183 results on '"Tohru Oishi"'
Search Results
2. Convergent Synthesis of the WXYZA′B′C′D′E′F′ Ring Segment of Maitotoxin
- Author
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Keitaro Umeno, Hisaaki Onoue, Keiichi Konoki, Kohei Torikai, Yoko Yasuno, Masayuki Satake, and Tohru Oishi
- Subjects
General Chemistry - Published
- 2022
3. Total Synthesis of Amphidinol 3
- Author
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Yuma Wakamiya and Tohru Oishi
- Subjects
Chemistry ,Organic Chemistry ,Organic chemistry ,Total synthesis ,Amphidinol 3 - Published
- 2021
4. Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study
- Author
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Michio Murata, Hiroshi Tsuchikawa, Shinya Hanashima, Tohru Oishi, Sangjae Seo, Tomoya Yamamoto, Kosuke Funahashi, Taiga Suzuki, Shigeru Matsuoka, Nobuaki Matsumori, Mayank Kumar Dixit, Yuichi Umegawa, Yasuo Nakagawa, and Wataru Shinoda
- Subjects
Ergosterol ,chemistry.chemical_compound ,Molecular dynamics ,Membrane ,Multidisciplinary ,Solid-state nuclear magnetic resonance ,Chemistry ,Antifungal drug ,Biophysics ,Molecule ,Nuclear magnetic resonance spectroscopy ,Ion channel - Abstract
Amphotericin B, an antifungal drug with a long history of use, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of fungal sterol, ergosterol. A stable assembly consisting of seven drug molecules was observed to form an ion conductive channel. The structure is somewhat similar to the upper half of the barrel-stave model proposed in the 1970s but substantially different in the number of molecules and in their arrangement. The high-resolution structure explains many previous findings, including structure-activity relationships of the drug, which will be useful for improving drug efficacy and reducing adverse effects.
- Published
- 2022
5. Structure Determination, Chemical Synthesis, and Evaluation of Biological Activity of Super Carbon Chain Natural Products
- Author
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Tohru Oishi
- Subjects
Maitotoxin ,Carbon chain ,Molecular mass ,010405 organic chemistry ,Microorganism ,Biological activity ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Chemical synthesis ,Amphidinol 3 ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Organic chemistry - Abstract
Marine microorganisms are known to produce natural products, so called super carbon chain compounds whose molecular weights (MWs) exceed one thousand, such as amphidinol 3 (AM3) and maitotoxin (MTX...
- Published
- 2020
6. Chemical Synthesis, Structure Determination, and Evaluation of Biological Activity of Sperm Activating and Attracting Factors Isolated from Ascidias
- Author
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Tohru Oishi and Hiroshi Tsuchikawa
- Subjects
Ascidia ,biology ,Biochemistry ,Chemistry ,Organic Chemistry ,Biological activity ,Chemotaxis ,biology.organism_classification ,Chemical synthesis ,Sperm - Published
- 2020
7. Simple Apparatus for Adding Small Amounts of Powder Materials under an Inert Atmosphere
- Author
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Kohei Torikai, Yohei Joh, Tohru Oishi, Shamansur S. Sagdullaev, Khamid U. Khodjaniyazov, and Milandip Karak
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Glovebox ,Moisture ,Chemical engineering ,010405 organic chemistry ,Chemistry ,Simple (abstract algebra) ,Organic Chemistry ,Contamination ,010402 general chemistry ,Inert gas ,01 natural sciences ,0104 chemical sciences - Abstract
Addition of reactants under an inert atmosphere is a fundamental but extremely important technique in synthetic chemistry. Although this is achievable in many cases by using a glove box or a Schlenk-and-syringe technique, the direct addition of powder (solid) materials without contamination by air or moisture has been difficult, especially in the later stages of a reaction. Here, we offer a simple and small apparatus to realize powder addition with easy handling. Use of this apparatus permitted one-pot glycosylation reactions that required extremely dry conditions to be performed in a highly reproducible manner.
- Published
- 2019
8. Unified Synthesis of the DEF and GHI Ring Systems of Maitotoxin
- Author
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Takaya Yasudomi, Makoto Ebine, Kohei Torikai, Hiroyuki Yakushiji, and Tohru Oishi
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Maitotoxin ,chemistry.chemical_compound ,chemistry ,010405 organic chemistry ,Stereochemistry ,Furan ,General Chemistry ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,Derivative (chemistry) ,0104 chemical sciences - Abstract
Unified synthesis of 6/6/6-tricyclic ethers corresponding to the DEF and GHI ring systems of maitotoxin was achieved from a common intermediate prepared from a furan derivative and a terminal olefi...
- Published
- 2019
9. 1,2-trans Glycosylation via Neighboring Group Participation of 2-O-Alkoxymethyl Groups: Application to One-Pot Oligosaccharide Synthesis
- Author
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Milandip Karak, Kohei Torikai, Masahiko Suenaga, Yohei Joh, and Tohru Oishi
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chemistry.chemical_classification ,Glycosylation ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Oxocarbenium ,Substituent ,Glycosidic bond ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Intramolecular force ,Reactivity (chemistry) ,Stereoselectivity ,Physical and Theoretical Chemistry ,Selectivity - Abstract
The use of 2- O-alkoxymethyl groups as effective stereodirecting substituents for the construction of 1,2- trans glycosidic linkages is reported. The observed stereoselectivity arises from the intramolecular formation of a five-membered cyclic architecture between the 2- O-alkoxymethyl substituent and the oxocarbenium ion, which provides the expected facial selectivity. Furthermore, the observed stereocontrol and the extremely high reactivity of 2- O-alkoxymethyl-protected donors allowed development of a one-pot sequential glycosylation strategy that should become a powerful tool for the assembly of oligosaccharides.
- Published
- 2019
10. A Synthetic Approach to the Channel Complex Structure of Antibiotic in a Membrane: Backbone 19F-Labeled Amphotericin B for Solid-State NMR Analysis
- Author
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Tohru Oishi, Yuichi Umegawa, Michio Murata, and Hiroshi Tsuchikawa
- Subjects
Membrane ,Channel complex ,Solid-state nuclear magnetic resonance ,medicine.drug_class ,Chemistry ,Amphotericin B ,Organic Chemistry ,Antibiotics ,medicine ,Combinatorial chemistry ,medicine.drug - Published
- 2018
11. Total Synthesis of Amphidinol 3: A General Strategy for Synthesizing Amphidinol Analogues and Structure-Activity Relationship Study
- Author
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Nobuaki Matsumori, Tohru Oishi, Yuma Wakamiya, and Makoto Ebine
- Subjects
Carbon chain ,Models, Molecular ,Natural product ,Antifungal Agents ,Stereochemistry ,Absolute configuration ,Total synthesis ,General Chemistry ,Alkenes ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,Amphidinol 3 ,0104 chemical sciences ,Stereocenter ,chemistry.chemical_compound ,Structure-Activity Relationship ,Colloid and Surface Chemistry ,chemistry ,Structure–activity relationship ,Moiety ,Pyrans - Abstract
Amphidinol 3 (AM3) is a potent antifungal produced by the dinoflagellate Amphidinium klebsii. It was difficult to determine the absolute configuration of AM3 by using the scarce natural product due to the presence of numerous stereogenic centers on the acyclic carbon chain. Since the absolute configuration was partially determined on the basis of insufficient evidence, the originally proposed structure has been revised three times. Although recent progress on structure determination by computational analysis is remarkable, total synthesis is still the most reliable way to confirm structures. The first total synthesis of AM3 was achieved via expeditious assembly of three components in five steps, confirming the revised structure of AM3 after more than 20 years since its first discovery. The established synthetic route would be a general strategy for synthesizing amphidinol congeners. An artificial and simplified analogue of AM3, which elicited antifungal activity comparable to that of AM3, was designed and synthesized. This is the first example of a biologically active artificial analogue possessing a shorter polyol moiety, providing insight on the antifungal mode-of-action.
- Published
- 2020
12. Synthesis of anti-tubercular marine alkaloids denigrins A and B
- Author
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Tohru Oishi, Milandip Karak, and Kohei Torikai
- Subjects
Serviceability (structure) ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Maleic anhydride ,010402 general chemistry ,Key features ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Drug Discovery ,Organic chemistry ,Aldol condensation ,Anti tubercular - Abstract
The first synthesis of anti-tubercular marine alkaloids denigrins A and B were accomplished in three and five steps and 62% and 31% overall yields respectively, from maleic anhydride. The key features of the synthesis include efficient Mizoroki-Heck reaction, geometry-controlled vinylogous aldol condensation, and one-pot lactamization. The synthesis first demonstrates the serviceability of maleic anhydride in palladium-catalyzed cross-coupling reactions with diaryliodonium salt.
- Published
- 2018
13. Synthesis and Stereochemical Revision of the C31–C67 Fragment of Amphidinol 3
- Author
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Michio Murata, Tohru Oishi, Yuma Wakamiya, Makoto Ebine, Hiroyuki Omizu, Mariko Murayama, and Nobuaki Matsumori
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Biological Products ,Magnetic Resonance Spectroscopy ,Natural product ,010405 organic chemistry ,Stereochemistry ,Chemistry ,Molecular Conformation ,Absolute configuration ,Stereoisomerism ,General Medicine ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Tetrahydropyran ,Alkenes ,010402 general chemistry ,01 natural sciences ,Chemical synthesis ,Catalysis ,Amphidinol 3 ,0104 chemical sciences ,Stereocenter ,chemistry.chemical_compound ,Fragment (logic) ,Pyrans - Abstract
Amphidinol 3 (AM3) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. Although the absolute configuration of AM3 was determined in 1999 by extensive NMR analysis and degradation of the natural product, it was a daunting task because of the presence of numerous stereogenic centers on the acyclic carbon chain and the limited availability from natural sources. Thereafter, revisions of the absolute configurations at C2 and C51 were reported in 2008 and 2013, respectively. Reported herein is the revised absolute configuration of AM3: 32S, 33R, 34S, 35S, 36S, and 38S based on the chemical synthesis of partial structures corresponding to the C31-C67 fragment of AM3 in combination with degradation of the natural product. The revised structure is unique in that both antipodal tetrahydropyran counterparts exist on a single carbon chain. The structural revision of AM3 may affect proposed structures of congeners related to the amphidinols.
- Published
- 2018
14. Synthesis and Complete Structure Determination of a Sperm-Activating and -Attracting Factor Isolated from the Ascidian Ascidia sydneiensis
- Author
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Michio Murata, Ken Sakai, Kosei Yamauchi, Tomohiro Watanabe, Manabu Yoshida, Nobuaki Matsumori, Hiroshi Tsuchikawa, Shu Lin, Tohru Oishi, Masaaki Morisawa, Makoto Ebine, and Hajime Shibata
- Subjects
Male ,Magnetic Resonance Spectroscopy ,Pinacol coupling reaction ,Ketone ,Stereochemistry ,medicine.medical_treatment ,Pharmaceutical Science ,010402 general chemistry ,01 natural sciences ,Analytical Chemistry ,Steroid ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Side chain ,Animals ,Urochordata ,Pharmacology ,chemistry.chemical_classification ,Biological Products ,Natural product ,010405 organic chemistry ,Organic Chemistry ,Absolute configuration ,Diastereomer ,Spermatozoa ,0104 chemical sciences ,Complementary and alternative medicine ,chemistry ,Molecular Medicine ,Steroids ,Stereoselectivity - Abstract
For the complete structure elucidation of an endogenous sperm-activating and -attracting factor isolated from eggs of the ascidian Ascidia sydneiensis ( Assydn-SAAF), its two possible diastereomers with respect to C-25 were synthesized. Starting from ergosterol, the characteristic steroid backbone was constructed by using an intramolecular pinacol coupling reaction and stereoselective reduction of a hydroxy ketone as key steps, and the side chain was introduced by Julia-Kocienski olefination. Comparison of the NMR data of the two diastereomers with those of the natural product led to the elucidation of the absolute configuration as 25 S; thus the complete structure was determined and the first synthesis of Assydn-SAAF was achieved.
- Published
- 2018
15. Convergent Syntheses of the WXYZ Ring of Maitotoxin and the HIJK Ring of Brevisulcenal-F
- Author
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Tohru Oishi, Naoya Osato, Masayuki Satake, Yoshiki Toma, Hisaaki Onoue, Makoto Ebine, and Kohei Torikai
- Subjects
chemistry.chemical_classification ,Maitotoxin ,Ketone ,010405 organic chemistry ,Chemistry ,Dihydropyran ,Stereochemistry ,Acetylide ,chemistry.chemical_element ,Ether ,General Chemistry ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,Aldehyde ,0104 chemical sciences ,chemistry.chemical_compound ,Lithium - Abstract
A convergent method to construct the 6/7/6/6-tetracyclic ether system possessing contiguous angular methyl groups was developed. The key steps of the synthesis involve coupling of a lithium acetylide and an aldehyde, cyclodehydration of a hydroxy ketone to form a dihydropyran, ring expansion of a six-membered ring ketone into a seven-membered one, and methylation of a mixed-thioacetal. Based on this strategy, syntheses of the WXYZ ring of maitotoxin and the HIJK ring of brevisulcenal-F were achieved, and the stereochemistry of the HIJK ring of brevisulcenal-F was confirmed.
- Published
- 2018
16. Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents
- Author
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Kaoru Umehara, Rintaro Koga, Xiaohui Liu, Kenji Watanabe, Kohei Torikai, Yasuyuki Shimohigashi, Hiroshi Noguchi, Tatsuya Kitano, and Tohru Oishi
- Subjects
medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Estrogen receptor ,Antineoplastic Agents ,Pharmacology ,010402 general chemistry ,Binding, Competitive ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,Estrogen-related receptor alpha ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Receptor ,Molecular Biology ,Estrogen receptor beta ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Estrogen Antagonists ,Estrogens ,0104 chemical sciences ,Receptors, Estrogen ,Nuclear receptor ,Estrogen ,Drug Design ,MCF-7 Cells ,Acridines ,Molecular Medicine ,Estrogen-related receptor gamma ,Drug Screening Assays, Antitumor ,Estrogen receptor alpha ,hormones, hormone substitutes, and hormone antagonists ,HeLa Cells - Abstract
Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC50 < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
- Published
- 2017
17. 1-Naphthylmethyl and 1-naphthylmethoxymethyl protecting groups: New members of the benzyl- and benzyloxymethyl-type family
- Author
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Yohei Joh, Tohru Oishi, Kohei Torikai, and Takuya Sato
- Subjects
Strong acids ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Nucleophile ,Hydrogenolysis ,Drug Discovery ,Organic chemistry ,Ceric ammonium nitrate - Abstract
1-Naphthylmethyl (NAPI) and 1-naphthylmethoxymethyl (NAPOMI) protecting groups were developed as new members of the benzyl- and benzyloxymethyl-type family. NAPI and NAPOMI can be introduced under conventional conditions, such as NAPIBr/NaH/room temperature (rt), or NAPOMICl/i-Pr2EtN/rt. They can also be removed under conventional conditions, e.g., by dichlorodicyanobenzoquinone (DDQ)- or ceric ammonium nitrate (CAN)-mediated oxidation, or by hydrogenolysis. The specific advantages of these new protecting groups are: i) a less costly synthesis of NAPOMICl compared to NAPOMIICl, ii) the possibility to remove NAPOMII selectively in the presence of NAPOMI by DDQ-mediated oxidation, and iii) the compatibility with strong acids even in the presence of hard nucleophiles.
- Published
- 2017
18. Flow Synthesis of (3R)- and (3S)-(E)-1-Iodohexa-1,5-dien-3-ol: Chiral Building Blocks for Natural Product Synthesis
- Author
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Tomoyuki Koge, Tohru Oishi, Shuji Akai, Sota Katayama, and Satoko Katsuragi
- Subjects
chemistry.chemical_compound ,Natural product ,Flow (mathematics) ,010405 organic chemistry ,Chemistry ,Organic chemistry ,General Chemistry ,Optically active ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences - Abstract
A concise procedure to prepare optically active (3R)- and (3S)-(E)-1-iodohexa-1,5-dien-3-ol was developed. Ethyl (E)-3-iodoacrylate was converted to racemic (E)-1-iodohexa-1,5-dien-3-ol under flow ...
- Published
- 2018
19. Structure-Activity Relationship Studies of Maitotoxin Based on Chemical Synthesis
- Author
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Tohru Oishi
- Subjects
Maitotoxin ,Hydroboration ,chemistry.chemical_compound ,chemistry ,Aldol reaction ,Stereochemistry ,Intramolecular force ,Achmatowicz reaction ,Structure–activity relationship ,Ring (chemistry) ,Chemical synthesis - Abstract
Structure-activity relationship studies of maitotoxin (MTX), a marine natural product comprised of ladder-shaped polyethers, were examined by using chemically synthesized partial structures of MTX. The WXYZA′B′C′ ring was synthesized in a highly convergent manner based on the convergent method via two-rings construction. The QRS ring was synthesized via Achmatowicz reaction, chemoselective methylation, and ring expansion. The C′D′E′F′ ring was synthesized via Suzuki-Miyaura coupling and Pd(II)-catalyzed 6-exo cyclization. Both enantiomers of the LMNO ring were synthesized via Nozaki-Hiyama-Kishi reaction, intramolecular oxa-Michael addition, and aldol reaction. The NOPQR(S) ring was synthesized via the alkyne-aldehyde coupling of the QR(S) and the NO rings, dehydrative cyclization, and hydroboration. The inhibitory activity of the synthetic specimens against MTX-induced Ca2+ influx was evaluated, and the hydrophobic parts elicited more potent activity than the hydrophilic parts.
- Published
- 2019
20. Synthetic Study of the C’D’E’ Ring System of Maitotoxin via Furan Based Strategy
- Author
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Yoko Yasuno, Tohru Oishi, Yuta Watanabe, and Kohei Torikai
- Subjects
Pharmacology ,Maitotoxin ,chemistry.chemical_compound ,chemistry ,Stereochemistry ,Furan ,Organic Chemistry ,Analytical Chemistry - Published
- 2021
21. Synthesis of a Truncated Analog of Amphidinol 3 Corresponding to the C21–C39/C52–C67 Section
- Author
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Makoto Ebine, Tohru Oishi, Naoto Yanai, and Yuri Takada
- Subjects
Antifungal ,010405 organic chemistry ,Chemistry ,Stereochemistry ,medicine.drug_class ,General Chemistry ,Tetrahydropyran ,010402 general chemistry ,Polyene ,01 natural sciences ,Combinatorial chemistry ,Amphidinol 3 ,0104 chemical sciences ,chemistry.chemical_compound ,medicine - Abstract
As a part of structure–activity relationship studies to elucidate structure requirements for eliciting antifungal activity, an artificial analog of amphidinol 3 (AM3) was designed. A truncated analog corresponding to the C21–C39/C52–C67 section was synthesized by using Suzuki–Miyaura coupling and Julia–Kocienski olefination as key steps. An expeditious and versatile method to construct the C53–C67 polyene section was also developed based on a linchpin strategy via successive cross-coupling reactions. The analog elicited no antifungal activity, suggesting that the two tetrahydropyran rings of AM3 are necessary to elicit antifungal activity.
- Published
- 2017
22. Tuned Classical Thermal Aromatization Furnishing an Estrogenic Benzoacridine
- Author
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Tohru Oishi, Rintaro Koga, and Kohei Torikai
- Subjects
chemistry.chemical_compound ,Chemistry ,Organic Chemistry ,Aromatization ,Biological activity ,Combinatorial chemistry ,Derivative (chemistry) - Abstract
The diversity-oriented doubling strategy, which generates two 12-arylbenzoacridines from a single triarylmethanol precursor was developed to construct a library of drug candidates for the identification of biologically active compounds. Exploration of this 12-arylbenzoacridine library furnished a 4′-OH derivative as an estrogenic compound.
- Published
- 2015
23. Stereoselective Synthesis of the C1–C29 Part of Amphidinol 3
- Author
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Aya Umeda, Takeshi Tsuruda, Tohru Oishi, and Makoto Ebine
- Subjects
chemistry.chemical_classification ,Molecular Structure ,Double bond ,Chemistry ,Stereochemistry ,Acetylide ,Organic Chemistry ,Regioselectivity ,Stereoisomerism ,Alkenes ,Lithium ,Metathesis ,Catalysis ,Stereocenter ,chemistry.chemical_compound ,Dihydroxylation ,Stereoselectivity ,Macrolides ,Pyrans - Abstract
Stereoselective synthesis of the C1-C29 part of amphidinol 3 (AM3) was achieved. The C1-C20 part was assembled from three building blocks via regioselective cross metathesis to form the C4-C5 double bond and addition of an alkenyllithium and a lithium acetylide to two Weinreb amides followed by asymmetric reduction to form the C9-C10 and C14-C15 bonds, respectively. The C21-C29 part was synthesized via successive cross metathesis and oxa-Michael addition sequence to construct the 1,3-diol system at C25 and C27 and Brown asymmetric crotylation to introduce the stereogenic centers at C23 and C24. Coupling of the C1-C20 and C21-C29 parts was achieved by Julia-Kocienski olefination and regio- and stereoselective dihydroxylation of the C20-C21 double bond in the presence of the C4-C5 and C8-C9 double bonds to afford the C1-C29 part of AM3.
- Published
- 2015
24. Axial Hydrogen at C7 Position and Bumpy Tetracyclic Core Markedly Reduce Sterol’s Affinity to Amphotericin B in Membrane
- Author
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Naohiro Matsushita, Yasuo Nakagawa, Ken'ichi Nonomura, Shinya Hanashima, Nobuaki Matsumori, Michio Murata, Tetsuro Takano, Yuichi Umegawa, Tohru Oishi, and Hiroshi Tsuchikawa
- Subjects
Models, Molecular ,Antifungal Agents ,Double bond ,Stereochemistry ,medicine.medical_treatment ,Molecular Conformation ,Antifungal drug ,Biochemistry ,Steroid ,chemistry.chemical_compound ,Alicyclic compound ,Amphotericin B ,polycyclic compounds ,medicine ,Humans ,chemistry.chemical_classification ,Ergosterol ,Cholesterol ,Cell Membrane ,Fungi ,technology, industry, and agriculture ,bacterial infections and mycoses ,Sterol ,Sterols ,Membrane ,Mycoses ,chemistry ,Liposomes ,lipids (amino acids, peptides, and proteins) - Abstract
The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic portion, is largely unknown. Thus, to investigate the mode of interaction between AmB and the sterol core, we assessed the affinity of AmB to various sterols with different alicyclic structures. Ion flux assays and UV spectral measurements clearly revealed the importance of the Δ7-double bond of the sterol B-ring for interaction with the drug. AmB showed lower affinity for triene sterols, which have double bonds at the Δ5, Δ7, and Δ9 positions. Intermolecular distance measurements by (13)C{(19)F} rotational echo double resonance (REDOR) revealed that the AmB macrolide ring is in closer contact with the steroid core of Erg than it is with the Cho core in the membrane. Conformational analysis suggested that an axial hydrogen atom at C7 of Δ5-sterol (2, 6) and the protruded A-ring of Δ5,7,9-sterol (4, 8) sterically hampered face-to-face contact between the van der Waals surface of the sterol core and the macrolide of AmB. These results further suggest that the α-face of sterol alicycle interacts with the flat macrolide structure of AmB.
- Published
- 2015
25. Syntheses and Biological Activities of the LMNO, ent-LMNO, and NOPQR(S) Ring Systems of Maitotoxin
- Author
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Kohei Torikai, Erina Ishikawa, Makoto Ebine, Keiichi Konoki, Hisaaki Onoue, Riho Marubayashi, Michio Murata, and Tohru Oishi
- Subjects
Stereochemistry ,Molecular Conformation ,Alkyne ,010402 general chemistry ,Ring (chemistry) ,Nitric Oxide ,01 natural sciences ,Aldehyde ,chemistry.chemical_compound ,Aldol reaction ,Animals ,Pyrans ,chemistry.chemical_classification ,Maitotoxin ,Aldehydes ,Dose-Response Relationship, Drug ,010405 organic chemistry ,Pummerer rearrangement ,Organic Chemistry ,Oxocins ,Stereoisomerism ,Glioma ,P ring ,Ketones ,0104 chemical sciences ,Rats ,Hydroboration ,chemistry ,Calcium ,Marine Toxins - Abstract
Structure–activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki–Hiyama–Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca2+ influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18%...
- Published
- 2017
26. Design and Synthesis of Artificial Ladder-Shaped Polyethers for Exploring Biological Functions
- Author
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Tohru Oishi
- Subjects
Pharmacology ,Thesaurus (information retrieval) ,Information retrieval ,Chemistry ,Organic Chemistry ,Analytical Chemistry - Published
- 2019
27. Synthesis and Biological Activity of the QRS Ring System of Maitotoxin
- Author
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Tomomi Baba, Kohei Torikai, Tohru Oishi, Hisaaki Onoue, Makoto Ebine, and Keiichi Konoki
- Subjects
Maitotoxin ,QRS complex ,chemistry.chemical_compound ,chemistry ,biology ,Stereochemistry ,Dinoflagellate ,Biological activity ,General Chemistry ,Ring (chemistry) ,biology.organism_classification - Abstract
Maitotoxin (MTX) is a ladder-shaped polyether produced by an epiphytic dinoflagellate. As a part of our structure–activity relationship studies using synthetic partial structures of MTX, the QRS ri...
- Published
- 2014
28. Synthesis and Structure Revision of the C43–C67 Part of Amphidinol 3
- Author
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Yosuke Konno, Michio Murata, Ken Sakai, Mitsunori Kanemoto, Yoshiyuki Manabe, Makoto Ebine, Tohru Oishi, and Nobuaki Matsumori
- Subjects
Magnetic Resonance Spectroscopy ,Molecular Structure ,Stereochemistry ,Organic Chemistry ,Absolute configuration ,Stereoisomerism ,Tetrahydropyran ,Nuclear magnetic resonance spectroscopy ,Alkenes ,Biochemistry ,Nmr data ,Amphidinol 3 ,chemistry.chemical_compound ,chemistry ,Moiety ,Stereoselectivity ,Physical and Theoretical Chemistry ,Oxidation-Reduction ,Pyrans - Abstract
Stereoselective synthesis of the C43-C67 part of amphidinol 3 (AM3) and its C51-epimer was achieved starting from a common intermediate corresponding to the tetrahydropyran moiety of AM3, via asymmetric oxidations and Julia-Kocienski olefination. By comparing NMR data of the synthetic specimens with those of AM3, the absolute configuration at C51 of AM3 was revised from R to S.
- Published
- 2013
29. The Structure of the Bimolecular Complex between Amphotericin B and Ergosterol in Membranes Is Stabilized by Face-to-Face van der Waals Interaction with Their Rigid Cyclic Cores
- Author
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Yasuo Nakagawa, Shinya Hanashima, Tomoya Yamamoto, Tohru Oishi, Naohiro Matsushita, Michio Murata, Yuichi Umegawa, Hiroshi Tsuchikawa, and Nobuaki Matsumori
- Subjects
0301 basic medicine ,Models, Molecular ,Fluorine Radioisotopes ,Antifungal Agents ,Magnetic Resonance Spectroscopy ,Trimethylsilyl ,Stereochemistry ,animal diseases ,Lipid Bilayers ,Molecular Conformation ,010402 general chemistry ,Antiparallel (biochemistry) ,01 natural sciences ,Biochemistry ,Ion Channels ,03 medical and health sciences ,chemistry.chemical_compound ,Streptomyces nodosus ,Amphotericin B ,Ergosterol ,parasitic diseases ,Moiety ,Lipid bilayer ,Carbon Isotopes ,030102 biochemistry & molecular biology ,biology ,urogenital system ,Circular Dichroism ,Cell Membrane ,Provitamins ,technology, industry, and agriculture ,Nuclear magnetic resonance spectroscopy ,bacterial infections and mycoses ,biology.organism_classification ,Polyene ,0104 chemical sciences ,chemistry - Abstract
Amphotericin B (AmB) is a polyene macrolide antibiotic isolated from Streptomyces nodosus. The antifungal activity of AmB can be attributed to the formation of an ion-channel assembly in the presence of ergosterol (Erg), in which there are two different AmB-Erg orientations, parallel and antiparallel, as reported previously. In this study, to elucidate the structures of those AmB-Erg complexes based on solid-state nuclear magnetic resonance, a (19)F-labeled AmB derivative was newly prepared by a hybrid synthesis that utilized degradation products from the drug. Using the 2-(trimethylsilyl)ethoxymethyl (SEM) group as the protecting group for the carboxylic acid moiety of AmB, the fully deprotected labeled AmB compounds were obtained successfully. Then, these labeled AmBs were subjected to (13)C{(19)F} rotational-echo double-resonance (REDOR) experiments in hydrated lipid bilayers. The results indicated the coexistence of parallel and antiparallel orientations for AmB and Erg pairing, at a ratio of 7:3. A total of six distances between AmB and Erg were successfully obtained. Geometry analysis using the distance constraints derived from the REDOR experiments provided the plausible AmB-Erg complex structure for both the parallel and antiparallel interactions. The flat macrolide of AmB and the tetracyclic core of Erg closely contacted in a face-to-face manner, thus maximizing the van der Waals interaction between the two molecules. This interaction can be attributed to the coexistence of both the parallel and antiparallel orientations.
- Published
- 2016
30. Direct interaction between amphotericin B and ergosterol in lipid bilayers as revealed by [super 2]H NMR spectroscopy
- Author
-
Matsumori, Nobuaki, Tahara, Kazuaki, Yamamoto, Hiroko, Morooka, Atsushi, Mototsugu Doi, Tohru Oishi, and Michio Murata
- Subjects
Amphotericin B -- Chemical properties ,Ergosterol -- Chemical properties ,Lipid membranes -- Structure ,Lipid membranes -- Chemical properties ,Nuclear magnetic resonance spectroscopy -- Usage ,Chemistry - Abstract
The NMR spectroscopy technique is employed to analyze the direct interaction taking place between amphotericin B (AmB) and ergosterol in lipid bilayers. The results prove the existence of a direct intermolecular interaction between the two components in the bilayers.
- Published
- 2009
31. Comprehensive Molecular Motion Capture for Sphingomyelin by Site-Specific Deuterium Labeling
- Author
-
Takashi Suzuki, Hiroki Okazaki, Toshiyuki Yamaguchi, Hiroshi Tsuchikawa, Nobuaki Matsumori, Michio Murata, Mototsugu Doi, Tohru Oishi, and Tomokazu Yasuda
- Subjects
Chemistry ,Lipid Bilayers ,Molecular Conformation ,technology, industry, and agriculture ,Quadrupole splitting ,Deuterium ,Biochemistry ,Molecular conformation ,Sphingomyelins ,Motion ,Cholesterol ,Membrane Microdomains ,Nuclear magnetic resonance ,Order (biology) ,Phosphatidylcholines ,Molecular motion ,Biophysics ,Molecule ,lipids (amino acids, peptides, and proteins) ,Sphingomyelin ,Nuclear Magnetic Resonance, Biomolecular ,Lipid raft - Abstract
Lipid rafts have attracted much attention because of their significant functional roles in membrane-associated processes. It is thought that sphingomyelin and cholesterol are essential for forming lipid rafts; however, their motion characteristics are not fully understood despite numerous studies. Here we show accurate local motions encompassing an entire sphingomyelin molecule, which were captured by measuring quadrupole splittings for 19 kinds of site-specifically deuterated sphingomyelins (that is, molecular motion capture of sphingomyelin). The quadrupole splitting profiles, which are distinct from those reported from perdeuterated sphingomyelins or simulation studies, reveal that cholesterol enhances the order in the middle parts of the alkyl chains more efficaciously than at the shallow positions. Comparison with dimyristoylphosphocholine bilayers suggests that cholesterol is deeper in sphingomyelin bilayers, which likely explains the so-called umbrella effect. The experiments also demonstrate that (i) the C2'-C3' bond predominantly takes the gauche conformation, (ii) the net ordering effect of cholesterol in sphingomyelin bilayers is not larger than that in phosphatidylcholine bilayers, (iii) cholesterol has no specific preference for the acyl or sphingosine chain, (iv) the acyl and sphingosine chains seem mismatched by about two methylene lengths, and (v) the motion of the upper regions of sphingomyelin chains is less temperature dependent than that of lower regions probably due to intermolecular hydrogen bond formation among SM molecules. These insights into the atomic-level dynamics of sphingomyelin provide critical clues to understanding the mechanism of raft formation.
- Published
- 2012
32. Convergent Method via ^|^alpha;-Cyano Ethers: A Powerful Strategy for Synthesizing Ladder-Shaped Polyethers
- Author
-
Tohru Oishi
- Subjects
Chemistry ,Organic Chemistry ,Combinatorial chemistry - Published
- 2012
33. Head-to-Tail Interaction between Amphotericin B and Ergosterol Occurs in Hydrated Phospholipid Membrane
- Author
-
Hiroshi Tsuchikawa, Michio Murata, Kazuaki Tahara, Yasuo Nakagawa, Nobuaki Matsumori, Tohru Oishi, and Yuichi Umegawa
- Subjects
Models, Molecular ,Antifungal ,Antifungal Agents ,medicine.drug_class ,Stereochemistry ,Lipid Bilayers ,Phospholipid ,Saccharomyces cerevisiae ,Biochemistry ,chemistry.chemical_compound ,Amphotericin B ,Ergosterol ,polycyclic compounds ,medicine ,Nuclear Magnetic Resonance, Biomolecular ,Phospholipids ,Carbon Isotopes ,Molecular interactions ,Chemistry ,Cell Membrane ,Deuterium Exchange Measurement ,Phosphorus Isotopes ,Water ,biochemical phenomena, metabolism, and nutrition ,Resonance (chemistry) ,Membrane ,Pairing ,Phosphatidylcholines ,lipids (amino acids, peptides, and proteins) ,medicine.drug - Abstract
Amphotericin B (AmB) is thought to exert its antifungal activity by forming an ion-channel assembly in the presence of ergosterol. In the present study we aimed to elucidate the mode of molecular interactions between AmB and ergosterol in hydrated phospholipid bilayers using the rotational echo double resonance (REDOR) spectra. We first performed (13)C{(19)F}REDOR experiments with C14-(19)F-labeled AmB and biosynthetically (13)C-labeled ergosterol and implied that both "head-to-head" and "head-to-tail" orientations occur for AmB-ergosterol interaction in the bilayers. To further confirm the "head-to-tail" pairing, (13)C-labeled ergosterol at the dimethyl terminus (C26/C27) was synthesized and subjected to the REDOR measurements. The spectra unambiguously demonstrated the presence of a "head-to-tail" orientation for AmB-ergosterol pairing. In order to obtain information on the position of the dimethyl terminus of ergosterol in membrane, (13)C{(31)P}REDOR were carried out using the labeled ergosterol and the phosphorus atom of a POPC headgroup. Significant REDOR dephasing was observed at the C26/C27 signal of ergosterol in the presence of AmB, but not in the absence of AmB, clearly indicating that the side-chain terminus of ergosterol in the AmB complex comes close to the bilayer surface.
- Published
- 2011
34. Conformations of Spermine in Adenosine Triphosphate Complex: The Structural Basis for Weak Bimolecular Interactions of Major Cellular Electrolytes
- Author
-
Michio Murata, Tohru Oishi, Tetsuo Demura, Toshiyuki Yamaguchi, Keisuke Maruyoshi, and Nobuaki Matsumori
- Subjects
Conformational change ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Population ,Molecular Conformation ,Catalysis ,Electrolytes ,chemistry.chemical_compound ,Adenosine Triphosphate ,Polyamines ,Moiety ,education ,Conformational isomerism ,education.field_of_study ,Chemistry ,fungi ,Organic Chemistry ,Hydrogen Bonding ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Quaternary Ammonium Compounds ,Spermidine ,Isotope Labeling ,Spermine ,Polyamine ,Adenosine triphosphate - Abstract
Selectively (2)H- and (13)C-labeled spermines (SPM) were efficiently synthesized and analyzed by NMR spectroscopy to determine the spin-spin coupling constants for six conformationally relevant bonds. SPM that is composed of three alkyl moieties, a butanylene, and two propanylene chains undergoes a conformational change when interacting with multivalent anions (e.g., adenosine triphosphate (ATP), ATP-Mg(2+) , and tripolyphosphate). Upon interaction with ATP, the C-C bonds, which affect the distance between the neighboring pairs of ammonium groups (i.e., N1/N5 and N5/N5'), increase the population of gauche rotamers by 17-20% relative to those in the 4 HCl salt of SPM. However, the trend in increments of the gauche conformers for the SPM-ATP complex profoundly differs from that of the spermidine (SPD)-ATP complex. This implies that SPM may preferentially recognize the adenyl group of ATP rather than the tripolyphosphate moiety. This may account for the higher affinity of SPM to ATP-Mg(2+) than with that of SPD, which chiefly interacts with β- and γ-phosphates and is easily replaced by Mg(2+) . These results may provide a clue for the further understanding of the structural basis of polyamine biological functions.
- Published
- 2011
35. Stereoselective Synthesis of the C31−C40/C43−C52 Unit of Amphidinol 3
- Author
-
Tohru Oishi, Mitsunori Kanemoto, and Michio Murata
- Subjects
Chemistry ,Stereochemistry ,Organic Chemistry ,Molecular Conformation ,Enantioselective synthesis ,Stereoisomerism ,Tetrahydropyran ,Alkenes ,Metathesis ,Ring (chemistry) ,Chemical synthesis ,Stereocenter ,chemistry.chemical_compound ,Stereoselectivity ,Sharpless asymmetric dihydroxylation ,Pyrans - Abstract
A concise synthesis of a tetrahydropyran ring system corresponding to the C31-C40 and C43-C52 units of amphidinol 3 is described. Successive chemoselective reactions, i.e., cross-metathesis to differentiate the iodoolefin from the terminal olefin and Sharpless asymmetric dihydroxylation on the resulting E-olefin, resulted in expeditious synthesis of an intermediate that was then cross-coupled to afford an E,E-diene system. Four contiguous stereogenic centers were installed via construction of the tetrahydropyran ring by means of Katsuki-Sharpless asymmetric epoxidation, 6-endo-tet cyclization, and Sharpless asymmetric dihydroxylation.
- Published
- 2009
36. Direct Interaction between Amphotericin B and Ergosterol in Lipid Bilayers As Revealed by 2H NMR Spectroscopy
- Author
-
Tohru Oishi, Atsushi Morooka, Nobuaki Matsumori, Michio Murata, Kazuaki Tahara, Hiroko Yamamoto, and Mototsugu Doi
- Subjects
Antifungal Agents ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Movement ,Lipid Bilayers ,Biochemistry ,Catalysis ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Amphotericin B ,Ergosterol ,polycyclic compounds ,medicine ,Molecule ,Lipid bilayer ,POPC ,Phospholipids ,urogenital system ,technology, industry, and agriculture ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,bacterial infections and mycoses ,NMR spectra database ,Membrane ,chemistry ,Isotope Labeling ,lipids (amino acids, peptides, and proteins) ,medicine.drug - Abstract
Although amphotericin B (AmB) is thought to exert its antifungal activity by forming transmembrane ion-permeable self-assemblies together with ergosterol, no previous study has directly proven AmB-ergosterol interaction. To establish the interaction, we measured (2)H NMR using deuterium-labeled sterols and AmB. The (2)H NMR spectra of deuterated ergosterol in palmitoyloleoylphosphatidylcholine (POPC) bilayers showed that fast axial diffusion of erogosterol was almost completely inhibited by the coexistence of AmB. Conversely, cholesterol mobility in POPC membrane was essentially unchanged with or without AmB. These results unequivocally demonstrate that ergosterol has significant interaction with AmB in POPC bilayers. In addition, we examined the mobility of AmB using deuterium-labeled AmB, and found that, although AmB is almost immobilized in sterol-free and cholesterol-containing POPC membranes, a certain ratio of AmB molecules acquires mobility in the presence of ergosterol. The similar mobility of AmB and ergosterol in POPC bilayers confirmed the idea of the direct intermolecular interaction between ergosterol and AmB.
- Published
- 2009
37. Ion channel complex of antibiotics as viewed by NMR
- Author
-
Yusuke Kasai, Yuichi Umegawa, Naohiro Matsushita, Michio Murata, Hiroshi Tsuchikawa, Nobuaki Matsumori, and Tohru Oishi
- Subjects
Ergosterol ,urogenital system ,Chemistry ,Stereochemistry ,General Chemical Engineering ,technology, industry, and agriculture ,General Chemistry ,bacterial infections and mycoses ,Polyene ,chemistry.chemical_compound ,Ion channel complex ,Solid-state nuclear magnetic resonance ,Covalent bond ,parasitic diseases ,Moiety ,lipids (amino acids, peptides, and proteins) ,Lipid bilayer ,Conjugate - Abstract
Amphotericin B (AmB) exerts its pharmacological effects by forming a barrel-stave assembly in fungal membranes. To examine the interaction between AmB and ergosterol or cholesterol, 13C- and 19F-labeled covalent conjugates were prepared and subjected to solid-state NMR measurements. Using rotor-synchronous double resonance experiments such as REDOR and RDX, we estimated the distance between the fluorine atom and its nearest carbon in the heptaene moiety to be less than 8.6 Å, indicating that the B ring of ergosterol comes close to the AmB polyene moiety. Conformational search of the AmB-ergosterol conjugate using the NMR-derived constraints suggested that ergosterol molecules surround the AmB assembly in contrast to the conventional image where ergosterol is inserted into AmB molecules. AmB-AmB bimolecular interaction was examined by using 13C- and 19F-labeld AmBs in dimyritoylphosphatidylcholine membrane without sterols. 13C-19F dipolar interactions deriving from both head-to-head and head-to-tail orientations were observed in the REDOR experiments. The interactions between AmB and acyl chains of the phospholipid were also detected.
- Published
- 2009
38. Surface plasmon resonance-based detection of ladder-shaped polyethers by inhibition detection method
- Author
-
Kohei Torikai, Yasukatsu Oshima, Nobuaki Matsumori, Michio Murata, Ryota Mouri, Tohru Oishi, and Satoru Ujihara
- Subjects
Clinical Biochemistry ,Mollusk Venoms ,Pharmaceutical Science ,Ether ,Biochemistry ,Ciguatoxins ,chemistry.chemical_compound ,parasitic diseases ,Drug Discovery ,Biotinylation ,Surface plasmon resonance ,Molecular Biology ,Brevetoxin B ,chemistry.chemical_classification ,Chromatography ,Chemistry ,Oxocins ,Organic Chemistry ,Phosphodiesterase ,Surface Plasmon Resonance ,Cyclic Nucleotide Phosphodiesterases, Type 2 ,Enzyme ,Biophysics ,Molecular Medicine ,Marine Toxins ,Yessotoxin ,Quantitative analysis (chemistry) ,Ethers - Abstract
Ladder-shaped polyether (LSP) compounds represented by brevetoxins and ciguatoxins were largely discovered in association with seafood poisoning. Thus, a quick quantification method for LSPs is potentially important. We examined a surface plasmon resonance method using desulfated-yessotoxin (dsYTX) immobilized on a sensor chip and phosphodiesterase PDEII in a inhibition detection mode. Yessotoxin, brevetoxin B and synthetic LSP derivatives showed clear inhibition against PDEII binding to the immobilized dsYTX, by which their half inhibitory concentrations were successfully estimated. This inhibition method appeared to be superior in specificity to direct binding assays where binding proteins to LSP was immobilized on a sensor chip.
- Published
- 2009
39. Conformational Change of Spermidine upon Interaction with Adenosine Triphosphate in Aqueous Solution
- Author
-
Tohru Oishi, Takeshi Sagane, Keisuke Maruyoshi, Tetsuo Demura, Nobuaki Matsumori, Michio Murata, Kaori Nonaka, and Toshiyuki Yamaguchi
- Subjects
Conformational change ,Magnetic Resonance Spectroscopy ,Spermidine ,Stereochemistry ,Molecular Conformation ,Spermine ,Diamines ,Catalysis ,chemistry.chemical_compound ,Adenosine Triphosphate ,Isomerism ,Polyphosphates ,Putrescine ,Carbon Isotopes ,Organic Chemistry ,Water ,Hydrogen Bonding ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Deuterium ,chemistry ,Isotope Labeling ,Proton NMR ,Adenosine triphosphate ,DNA - Abstract
Endogenous polyamines, represented by putrescine, spermidine, and spermine, are known to exert their physiological functions by interacting with polyanionic biomolecules such as DNA, RNA, adenosine triphosphate (ATP), and phospholipids. Very few examples of conformation analysis have been reported for these highly flexible polymethylene compounds, mainly due to the lack of appropriate methodologies. To understand the molecular basis of the weak interaction between polyamines and polyanions that underlies their physiological functions, we aimed to elucidate the solution conformation of spermidine by using diastereospecifically deuterated and (13)C-labeled derivatives (1-7), which were designed to diagnose the orientation of seven conformationally relevant bonds in spermidine. (1)H-(1)H and (13)C-(1)H NMR coupling constants ((3)J(H,H) and (3)J(C,H)) were successfully determined for a spermidine-ATP complex. The relevant coupling constants markedly decreased upon complexation. The results reveal that spermidine, when interacting with ATP, undergoes changes that make the conformation more bent and forms the complex with the triphosphate part of ATP in an orientation-sensitive manner.
- Published
- 2009
40. Design and Synthesis of Ladder-Shaped Polyethers and Evaluation of the Interaction with Transmembrane Proteins
- Author
-
Tohru Oishi, Futoshi Hasegawa, and Kohei Torikai
- Subjects
musculoskeletal diseases ,Maitotoxin ,Stereochemistry ,Organic Chemistry ,Convergent synthesis ,medicine.disease ,Ring (chemistry) ,Hemolysis ,Transmembrane protein ,chemistry.chemical_compound ,chemistry ,medicine ,Side chain ,Molecular probe - Abstract
Ladder–shaped polyether (LSP) toxins are thought to bind to transmembrane (TM) proteins. To elucidate the interactions of LSPs with TM proteins, artificial ladder–shaped polyethers (ALPs) possessing simple iterative structure with different number of rings were synthesized based on the convergent method via α–cyano ethers. The interaction of these ALPs with TM proteins was evaluated, and we found that the difference of activities among the ALPs can be accounted for by the concept of “hydrophobic matching” i. e. lengths of the hydrophobic region including the side chains of ALPs are ca. 25 A, which match the lengths of the hydrophobic region of α–helical TM proteins. The partial structure corresponding to the WXYZA’B’C’ ring system of maitotoxin (MTX) was synthesized based on the convergent method via α–cyano ethers, and we found that hemolysis of human red blood cells induced by MTX was blocked by the fragment. The hydrophobic portion of MTX is expected to be promising molecular probes for identifying the target proteins of MTX.
- Published
- 2009
41. Design, Synthesis, and Biological Evaluation of Fluorinated Analogues of Salicylihalamide
- Author
-
Hiroshi Kanazawa, Tohru Oishi, Yoshinori Sugimoto, Michio Murata, Keiichi Konoki, and Masafumi Matsushita
- Subjects
Vacuolar Proton-Translocating ATPases ,Cell Survival ,Swine ,medicine.drug_class ,Stereochemistry ,Antineoplastic Agents ,Carboxamide ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Chlorocebus aethiops ,Drug Discovery ,medicine ,Animals ,Chromaffin Granules ,Cytotoxicity ,chemistry.chemical_classification ,Natural product ,biology ,Chemistry ,Biological activity ,Bridged Bicyclo Compounds, Heterocyclic ,Small molecule ,Enzyme inhibitor ,Drug Design ,COS Cells ,biology.protein ,Molecular Medicine ,Lactone - Abstract
Salicylihalamide A (SA), a benzolactone enamide compound, possesses potent cytotoxicity against human tumor cell lines. SA is a selective inhibitor of mammalian vacuolar type H(+)-ATPase (V-ATPase), and is distinct from previously known V-ATPase inhibitors such as bafilomycins and concanamycins that do not discriminate between mammalian and nonmammalian V-ATPases. Because of its potent antitumor activity and structural simplicity, SA is a promising candidate for an anticancer drug. Although a number of structure-activity relation studies using synthetic analogues have been reported, no fluorinated derivative of SA has been evaluated even though selective addition of a fluorine atom into a therapeutic small molecule candidate often enhances pharmacokinetic and physicochemical properties. We designed and synthesized fluorinated analogues of SA and evaluated their V-ATPase inhibitory activities. Compared to the natural product, the synthetic analogues were potent V-ATPase inhibitors, suggesting that these analogues are potential drug candidates and potential molecular probes for mode-of-action studies using fluorine-based analytical methods such as (19)F-NMR spectroscopy.
- Published
- 2008
42. Combinatorial Synthesis of the 1,5-Polyol System Based on Cross Metathesis: Structure Revision of Amphidinol 3
- Author
-
Respati T. Swasono, Tohru Oishi, Michio Murata, Mitsunori Kanemoto, and Nobuaki Matsumori
- Subjects
chemistry.chemical_classification ,Magnetic Resonance Spectroscopy ,Polymers ,Stereochemistry ,Chemistry ,Organic Chemistry ,Diastereomer ,Absolute configuration ,Stereoisomerism ,Alkenes ,Metathesis ,Combinatorial synthesis ,Biochemistry ,Combinatorial chemistry ,Amphidinol 3 ,Polyol ,Combinatorial Chemistry Techniques ,Physical and Theoretical Chemistry ,Pyrans - Abstract
Combinatorial synthesis of a 1,5-polyol system corresponding to the C1-C14 unit of amphidinol 3 (AM3) and its diastereomers was achieved via chemoselective cross metathesis as the key step. Comparison of (13)C NMR data of the synthetic specimens with that of AM3 led to a controversy regarding the originally proposed structure. From GC-MS analysis of the degradation product, the absolute configuration at C2 of AM3 has been revised to be R.
- Published
- 2008
43. Valosin-containing protein/p97 interacts with sperm-activating and sperm-attracting factor (SAAF) in the ascidian egg and modulates sperm-attracting activity
- Author
-
Michio Murata, Aru Konno, Tohru Oishi, Manabu Yoshida, Eri Kondoh, and Kazuo Inaba
- Subjects
Male ,Valosin-containing protein ,Protein subunit ,Cell Cycle Proteins ,Biology ,Sperm chemotaxis ,Valosin Containing Protein ,medicine ,Animals ,Ciona intestinalis ,Ovum ,Adenosine Triphosphatases ,Sperm-Ovum Interactions ,Germinal vesicle ,urogenital system ,Endoplasmic reticulum ,Cell Biology ,biology.organism_classification ,Oocyte ,Spermatozoa ,Sperm ,Sperm Transport ,Cell biology ,medicine.anatomical_structure ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Female ,Peptides ,Developmental Biology - Abstract
Sperm chemotaxis toward an egg is observed in many animals, and the control of sperm-attracting activity is thought to play an important role in ensuring fertilization. However, the mechanism underlying the release of a sperm attractant from an egg is still obscure. In this study, we examined the systems involved in the release of sperm-activating and sperm-attracting factor (SAAF), which is the sperm attractant of the ascidian Ciona intestinalis. Here, we show that the egg acquires sperm-attracting activity after germinal vesicle breakdown. Further, since the cytoplasmic extracts of immature oocytes exhibit no sperm-attracting activity, the SAAF in oocytes may be activated after germinal vesicle breakdown. We found 13 SAAF-binding proteins in an egg plasma membrane extract and identified five proteins by proteomic analysis: valosin-containing protein (VCP)/p97, proteasome alpha 2 subunit, MGC97756 protein, proteasome subunit Y, and beta-tubulin. In particular, the interaction between VCP/p97 and SAAF was confirmed by a pull-down assay. VCP/p97 is initially localized in the germinal vesicle, and during oocyte maturation, it shifts to the endoplasmic reticulum in the cortical regions. Thus, VCP/p97 is a potential modulator of SAAF release from the egg.
- Published
- 2008
44. Convergent Synthesis of the A-J Ring System of Yessotoxin
- Author
-
Hiroaki Minato, Tomoyoshi Imaizumi, Koji Watanabe, Michio Murata, Kohei Torikai, and Tohru Oishi
- Subjects
chemistry.chemical_compound ,Ring-closing metathesis ,chemistry ,Stereochemistry ,Organic Chemistry ,Convergent synthesis ,Yessotoxin ,Ring (chemistry) ,Unit (ring theory) - Abstract
A highly convergent synthesis of the A-J ring system of yessotoxin was achieved. A convergent strategy via a-cyano ethers was extensively applied in the assembly of the F and IJ ring frag- ments to afford the FGHIJ ring unit, followed by coupling with the ABC ring unit.
- Published
- 2008
45. Structural Features of Dinoflagellate Toxins Underlying Biological Activity as Viewed by NMR
- Author
-
Tohru Oishi, Michio Murata, Nobuaki Matsumori, and Keiichi Konoki
- Subjects
Maitotoxin ,chemistry.chemical_compound ,biology ,Chemistry ,Stereochemistry ,Dinoflagellate ,Biological activity ,General Chemistry ,biology.organism_classification - Abstract
Marine dinoflagellates are a rich source of structurally and biologically intriguing secondary metabolites. Among those, maitotoxin may be one of the best known examples, which is the largest natur...
- Published
- 2008
46. Amphotericin B covalent dimers with carbonyl-amino linkage: a new probe for investigating ion channel assemblies
- Author
-
Michio Murata, Nobuaki Matsumori, Tohru Oishi, and Yuichi Umegawa
- Subjects
chemistry.chemical_compound ,Stereochemistry ,Chemistry ,Covalent bond ,Dimer ,Organic Chemistry ,Drug Discovery ,Molecule ,Biochemistry ,Linker ,Ion channel ,Ion - Abstract
Based on an amphotericin B (AmB) ion-channel model where the close proximity of neighboring molecules is effected by interaction between carboxyl and amino groups, we prepared covalent dimers of AmB connected between these functionalities. While directly connected and short-tethered derivatives (2 and 3) lacked the activities, dimer 4 with a longer linker revealed K+ ion flux activity, suggesting that some distance and/or flexibility between the carboxyl and amino groups in adjacent molecules is required for the formation of ion-permeable complex in biomembranes.
- Published
- 2007
47. 2-Naphthylmethoxymethyl as a Mildly Introducible and Oxidatively Removable Benzyloxymethyl-Type Protecting Group
- Author
-
Kohei Torikai, Tohru Oishi, and Takuya Sato
- Subjects
Nap ,Group (periodic table) ,Chemistry ,Organic Chemistry ,medicine ,Organic chemistry ,Physical and Theoretical Chemistry ,Protecting group ,Biochemistry ,Chloride ,medicine.drug - Abstract
2-Naphthylmethoxymethyl (NAPOM) was developed for the protection of various hydroxy (including phenolic hydroxy and carboxy) and mercapto groups. The NAPOM group can be introduced in extremely mild conditions (naphthylmethoxymethyl chloride, 2,6-lutidine, room temperature) without concomitant acyl migration in a 1,2-diol system. Furthermore, selective removal of NAPOM in the presence of naphthylmethyl (NAP) and p-methoxybenzyl (PMB) groups and, conversely, that of PMB in the presence of NAPOM were realized. These results, as well as its easy handling and compatibility with various solvents, show that NAPOM is a novel and useful choice as a protecting group.
- Published
- 2015
48. Synthesis of 28-19F-amphotericin B methyl ester
- Author
-
Naohiro Matsushita, Tohru Oishi, Nobuaki Matsumori, Hiroshi Tsuchikawa, and Michio Murata
- Subjects
Natural product ,Stereochemistry ,Organic Chemistry ,chemistry.chemical_element ,bacterial infections and mycoses ,Polyene ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,chemistry ,Amphotericin B methyl ester ,Amphotericin B ,Drug Discovery ,medicine ,Fluorine ,Moiety ,Derivative (chemistry) ,medicine.drug - Abstract
A fluorinated amphotericin B (AmB) derivative, 28-19F-AmB methyl ester (3), labeled at the polyene moiety, was synthesized by combining chemical synthesis with degradation of a natural product via cross-coupling reactions and macrolactonization. The fluorinated derivative 3 showed antifungal activity similar to that of AmB, and is expected to be a powerful tool for NMR-based investigation of the mechanism of ion-channel formation.
- Published
- 2006
49. Synthesis of the ABC and IJ ring fragments of yessotoxin
- Author
-
Miho Suzuki, Tohru Oishi, Koji Watanabe, and Michio Murata
- Subjects
Sharpless epoxidation ,Chemistry ,Stereochemistry ,Organic Chemistry ,2-lithiofuran ,Epoxide ,Ether ,Ring (chemistry) ,Biochemistry ,chemistry.chemical_compound ,Intramolecular force ,Drug Discovery ,Yessotoxin ,Trifluoromethanesulfonate - Abstract
Synthesis of a 6/6/6 tricyclic ether system (3) corresponding to the ABC ring fragment of yessotoxin (1) has been achieved via coupling of a triflate and a 2-lithiofuran followed by intramolecular hetero-Michael addition. The IJ ring fragment (4) of 1 was readily synthesized via successive Sharpless epoxidation and 6-endo cyclization of the resulting vinyl epoxide.
- Published
- 2006
50. 1,2-trans Glycosylation via Neighboring Group Participation of 2‑O‑Alkoxymethyl Groups: Application to One-Pot Oligosaccharide Synthesis.
- Author
-
Karak, Milandip, Yohei Joh, Suenaga, Masahiko, Tohru Oishi, and Kohei Torikai
- Published
- 2019
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