著者

Shunta Sato Wataru Sasaki Tomoyuki Sekino Tatsuhiko Yoshino Masahiro Kojima Shigeki Matsunaga

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.2, pp.79-82, 2023-02-01 (Released:2023-02-01)

参考文献数

37

---

Metallaphotoredox-catalyzed allylation represents an emerging synthetic methodology that enables allylic substitution using nucleophilic radical species. The C–H allylation of N-aryl tetrahydroisoquinolines is an innovative example in this area and allows access to synthetically useful precursors for the further derivatization of tetrahydroisoquinolines. However, previous methods have required the use of noble metals, which has hampered their application due to concerns over their sustainability. Here we report the C–H allylation of N-aryl tetrahydroisoquinolines using a cobalt/organophotoredox dual catalyst system. Based on precedent, control experiments and controlled irradiation experiments, a mechanism for the cobalt/photoredox-catalyzed allylation that involves a π-allyl cobalt complex is proposed.

著者

Keisuke Kinoshita Miyuki Yamaguchi Hirohisa Sasou Hideyuki Konishi Kei Manabe

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.2, pp.175-182, 2023-02-01 (Released:2023-02-01)

参考文献数

51

被引用文献数

1

---

Palladium-catalyzed, hydroxy-group-directed C–H arylation of [1,1′-biphenyl]-2-ols with chloroarenes was performed. The reaction showed a broad substrate scope and was successfully applied to pharmaceuticals containing a chloro group. Using 2-heteroarylphenols instead of [1,1′-biphenyl]-2-ols also yielded the desired products. The arylated product was further transformed into a triphenylene derivative.

著者

Hidetomo Yokoo Seiji Tanaka Eiichi Yamamoto Genichiro Tsuji Yosuke Demizu Nahoko Uchiyama

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.1, pp.58-63, 2023-01-01 (Released:2023-01-01)

参考文献数

33

被引用文献数

1

---

Understanding the characteristics of crystal polymorphism of active pharmaceutical ingredients and analyzing them with high sensitivity is important for quality of drug products, appropriate characterization strategies, and appropriate screening and selection processes. However, there are few methods to measure intra- and intermolecular correlations in crystals other than X-ray crystallography, for which it is sometimes difficult to obtain suitable single crystals. Recently, solid-state NMR has been recognized as a straightforward method for measuring molecular correlations. In this study, we selected ranitidine hydrochloride, which is known to exist in two forms, 1 and 2, as the model drug and investigated each form using solid-state NMR. In conducting the analysis, rotating the sample tube, which had a 1-mm inner diameter, increased the solid-state NMR resolution at 70 kHz. The 1H–14N dipolar-based heteronuclear multiple quantum coherence (D-HMQC) analysis revealed the intermolecular correlation of Form 1 between the N atom of the nitro group and a proton of the furan moiety, which were closer than those of the intramolecular correlation reported using single X-ray crystal analysis. Thus, 1H–14N D-HMQC analysis could be useful for characterizing intermolecular interaction in ranitidine hydrochloride crystals. In addition, we reassigned the 13C solid-state NMR signals of ranitidine hydrochloride according to the liquid-state and multiple solid-state NMR experiments.

著者

山崎 幹夫 松尾 光芳 柴田 承二

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.13, no.8, pp.1015-1017, 1965-08-25 (Released:2008-03-31)

被引用文献数

16 23

著者

Lili Li Ning Wang Qizhong Jin Qian Wu Yafang Liu Yan Wang

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.65, no.11, pp.1004-1010, 2017-11-01 (Released:2017-11-01)

参考文献数

35

被引用文献数

17 20

---

Tong-Qiao-Huo-Xue Decoction (TQHXD) is a classical prescription in traditional Chinese medicine treating blood stagnation in the head and facial channels, especially cerebral ischemia. We investigate the effect of TQHXD on the expressions of related proteins of the blood–brain barrier (BBB) and analysis of constituents in the cerebrospinal fluid (CSF) on cerebral ischemic model rats. Here, we demonstrate that TQHXD protected the hippocampus neurons, reduced the opening of tight junction (TJ) and decreased the permeability of BBB by up-regulating ZO-1, occludin, claudin-5 expressions, down-regulating aquaporin-4 (AQP-4) and matrix metalloproteinase-9 (MMP-9) expressions. Meanwhile, we detected Muscone, ligustilide and hydroxysafflor yellow A in CSF on cerebral ischemic model rats. These compounds could be identified as the main active ingredients of TQHXD on protecting the damaged BBB. These results suggest that TQHXD could act as a potential neuroprotective agent against BBB damage for cerebral ischemia.

著者

Keita Yaginuma Shuichi Tanabe Takuya Miyano Hiroshi Nakagawa Satoshi Suzuki Shuichi Ando Manabu Kano

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.68, no.9, pp.855-863, 2020-09-01 (Released:2020-09-01)

参考文献数

24

被引用文献数

3

---

In-line monitoring of granule water content during fluid bed granulation is important to control drug product qualities. In this study, a practical scale-free soft sensor to predict water content was proposed to cope with the manufacturing scale changes in drug product development. The proposed method exploits two key ideas to construct a scale-free soft sensor. First, to accommodate the changes in the manufacturing scale, the process parameters (PPs) that are critical to water content at different manufacturing scales were selected as input variables. Second, to construct an accurate statistical model, locally weighted partial least squares regression (LW-PLSR), which can cope with collinearity and nonlinearity, was utilized. The soft sensor was developed using both laboratory (approx. 4 kg) data and pilot (approx. 25 kg) scale data, and the prediction accuracy in the commercial (approx. 100 kg) scale was evaluated based on the assumption that the process was scaled-up from the pilot scale to the commercial scale. The developed soft sensor exhibited a high prediction accuracy, which was equivalent to the commonly used near-infrared (NIR) spectra-based method. The proposed method requires only standard instruments; therefore, it is expected to be a cost-effective alternative to the NIR spectra-based method.

著者

Takashi Nakada Kiyoshi Sugihara Takahiro Jikoh Yuki Abe Toshinori Agatsuma

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.67, no.3, pp.173-185, 2019-03-01 (Released:2019-03-01)

参考文献数

82

被引用文献数

98 212

---

A major limitation of traditional chemotherapy for cancer is dose-limiting toxicity, caused by the exposure of non-tumor cells to cytotoxic agents. Use of molecular targeted drugs, such as specific kinase inhibitors and monoclonal antibodies, is a possible solution to overcome this limitation and has achieved clinical success so far. Use of an antibody–drug conjugate (ADC) is a rational strategy for improving efficacy and reducing systemic adverse events. ADCs use antibodies selectively to deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. Lessons learned from clinical failure of early ADCs during the 1980s to 90s have recently led to improvements in ADC technology, and resulted in the approval of four novel ADCs. Nonetheless, further advances in ADC technology are still required to streamline their clinical efficacy and reduce toxicity. [fam-] Trastuzumab deruxtecan (DS-8201a) is a next-generation ADC that satisfies these requirements based on currently available evidence. DS-8201a has several innovative features; a highly potent novel payload with a high drug-to-antibody ratio, good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo; the released cytotoxic payload could exert a bystander effect. With respect to its preclinical profiles, DS-8201a could provide a valuable therapy with a great potential against HER2-expressing cancers in clinical settings. In a phase I trial, DS-8201a showed acceptable safety profiles with potential therapeutic efficacy, with the wide therapeutic index.

著者

Masaya Denda Akira Otaka

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.5, pp.316-323, 2022-05-01 (Released:2022-05-01)

参考文献数

53

被引用文献数

1

---

The growing interest in artificial proteins modified by synthetic functional units has fueled the demand for their facile preparation. Native chemical ligation (NCL) enables the chemoselective condensation of peptide thioesters with a cysteine-installed synthetic partner and has enjoyed great success in the production of artificial proteins with up to 100–150 residues. A practical method for converting expressed proteins to the corresponding thioesters should lead to significant progress in the NCL-mediated technology. This account describes our recent contributions to the conversion of naturally occurring peptides to the corresponding thioesters by chemical or chemoenzymatic protocols aiming at their future prevalent use in the preparation of sophisticated protein biologics.

著者

Yu Ishima Toru Maruyama Masaki Otagiri Victor T. G. Chuang Tatsuhiro Ishida

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.5, pp.330-333, 2022-05-01 (Released:2022-05-01)

参考文献数

48

被引用文献数

21

---

Albumin, the most abundant protein in human serum, is applied to various diseases as a drug delivery carrier because of its superior blood retention, high biocompatibility, and a wide variety of drug binding abilities. Albumin is known to distribute widely in the blood and various interstitial fluids and organs. Different albumin receptors skillfully regulate the distribution characteristics of albumin in the body. Albumin receptors are a group of diverse proteins, such as FcRn, gp60, gp18, megalin, cubilin, SPARC, and CD36. Their tissue distributions in vivo are unique, with different albumin’s recognition sites. Therefore, the distribution of albumin in vivo is ingeniously controlled by these multiple albumin receptors. Reevaluation of these albumin receptors opens up new possibilities for applying albumin as a drug delivery carrier. If the tissue distributions of albumin receptors were known and the albumin recognition site of the receptor was identified, organ-specific active targeting would be possible. In this review, we would like to scrutinize what is currently known and share information to develop next-generation albumin carriers that focus on interactions with albumin receptors.

著者

Kazuki Ohshima Shuji Ohsaki Hideya Nakamura Satoru Watano

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.5, pp.383-390, 2022-05-01 (Released:2022-05-01)

参考文献数

37

被引用文献数

3

---

Numerous efforts have been devoted to improving the solubility of poorly water-soluble drugs. Recently, it was reported that the use of metal-organic frameworks (MOFs), which are a new class of porous materials consisting of metal ions and organic ligands, is effective in improving the solubility of poorly water-soluble drugs. Our previous study demonstrated an improvement in the solubility of indomethacin (IDM) triggered by the zeolitic imidazolate framework-8 (ZIF-8). The present study aimed to elucidate the solubilization mechanism using the ZIF series, namely, ZIF-8, ZIF-67, and ZIF-L. It was confirmed that the solubility of ZIF-trapped IDM and ibuprofen (IBU) was enhanced compared to the raw drugs, regardless of the ZIF type. This study focused on 2-methylimidazole (2-MIM), which is commonly used as a ZIF organic ligand. Both IDM and IBU were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the solubility of the drugs. Inductively coupled plasma measurements also confirmed the presence of metal ions of ZIFs in the supernatant solution after the drug release tests, indicating the decomposition of ZIFs during drug release. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIF particles. We observed that the drugs loaded on the ZIFs were released simultaneously with the decomposition of some of the ZIFs. The 2-MIM molecules were also released concurrently. The presence of 2-MIM improved the solubility of poorly water-soluble drugs.

著者

Sitaram Bhavaraju Subramanya G. Sreerama David Taylor Steven Rau

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.3, pp.226-229, 2022-03-01 (Released:2022-03-01)

参考文献数

29

被引用文献数

1

---

Quantitative proton NMR (qHNMR) methodology was employed for the stoichiometric (free base and the corresponding counterion) assessment of a ticagrelor process impurity, also referred to in the United States Pharmacopeia (USP), Pharmacopeial Forum as Ticagrelor Related Compound A (RC A), [(1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine (R)-mandelate], also called as Tica amine mandelate, a critical impurity that, when present during manufacturing, has a limit of not more than 0.0008%. The Tica amine is also a listed impurity E in the Ticagrelor monograph, in European Pharmacopeia. Because there was no existing NMR spectroscopic method in the literature specific to quantify the counterion (mandelic acid) in Ticagrelor RC A, this study aimed to fill the gap. Accurate stoichiometric measurement of this impurity serves to enhance product quality in the manufacturing of the ticagrelor active pharmaceutical ingredient (API). Using ethylene carbonate as an internal standard (IS), the qHNMR analysis on Ticagrelor impurity, revealed many key characteristics of the test mixture composition, including (free base and counterion). The results demonstrate that qHNMR has great potential for addressing several key quality attributes associated with chemical analyses such as detection, identification, quantification, and purity determination, as well as deriving molecular stoichiometry, all from the single proton spectrum.

著者

Tsukasa Hasegawa Riyo M. Imamura Tateki Suzuki Takao Hashiguchi Takao Nomura Satoko Otsuguro Katsumi Maenaka Michihito Sasaki Yasuko Orba Hirofumi Sawa Akihiko Sato Takayoshi Okabe Tetsuo Nagano Hirotatsu Kojima

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

pp.c21-01003, (Released:2021-12-21)

参考文献数

10

被引用文献数

6

---

Mass spectrometry is a powerful methodology for chemical screening to directly quantify substrates and products of enzymes, but its low throughput has been an issue. Recently, an acoustic liquid-handling apparatus (Echo®) used for rapid nano-dispensing has been coupled to a high-sensitivity mass spectrometer to create the Echo® MS system, and we applied this system to screening of SARS-CoV-2 3CL protease inhibitors. Primary screening of 32,033 chemical samples was completed in 12 hours. Among the hits showing selective, dose-dependent 3CL-inhibitory activity, 8 compounds showed antiviral activity in cell-based assay.

著者

田中 博道 内田 祐子 篠崎 操 早川 弘之 松田 彰 宮坂 貞

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.31, no.2, pp.787-790, 1983-02-25 (Released:2008-03-31)

参考文献数

17

被引用文献数

21 32

---

6-Chloro-9-(2, 3-O-isopropylidene-β-D-ribofuranosyl) purine (1) was found to be a suitable substrate for the preparation of C-8 substituted purine nucleosides. Thus, upon lithiation of 1 with LDA and successive reaction with various types of electrophiles, the C-8 substituted products were obtained. The C-6 chlorine atoms in these products were readily replaced by an amino group, a mercapto group, or hydrogen, providing a facile preparation of 8-substituted adenosines, 6-thioinosines, or nebularines.

著者

寺田 忠史 藤本 勝彦 野村 誠 山下 純一 / 小武内 尚 武田 節夫 南 慶典 吉田 健一郎 山口 秀夫 山田 雄次 Yuji YAMADA

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.41, no.5, pp.907-912, 1993-05-15 (Released:2008-03-31)

参考文献数

58

被引用文献数

6 10

---

1-β-Alkyl derivatives of 1-desoxypodophyllotoxin were synthesized, and their cytotoxicity and inhibitory effects on DNA topoisomerase II (Topo-II) and tubulin polymerization were examined.The reaction of epipodophyllotoxin derivatives (1a-c) with trimethylallylsilane in the presence of boron trifluoride etherate gave 1-β-allylated compounds (2a-c). The regiochemistry and the β-stereochemistry of the 1-allyl group were confirmed by comparison of the 13C-NMR spectra and NOE's (%) of 2c, podophyllotoxin (POD) and epipodophyllotoxin (1b). 1-β-Alkyl-1-desoxypodophyllotoxin derivatives (3-8) were prepared from 2b.None of the tested compounds (3-8) showed any inhibitory effect on Topo-II. 1-β-Propyl compound (3) and its 4'-demethyl compound (4) inhibited tubulin polymerization and the cytotoxicities of these compounds were equal to that of VP-16. 1-β-(2, 3-Dihydroxypropyl) compounds (5 and 8) and 1-β-(2, 3-diacetoxypropyl) compounds (6 and 7)showed no inhibitory effect on tubulin polymerization. Although 5 did not inhibit either Topo-II activity or tubulin polymerization, it showed a high cytotoxicity against sarcoma 180.

著者

Hiroyuki Hayakawa Hiromichi Tanaka Naoko Itoh Masako Nakajima Tadashi Miyasaka Kentaro Yamaguchi Yoichi Iitaka

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.6, pp.2605-2608, 1987-06-25 (Released:2009-10-19)

参考文献数

26

被引用文献数

30 42

---

The reaction of organolithium, Grignard, and organoaluminum reagents with 2'- and 3'-ketouridine derivatives was examined. For the reaction of 2', 5'-bis-0- (tert-butyldimethylsilyl) -3'-ketouridine, both organolithiums and organoaluminums seem to be practically useful. But only organoaluminums gave satisfactory yields in the reaction of 3', 5'-0- (tetraisopropyldisiloxan-1, 3-diyl) -2'-ketouridine.

著者

HIROSHI SUEMUNE TETSUJI HARABE ZHUO-FENG XIE KIYOSHI SAKAI

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.36, no.11, pp.4337-4344, 1988-11-25 (Released:2011-02-08)

参考文献数

14

被引用文献数

20 33

---

Asymmetric hydrolysis of 2, 2-bis (acetoxymethyl) cyclopentanone (5) using biocatalysts and its application to a formal synthesis of (-)-malyngolide are described.For the asymmetric induction at the quaternary carbon of 5, cholinesterase from electric eel was found to be effective to afford the (+)-monoacetate (6)(90%ee).Compound (+)-6 was easily converted to the synthetic intermediate (28) for (-)-malyngolide.

著者

末宗 洋 原部 哲治 酒井 浄

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.36, no.9, pp.3632-3637, 1988-09-25 (Released:2008-03-31)

参考文献数

10

被引用文献数

23 30

---

Two trihydroxy unsaturated C-18 fatty acids [(9S, 12S, 13S)-trihydroxyoctadeca-10E, 15Z-dienoic acid (methyl ester) and (9S, 12S, 13S)-trihydroxy-10E-octadecenoic acid (methyl ester)] isolated from rice plants as agents with activity against blast disease were synthesized from (+)-dimethyl tartrate.

著者

MASAHIRO SUZUKI HIROMICHI TANAKA TADASHI MIYASAKA

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.10, pp.4056-4063, 1987-10-25 (Released:2009-10-19)

参考文献数

14

被引用文献数

4 12

---

Several 5-carbon-substituted 1-β-D-ribofuranosylimidazole-4-carboxamides were synthesized via the direct C-5 lithiation of a protected 4-carboxamide derivative as the key reaction step. Wittig reaction of a 5-formyl derivative was also examined.

著者

尾崎 庄一郎 秋山 隆彦 森田 剛夫 久米川 昌浩 長瀬 敏夫 上原 宣昭 星 昭夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.38, no.11, pp.3164-3166, 1990-11-25 (Released:2008-03-31)

参考文献数

17

被引用文献数

12 12

---

Various kinds of 5'-O-unsaturated acyl 5-fluorouridines were synthesized to obtain 5-fluorouridine derivatives with low toxicity and high antitumor activity. Antitumor activity of the compounds against L-1210 leukemia in mice was examined, and the 5'-O-4-opentenoyl derivative showed the highest antitumor activity.

著者

尾崎 庄一郎 渡辺 裕 / 長瀬 敏雄 小笠原 富夫 古川 弘幸 上村 敦彦 石川 勝敏 / / 徳善 令子 AKIO HOSHI MASAAKI IIGO REIKO TOKUZEN

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.34, no.1, pp.150-157, 1986-01-25 (Released:2008-03-31)

参考文献数

14

被引用文献数

15 23

---

With the aim of diminishing the toxicity of 5-fluorouracil (1) and obtaining biologically active derivatives of 1 suitable for oral administration, α-alkoxyalkyl groups were introduced at the 1-, 3-and 1, 3-positions of 1. Alkoxyalkylation can be effected by four methods : (i) reaction of 1-alkoxyalkyl chloride (2) with 1, (ii) reaction of acetal with 2, 4-bis (trimethylsiloxy)-5-fluoropy-rimidine, (iii) addition reaction of α-unsaturated ether with 1, (iv) aminolysis of 1-alkylthio-carbonyl-3-(1-alkoxyalkyl)-5-fluorouracil. The toxicity of the products was less than that of 1, and some of these compounds showed moderate antitumor activity against L-1210 leukemia.