癌細胞のオートファジーを誘導する

Light emitting-diodes (LED) have various effects on living organisms and recent studies have shown the efficacy of visible light irradiation from LED for anticancer therapies. However, the mechanism of LED’s effects on cancer cells remains unclear. The aim of the present study was to investigate the effects of LED on colon cancer cell lines and the role of photoreceptor Opsin 3 (Opn3) on LED irradiation in vitro. Human colon cancer cells (HT-29 or HCT-116) were seeded onto laboratory dishes and irradiated with 465-nm LED at 30 mW/cm2 for 30 minutes. Cell Counting Kit-8 was used to measure cell viability, and apoptosis and caspase 3/8 expression were evaluated by AnnexinV/PI and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Autophagy and expression of LC-3 and beclin-1 were also evaluated by autophagy assays, RT-PCR and Western blotting. We further tested Opn3 knockdown by Opn3 siRNA and the Gi/o G-protein inhibitor NF023 in these assays. Viability of HT-29 and HCT-116 cells was lower in 465-nm LED-irradiated cultures than in control cultures. LC-3 and beclin-1 expressions were significantly higher in LED-irradiated cultures, and autophagosomes were detected in irradiated cells. The reductive effect of cancer cell viability following blue LED irradiation was reversed by Opn3 knockdown or NF023 treatment. Furthermore, increased LC-3 and beclin-1 expression that resulted from blue LED irradiation was suppressed by Opn3 knockdown or NF023 treatment. Blue LED irradiation suppressed the growth of colon cancer cells and Opn3 may play an important role as a photoreceptor

Stereoselective Synthesis of Tetrasubstituted Alkenes via a Cp*Co-III-Catalyzed C-H Alkenylation/Directing Group Migration Sequence

A highly atom economical and stereoselective synthesis of tetrasubstituted alpha,beta-unsaturated amides was achieved by a Cp*Co-III-catalyzed C-H alkenylation/directing group migration sequence. A carbamoyl directing group, which is typically removed after C-H functionalization, worked as an internal acylating agent and migrated onto the alkene moiety of the product. The directing group migration was realized with the Cp*Co-III catalyst, while a related Cp*Rh-III catalyst did not promote the migration process. The product was further converted into two types of tricyclic compounds, one of which had fluorescent properties

Pyrroloindolone Synthesis via a Cp*Co^III-Catalyzed Redox-Neutral Directed C–H Alkenylation/Annulation Sequence

A unique synthetic utility of a Cp*Co^III catalyst in comparison with related Cp*Rh^III catalysts is described. A C2-selective indole alkenylation/annulation sequence proceeded smoothly with catalytic amount of a [Cp*Co^III(C₆H₆)]­(PF₆)₂ complex and KOAc. Intramolecular addition of an alkenyl-Cp*Co species to a carbamoyl moiety gave pyrroloindolones in 58–89% yield in one pot. Clear difference was observed between the catalytic activity of the Cp*Co^III complex and those of Cp*Rh^III complexes, highlighting the unique nucleophilic activity of the organocobalt species. The Cp*Co^III catalysis was also suitable for simple alkenylation process of <i>N</i>-carbamoyl indoles, and broad range of alkynes, including terminal alkynes, were applicable to give C2-alkenylated indoles in 50–99% yield. Mechanistic studies on C–H activation step under Cp*Co^III catalysis with the aid of an acetate unit as well as evaluation of the difference between organo-Co^III species and organo-Rh^III species are also described

Site- and Regioselective Monoalkenylation of Pyrroles with Alkynes via Cp*Co^III Catalysis

A site-, regio-, <i>syn</i>-, and monoselective alkenylation of dimethylcarbamoyl-protected pyrroles proceeded using a catalytic amount of [Cp*Co­(CH₃CN)₃]­(SbF₆)₂ and KOAc. A variety of internal alkynes with several functional groups and a terminal alkyne afforded hydropyrrolation products in a selective manner in good to excellent yield. The site-selectivity (C2/C5 selectivity) observed for C3-substituted pyrroles is noteworthy because Cp*Rh^III-catalyzed conditions afforded only a moderate yield and low selectivity. The conditions described here provide general and straightforward access to unsymmetrically mono- and disubstituted pyrrole derivatives

Effects of Kamishoyosan, a Traditional Japanese Kampo Medicine, on Pain Conditions in Patients with Intractable Persistent Dentoalveolar Pain Disorder

There are patients who suffer from persistent dentoalveolar pain disorder (PDAP) which is a pain of the teeth, either dentoalveolar pain or nonodontogenic toothache, and its cause has not yet been identified. An effective intervention for PDAP has not yet been established. Interventions for patients with PDAP are generally pharmacological treatments such as antidepressants, anticonvulsants, and pregabalin. However, these medicines are not always effective for patients. The pain disorder in the orofacial region including temporomandibular disorder (TMD) and PDAP was effectively treated with our original exercise therapy. However, we did observe some intractable cases of PDAP even when our original exercise therapy was used. This paper presents our findings in which Kamishoyosan improved the pain intensity in 14 out of 15 PDAP patients refractory to our original exercise therapy

Effects of Kamishoyosan, a Traditional Japanese Kampo Medicine, on Pain Conditions in Patients with Intractable Persistent Dentoalveolar Pain Disorder

There are patients who suffer from persistent dentoalveolar pain disorder (PDAP) which is a pain of the teeth, either dentoalveolar pain or nonodontogenic toothache, and its cause has not yet been identified. An effective intervention for PDAP has not yet been established. Interventions for patients with PDAP are generally pharmacological treatments such as antidepressants, anticonvulsants, and pregabalin. However, these medicines are not always effective for patients. The pain disorder in the orofacial region including temporomandibular disorder (TMD) and PDAP was effectively treated with our original exercise therapy. However, we did observe some intractable cases of PDAP even when our original exercise therapy was used. This paper presents our findings in which Kamishoyosan improved the pain intensity in 14 out of 15 PDAP patients refractory to our original exercise therapy