Role of Pyridines in Medicinal Chemistry and Design of BACE1 Inhibitors Possessing a Pyridine Scaffold

Pyridine is a unique aromatic ring. Although pyridines are used industrially, pyridine moieties are present in many natural products, such as vitamins, coenzymes, and alkaloids, and also in many drugs and pesticides. Pyridine moieties are often used in drugs because of their characteristics such as basicity, water solubility, stability, and hydrogen bond-forming ability, and their small molecular size. Because pyridine rings are able to act as the bioisosteres of amines, amides, heterocyclic rings containing nitrogen atoms, and benzene rings, their replacement by pyridine moieties is important in drug discovery. Recently, we synthesized a series of BACE1 inhibitors by in silico conformational structure-based drug design and found an important role of pyridine moiety as a scaffold. In this chapter, we describe the important role of pyridines in medicinal chemistry and the development of β-secretase inhibitors possessing a pyridine scaffold for the treatment of Alzheimer’s disease

Isoacylpeptide Method for Long-Chain and Difficult Sequence-Containing Peptide Preparation

Peptides or small-size proteins are important substances for medicines, diagnosis, and molecular biology research. In organic synthesis, the peptide bonds formation is performed in an organic solution (liquid-phase peptide synthesis, LPPS), or on a resin (solid-phase peptides synthesis, SPPS). LPPS can prepare a high volume of peptides, but it is generally required long processes and high cost for peptides preparation and is not appropriate for long-chain peptides. SPPS can prepare long-chain peptides until 40 residues in a short time. However, it is difficult to obtain the pure peptides because of no purification of its intermediates. For a solution of these problems, Kent et al. reported native chemical ligation (NCL) method for the preparation of long-chain peptides. Because peptides with a long chain or difficult sequence formed β-sheet structure within a molecule, these peptides have high aggregability and low solubility, and their preparation and purification are generally difficult. Mutter et al. reported ‘pseudoproline’ method for difficult sequence-containing peptide preparation. We previously reported a series of prodrugs based on O-N intramolecular acyl migration. We reported ‘O-isoacylpeptide’ method for the preparation of difficult sequence-containing peptides using the prodrug strategy based on O-N intramolecular acyl migration

Discovery of BACE1 Inhibitors for the Treatment of Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia. According to the amyloid hypothesis, β-secretase (BACE1) is a promising molecular target for the development of anti-Alzheimer’s disease drugs. BACE1 triggers the formation of the amyloid-β (Aβ) peptides that are the main component of senile plaques in the brain of patients with Alzheimer’s disease. As BACE1 cleaves the amyloid precursor protein at the N-terminus of the Aβ domain, BACE1 inhibitors reduce the Aβ level in the brain. Previously, we designed a series of peptidic inhibitors that possessed a substrate transition-state analogue, and the structure-activity relationship of our inhibitors was evaluated, based on docking and scoring, using the docking simulation software Molecular Operating Environment (MOE). However, there was no association between the scoring values and the inhibitory activities at the P2 position. Hence, we hypothesized that the interaction of the P2 position of the inhibitor with the S2 site of BACE1 was critical for the mechanism of inhibition, and we proposed the novel concept of ‘electron donor bioisostere’ for drug discovery. Using this concept, we designed potent small molecule non-peptidic BACE1 inhibitors

Multidrug Sensitive Yeast Strains, Useful Tools for Chemical Genetics

The budding yeast Saccharomyces cerevisiae is a useful eukaryote model organism for application to chemical biology studies, for example, drug screening, drug evaluation, and target identification. To use yeast for chemical biology research, however, it has been necessary to construct yeast strains suitable for various compounds because of their high drug resistance. Hence, the deletion of all multidrug resistance genes except for those that are important for viability and for genetic experiments/manipulation could increase the drug sensitivity without influencing the transformation, mating, or sporulation efficiency. There are two major factors conferring multidrug resistance in S. cerevisiae: one is the drug efflux system and the other is the permeability barrier. We therefore constructed a strain which shows high sensitivity to multiple drugs by disrupting the drug efflux system using ATP-binding cassette transporters and suppressing the membrane barrier system by introducing an ERG6-inducible system. In this review, we discuss the construction of our multidrug-sensitive yeast strains and their application in chemical biology

Investigation of turbulence in reversed field pinch plasma by using microwave imaging reflectometry

Turbulence in the reversed field pinch (RFP) plasma has been investigated by using the microwave imaging reflectometry in the toroidal pinch experiment RX (TPE-RX). In conventional RFP plasma, the fluctuations are dominated by the intermittent blob-like structures. These structures are accompanied with the generation of magnetic field, the strong turbulence, and high nonlinear coupling among the high and low k modes. The pulsed poloidal current drive operation, which improves the plasma confinement significantly, suppresses the dynamo, the turbulence, and the blob-like structures.This work is supported by the NINS Imaging Science Project (Grant No. NIFS08KEIN0021), SOKENDAI (Grant No. NIFS08GLPP003), and the Budget for Nuclear Research of the Ministry of Education, Culture, Sports, Science and Technology of Japan

Prediction of Sound Pressure Level of Turbulent Noise Generated from Multiple-Disk Fans

We proposed a theory for estimating the spectral density distribution and over all sound pressure level of the turbulent noise radiated from multiple-disk fans. In the theory, correlations between the longitudinal and lateral correlation lengths, and the pressure spectral densities were used. The effects of casing on the radiated noise were experimentally made clear by comparing the spectral density distributions with and without casing. The validity of theoretically obtained formula was examined with respect to the effects of such parameters as; the gap between two disks, the rotational frequency, the number of disks, the thickness of disks, the radius of impeller and the flow rate. The agreement between the theoretical and the experimental results was fairly satisfactory

Comparison of postmenopausal endogenous sex hormones among Japanese, Japanese Brazilians, and non-Japanese Brazilians

<p>Abstract</p> <p>Background</p> <p>Differences in sex hormone levels among populations might contribute to the variation in breast cancer incidence across countries. Previous studies have shown higher breast cancer incidence and mortality among Japanese Brazilians than among Japanese. To clarify the difference in hormone levels among populations, we compared postmenopausal endogenous sex hormone levels among Japanese living in Japan, Japanese Brazilians living in the state of São Paulo, and non-Japanese Brazilians living in the state of São Paulo.</p> <p>Methods</p> <p>A cross-sectional study was conducted using a control group of case-control studies in Nagano, Japan, and São Paulo, Brazil. Participants were postmenopausal women older than 55 years of age who provided blood samples. We measured estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex hormone-binding globulin (SHBG) by immunoradiometric assay. A total of 363 women were included for the present analyses, comprising 185 Japanese, 44 Japanese Brazilians and 134 non-Japanese Brazilians.</p> <p>Results</p> <p>Japanese Brazilians had significantly higher levels of estradiol, bioavailable estradiol, estrone, testosterone and free testosterone levels, and lower SHBG levels, than Japanese. Japanese Brazilians also had significantly higher levels of bioavailable estradiol, estrone and DHEAS and lower levels of SHBG and androstenedione than non-Japanese Brazilians. Levels of estradiol, testosterone and free testosterone, however, did not differ between Japanese Brazilians and non-Japanese Brazilians. These differences were observed even after adjustment for known breast cancer risk factors. We also found an increase in estrogen and androgen levels with increasing body mass index, but no association for most of the other known risk factors.</p> <p>Conclusions</p> <p>We found higher levels of estrogens and androgens in Japanese Brazilians than in Japanese and levels similar to or higher than in non-Japanese Brazilians. Our findings may help explain the increase in the incidence and mortality rate of breast cancer among Japanese Brazilians.</p

New field‑in‑field with two reference points method for whole breast radiotherapy: Dosimetric analysis and radiation‑induced skin toxicities assessment

The usefulness of the field‑in‑field with two reference points (FIF w/ 2RP) method, in which the dose reference points are set simultaneously at two positions in the irradiation field and the high‑dose range is completely eliminated, was examined in the present study with the aim of decreasing acute skin toxicity in adjuvant breast radiotherapy (RT). A total of 573 patients with breast cancer who underwent postoperative whole breast RT were classified into 178 cases with wedge (W) method, 142 cases with field‑in‑field without 2 reference points (FIF w/o 2RP) method and 253 cases with FIF w/ 2RP method. Using the FIF w/ 2RP method, the high‑dose range was the lowest among the three irradiation methods. The planning target volume (PTV) V105% and the breast PTV for evaluation (BPe) V105% decreased to 0.09 and 0.10%, respectively. The FIF w/ 2RP method vs. the FIF w/o 2RP method had a strong association (η) with PTV V105% (η=0.79; P<0.001) and BPe V105% (η=0.76; P<0.001). The FIF w/ 2RP method had a significant impact on lowering the skin toxicity grade in weeks 3 and 4, and increasing the occurrence of skin toxicity grade 0. The FIF w/ 2RP method vs. the W method had a moderate association with skin toxicity grade at week 3 (η=0.49; P<0.001). Using the FIF w/ 2RP method, the high‑dose range V105% of the target decreased to 0%, and skin adverse events were decreased in conjunction. For patients with early‑stage breast cancer, particularly patients with relatively small‑sized breasts, the FIF w/ 2RP method may be an optimal irradiation method