Synthesis and application of trifluoroethoxy-substituted phthalocyanines and subphthalocyanines.

Phthalocyanines and subphthalocyanines are attracting attention as functional dyes that are applicable to organic solar cells, photodynamic therapy, organic electronic devices, and other applications. However, phthalocyanines are generally difficult to handle due to their strong ability to aggregate, so this property must be controlled for further applications of phthalocyanines. On the other hand, trifluoroethoxy-substituted phthalocyanines are known to suppress aggregation due to repulsion of the trifluoroethoxy group. Furthermore, the electronic characteristics of phthalocyanines are significantly changed by the strong electronegativity of fluorine. Therefore, it is expected that trifluoroethoxy-substituted phthalocyanines can be applied to new industrial fields. This review summarizes the synthesis and application of trifluoroethoxy-substituted phthalocyanine and subphthalocyanine derivatives.

A multicenter brain perfusion SPECT study evaluating idiopathic normal-pressure hydrocephalus on neurological improvement.

PURPOSE: This study was designed to investigate the specific cerebral blood flow (CBF) pattern in patients with idiopathic normal-pressure hydrocephalus (iNPH) and a predictive value for shunt responsiveness in a multicenter study (Study of Idiopathic Normal-Pressure Hydrocephalus on Neurological Improvement: SINPHONI). METHODS: Eighty-four iNPH patients underwent shunt operations using MRI selection criteria from the SINPHONI and were subjected to CBF single photon emission computed tomography (SPECT). The perfusion patterns on SPECT were classified: anterior-dominant CBF reduction type (A type), posterior-dominant CBF reduction type (P type), and mixed or diffuse CBF reduction type (M type). The predictive value of the CBF pattern for favorable shunt outcome was evaluated. RESULTS: Favorable outcomes were obtained in 76% (64/84) of patients, and shunt responsiveness was achieved in 85% (71/84) of patients. Areas of severely reduced relative CBF were demonstrated around the corpus callosum and in the sylvian fissure area, which included the effects of dilatations of the ventricles and sylvian fissures and relatively increased perfusion in the medial and lateral frontal, parietal, and occipital areas at high convexity. Forty-nine (58%) cases were A type, 25 (30%) cases were M type, and 10 (12%) cases were P type. A, M, and P type cases exhibited 83, 84, and 90% positive predictive values for shunt responsiveness, respectively. Mean modified Rankin scale and Mini-Mental State Examination scores of the A type group were significantly better than those of other groups. CONCLUSION: The iNPH patients showed various patterns of CBF reduction, but there was no significant difference in the predictive value among the three patterns, though CBF reduction patterns may suggest a severe condition of iNPH.

[A case of subacute myelitis with anti-aquaporin 4 antibody after thymectomy for myasthenia gravis: review of autoimmune diseases after thymectomy].

We report the case of a 60-year-old woman with myasthenia gravis (MG) and Basedow's disease who seven years after thymectomy developed subacute myelitis, a limited form of neuromyelitis optica (NMO). The patient presented with a centrally located long spinal cord lesion (LCL) on cervical cord MRI, anti-aquaporin 4 (AQP4) antibody in serum, and HLA DPB1*0501. Brain MRI showed no specific findings of classic multiple sclerosis (MS). CSF study showed elevated protein (67 mg/dl) but a normal IgG index (0.63) and no oligoclonal IgG bands. After repeated methylprednisolone pulse and immunoadsorption therapies, the T2-high signal lesion shrunk and tetraparesis improved. We reviewed the English and Japanese literature and found reports of 30 patients showing MS including NMO complicated with MG; 27 had been diagnosed as MS after thymectomy. Among these 27, 16 of 17 who were examined by spinal cord MRI and for anti-AQP4 antibodies were NMO. Only one patient with signs and symptoms localized to the optic nerves and spinal cord showed no LCL and was not examined for anti-AQP4 antibodies. In autoimmune disorders of the central nervous system after thymectomy in patients with MG, NMO is more predominant than classic MS.

Evidence of a threshold-effect for 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline liver carcinogenicity in F344/DuCrj rats.

To estimate potential human risk of exposure to a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a 2-year carcinogenicity test was conducted using male F344 rats administered MeIQx-containing diet at doses of 0 (control), 0.001, 1, and 100 ppm. The lowest dose 0.001 ppm was established as equivalent to the daily intake of this carcinogen in humans (0.2 to 2.6 microg/man/day). Significant decreases of survival rate and body weight gain were observed in rats treated with 100 ppm MeIQx. Histopathological examination revealed significant induction of hepatocellular carcinomas, adenomas, and development of glutathione S-transferase placental form-positive foci with MeIQx at 100 ppm. Moreover, the incidences of Zymbal's glands carcinoma, mammary fibroadenoma, and subcutaneous fibroma were found significantly increased in a 100 ppm MeIQx group. However, no significant induction of altered preneoplastic hepatocellular foci was observed in 0.001 and 1 ppm groups as compared to the controls. 8-Hydroxy-2'-deoxyguanosine levels in the rat liver DNA of the 100 ppm-treated group were not elevated, but MeIQx-DNA adduct formation increased as compared with the 1 ppm case, albeit without significance. No significant induction of any other neoplastic lesions related to the carcinogen administration was found in MeIQx-administered groups except for 100 ppm. These results imply that 1 ppm may be a no-effect level for MeIQx carcinogenesis.

Cerebral white matter damage in frontotemporal dementia assessed by diffusion tensor tractography.

INTRODUCTION: We used diffusion tensor imaging (DTI) to study white matter integrity in patients with frontotemporal dementia (FTD). METHODS: The subjects comprised 20 patients (9 men, 11 women) with FTD and 17 age-matched healthy controls (9 men, 8 women). Based on the data obtained from DTI, we performed tractography of the major cerebral pathways, including the pyramidal tracts, genu and splenium of the corpus callosum (CC), bilateral arcuate fasciculi (AF), inferior longitudinal fasciculi (ILF) and uncinate fasciculi (UF). We measured the values of fractional anisotropy (FA) in each fiber and statistically compared the findings in patients with those in controls. RESULTS: We found a significant decrease in FA values in the selected association fibers as well as anterior fibers of the CC in the patients with FTD. The greatest decrease in mean FA of the UF was seen in advanced FTD. On the other hand, there were no significant differences in FA in the bilateral pyramidal tracts. CONCLUSION: The features of FTD from the view point of cerebral white matter damage were revealed by tractography based on DTI. DTI is therefore considered to be a useful method, and may provide clues to elucidating the pathogenesis of FTD.

Super-Sensitive Protonation Behavior of Trifluoroethoxy-Substituted Phthalocyanines and Their Application to Solvent Discrimination.

The super-sensitive protonation behavior of trifluoroethoxy-substituted phthalocyanines (TFEO-Pcs) was carefully studied using UV-vis and fluorescence spectroscopy, as well as computational calculations. The practical utility of TFEO-Pcs in sensor technology was demonstrated by identifying chloroform samples from different commercial sources.

Trifluoroethoxy-Coated Subphthalocyanines Attract Small Arenes in Their π-Concave Cavity.

X-ray crystallographic analyses of a series of trifluoroethoxy-substituted subphthalocyanines disclosed that a molecule of toluene is clasped at the center of the molecular concave cavity. Twelve trifluoroethoxy substituents, which flexibly surround the toluene molecule to hold it on the 14 π-electron-conjugated surface of the subphthalocyanines, can also catch a molecule of benzene. In contrast, a nonsubstituted subphthalocyanine does not show the same phenomena, and two subphthalocyanine units are required to maintain a small aromatic compound in their concave cavity. DFT calculations of the complexes were conducted to better understand the arene clathrates. Trifluoroethoxy-substituted subphthalocyanines can be used to prepare arene clathrates as a result of their concave space. This is a unique approach to obtaining X-ray crystal structures of small noncrystalline aromatic compounds.

Trifluoroethoxy-Coated Subphthalocyanines Attract Small Arenes in Their π-Concave Cavity.

Invited for this month's cover is the group of Prof. Norio Shibata based at the Nagoya Institute of Technology, Japan. The cover picture shows the crystal structures of trifluoroethoxy-substituted subphthalocyanines which form crystalline clathrates with one small aromatic molecule, such as toluene or benzene, in their concave cavity. Twelve trifluoroethoxy substituents flexibly surround the small molecule to hold it on the 14π-electron conjugated surface of the subphthalocyanines. Read the full text of the article at 10.1002/cplu.201700508.

High sensitivity of fatty liver Shionogi (FLS) mice to diethylnitrosamine hepatocarcinogenesis: comparison to C3H and C57 mice.

The fatty liver Shionogi (FLS) mouse is a new inbred strain that spontaneously develops fatty liver with infiltration of mononuclear cells. Moreover, this mouse is known to frequently develop spontaneous hepatic cancers. Recently, human non-alcholic steatohepatitis (NASH) has been focused of attention regarding hepatocellular carcinoma. Therefore, this mouse has potential as a model for human hepatic cancer due to steatosis. It is of interest therefore, whether it exhibits elevated susceptibility not only regarding spontaneous tumor development but also to chemical hepatocarcinogens. To examine this concern, we examined diethylnitrosamine (DEN) hepatocarcinogenesis in FLS mice with 30ppm in drinking water for 26 weeks in comparison to two other strains of mice, C3H and C57. The induction of spontaneous and DEN-induced hepatic tumors was clearly increased in the FLS case, along with levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, as compared to the other strains, with or without DEN treatment. These results indicate that the oxidative DNA stress is intimately involved in hepatocarcinogenesis in FLS mice and provide further support for use of this mouse as a useful model for investigating hepatocarcinogenesis due to human hepatic steatosis.

Synthesis of chiral (tetrazolyl)methyl-containing acrylates via silicon-induced organocatalytic kinetic resolution of Morita-Baylis-Hillman fluorides.

Reported herein is a new approach for the asymmetric installation of a (tetrazolyl)methyl group via Si/F activation using organocatalytic kinetic resolution of racemic MBH-fluorides.

Regional cerebral blood flow in Alzheimer's disease: comparison between short and long-term donepezil therapy.

OBJECTIVE: Treatment with donepezil improves cognitive function of patients with Alzheimer's disease (AD) when compared to a placebo-controlled group. The purpose of this study was to investigate changes in regional cerebral blood flow (rCBF) of AD patients in short-term and long-term treatment with donepezil. METHODS: rCBF was measured by N-isopropyl-p-123I-iodoamphetamine (IMP) autoradiography method. CBF measurements were performed in 17 AD patients before treatment and after 3 months (short-term therapy) and 1 year (long-term therapy). Regions of interest were set at cerebral cortex and cerebellar hemisphere. We used absolute CBF and relative CBF expressed as ratio to cerebellar CBF. RESULTS: Significant increases in relative rCBF were noted in the frontal, parietal and temporal lobes at the end of short-term therapy. rCBF was decreased after the long-term therapy, whereas rCBF was still increased to a slight extent, as compared with the pre-treatment levels. Absolute rCBF showed minimal change and a tendency to decline. CONCLUSION: Relative rCBF significantly increased in the short-term donepezil therapy, while following the long-term therapy, rCBF decreased to the pre-treatment level.

Design, synthesis and optical properties of unsymmetrical subphthalocyanine trimer connected by phloroglucinol via axial positions.

An unsymmetrical subphthalocyanine trimer consisting of three different subphthalocyanine units was synthesized. Its optical and physical properties were investigated by UV/Vis, fluorescence spectrometry, cyclic voltammetry and computations. Energy transfer from the non-substituted subphthalocyanine unit to the perfluorinated subphthalocyanine unit via a trifluoroethoxy substituted unit is suggested.

Synthesis and optical properties of subphthalocyanine homo- and heterodimers axially connected via a hydroquinone linker.

Axially linked trifluoroethoxy (TFEO)-coated subphthalocyanine (SubPc) homo- and heterodimers were synthesized by two different axial ligand substitution methods. TFEO-SubPc homodimers were obtained directly from TFEO-SubPc boron chloride with o-, m-, and p-hydroquinones, while TFEO-SubPc heterodimers were synthesized via stepwise construction using a combination of the TFEO method and Torres' triflate method. The optical properties of the dimers obtained were investigated using UV-Vis and fluorescence spectrometry. Electron transfer was observed in the heterodimers, and TFEO-SubPc acted as an electron acceptor in the process. The electron transfer process differs depending on the o-, m-, and p-geometries of the hydroquinone linker, and is supported by computational calculations.

Synthesis of Phthalocyanines with a Pentafluorosulfanyl Substituent at Peripheral Positions.

The pentafluorosulfanyl (SF5) group is more electronegative, lipophilic and sterically bulky relative to the well-explored trifluoromethyl (CF3) group. As such, the SF5 group could offer access to pharmaceuticals, agrochemicals and optoelectronic materials with novel properties. Here, the first synthesis of phthalocyanines (Pcs), a class of compounds used as dyes and with potential as photodynamic therapeutics, with a SF5 group directly attached on their peripheral positions is disclosed. The key for this work is the preparation of a series of SF5-containing phthalonitriles, which was beautifully regio-controlled by a stepwise cyanation via ortho-lithiation/iodination from commercially available pentafluorosulfanyl arenes. The macrocyclization of the SF5-containing phthalonitriles to SF5-substituted Pcs required harsh conditions with the exception of the synthesis of ß-SF5-substituted Pc. The regiospecificity of the newly developed SF5-substituted Pcs observed by UV/Vis spectra and fluorescence quantum yields depend on the peripheral positon of the SF5 group.

Responses to donepezil in Alzheimer's disease and Parkinson's disease.

Alzheimer's disease is the most common cause of dementia, but Parkinson's disease also shows dementia in the later stages. Donepezil is a cholinesterase inhibitor used for the treatment of Alzheimer's disease. Variable responses to this drug suggest that Alzheimer's disease is clinically heterogeneous. In the clinical trial of tacrine, a first developed cholinesterase inhibitor, three cases markedly improved and, several years later, they were pathologically confirmed as dementia with Lewy bodies (DLB). In recent years, another cholinesterase inhibitor, rivastigmine, has also been reported to be effective for patients with DLB by a placebo-controlled, double-blind, multicenter study. Parkinson's disease with dementia, which is known to fulfill the pathological criteria of DLB, also shows a favorable response to donepezil. In some cases, not only does cognitive function improve, but also parkinsonism. Both DLB and Parkinson's disease with dementia show characteristic CBF patterns: While the parietal and temporal lobes are involved in Alzheimer's disease, the occipital lobe is additionally affected in these diseases. Alzheimer's disease and Parkinson's disease have been considered discrete disease entities. However, viewed from the aspects of response to donepezil treatment and CBF patterns, both diseases overlapped. A brain SPECT may be a useful tool to detect such treatable conditions.

Age-related alteration of haloperidol-serum protein binding.

Serum haloperidol levels were determined in 59 patients, 50-88-years-old, with psychosis, receiving long-term treatment with haloperidol. Although the total (bound and free form) haloperidol level in serum showed a linear correlation with daily dose, there was a larger variation in the relationship between free form and the daily dose compared with total because of inter-individual variation in the serum protein binding of haloperidol. The free fraction of haloperidol in serum increased with age. There was no difference in the ratio of total haloperidol level per daily dose between the adult and elderly groups, whereas the ratio of free haloperidol level per daily dose was significantly higher in the elderly than in the adult group. In the elderly, therefore, the therapeutic window of haloperidol should be assessed using free form level rather than total level, which is influenced by serum protein binding of the drug.

Peripheral neuropathy in Japanese patients with hepatitis C virus infection.

OBJECTIVE: The aim of this study was to report a series of Japanese patients with neuropathic symptoms following HCV infection. PATIENTS AND METHODS: Fifteen patients with neuropathic symptoms and HCV infection were studied retrospectively (neuropathy group). We evaluated clinical and electrophysiologic findings. As a control group, we investigated prospectively 11 patients with chronic HCV hepatitis without neuropathic symptoms. RESULTS: In the neuropathy group, the peripheral neuropathy was a multiple mononeuropathy (MM) in 8 patients, a polyneuropathy in 4 patients, a single cranial neuropathy in 2 patients, and a cervical radiculopathy in one patient. Five patients with MM had relapsing symptoms. Two patients showed a progression of neurologic symptoms following varicella zoster virus infection. Mixed cryoglobulinemia was noted in 4 of 13 tested patients. Circulating immunocomplexes were detected in 3 of 10 tested patients, and low complement (C3, C4, or CH50) levels were noted in 10 of 13 tested patients. Nerve conduction study (NCS) showed abnormal findings in 10 of 13 investigated patients. In the control group, only the frequency of low CH50 was significantly lower than that in the neuropathy group. Abnormal findings of NCS were found in 3 of 11 patients. CONCLUSION: We showed the presence of various types of neuropathies in patients with HCV infection. Our results suggest that relapsing MM is common in HCV positive neuropathy with or without cryoglobulinemia, and that the virus may modulate neurologic manifestations of other viral infections. Subclinical neuropathy may be present in some patients with HCV infection without neurologic symptoms.

[Development of a tree model that allows simple estimation of the required care level using the items of the basic investigation of long-term care insurance].

In long-term care insurance, the required care level of the disabled elderly is calculated from the results of the basic investigation. However, this calculation involves complex mathematical processes, and the estimation of the required care level at small facilities is difficult. We, therefore, developed a tree model that allows simple estimation of the required care level from the state of noticeable disabilities in daily activities. The model was prepared separately for dementia and physical disabilities. From the patients being cared for at Higashiyama Geriatric Hospital for the Elderly who had undergone primary rating, a total of 240 individuals consisting of 20 each in each of the 6 required care levels for both dementia and physical disabilities were selected, and the results of their primary rating were reviewed. "Putting on and taking off a jacket" and "care after urination", in which the required care levels increase relatively consistently as the investigation items progressed from those for "independent" to those for "totally assisted", were selected as the first selection items in dementia and physical disability models respectively. In a dementia model, the state of "putting on and taking off a jacket" and "care after urination" were matched for various required care levels as follows: "Independent"-->assistance needed, "observation needed" and "independent" in "standing up"-->required care level 1, "observation needed" and "not independent" in "standing up"-->required care level 2, "partly assisted"-->required care level 3, "totally assisted" and "not totally assisted" in "eating"-->required care level 4, and "totally assisted" and "totally assisted" in "eating"-->required care level 5. In a physical disability model, the state of "care after urination" was matched for various required care levels as follows: "Independent" and "independent" in "walking"-->assistance needed, "independent" and "not independent" in "walking"-->required care level 1, "direct or indirect assistance"-->required care level 2, "totally assisted" and "independent" or "observation needed" in "eating"-->required care level 3, "totally assisted" and "partly assisted" in "eating"-->required care level 4, "totally assisted" and "totally assisted" in "eating"-->required care level 5. The accuracy rate, i.e. the frequency of complete matching between the estimation of the required care level using this tree and that of the primary rating, was 71.1% in those with dementia and 66.7% in those with physical disabilities. The near accuracy rate, i.e. the frequency of matching between the two estimations within one rank higher or lower was 98.3% in those with dementia and 99.2% in those with physical disabilities. From these results, this tree model is considered to be useful for clinical rating.

A phthalocyanine-subphthalocyanine heterodinuclear dimer: comparison of spectroscopic properties with those of homodinuclear dimers of constituting units.

A phthalocyanine-subphthalocyanine heterodinuclear dimer has been disclosed for the first time with its unique flat-bowl-shaped structure revealed by X-ray crystallography. Its spectroscopic properties were compared with those of homodinuclear dimers of constituting units, as well as those of constituting monomeric units.