Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Tohru Oishi Last modified date:2019.06.22

Professor / Organic Chemistry Group / Department of Chemistry / Faculty of Sciences


Papers
1. Makoto Ebine, Yuri Takada, Naoto Yanai, Tohru Oishi, Synthesis of a truncated analog of amphidinol 3 corresponding to the C21C39/C52C67 section, Chemistry Letters, 10.1246/cl.170050, 46, 5, 662-664, 2017.01, As a part of structureactivity 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 C21C39/C52C67 section was synthesized by using SuzukiMiyaura coupling and JuliaKocienski olefination as key steps. An expeditious and versatile method to construct the C53C67 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..
2. Tomoyuki Koge, Yuma Wakamiya, Makoto Ebine, Tohru Oishi, Synthesis of an analog of amphidinol 3 corresponding to the c31-c67 section, Heterocycles, 10.3987/COM-18-13927, 96, 7, 1197-1202, 2018.01, An artificial analog corresponding to the C31-C67 section of amphidinol 3 (AM3) was designed as a part of the structure-activity relationship studies to elucidate structure requirements for eliciting antifungal activity. To reduce the number of synthetic steps, the 43-deoxy-51-epi derivative containing common tetrahydropyran ring system was designed and synthesized from a pivotal intermediate in 17 steps. The analog elicited no antifungal activity, suggesting that not only the two tetrahydropyran rings, but also polyol section of AM3 are necessary to elicit antifungal activity..
3. Hiroki Yamamoto, Kohei Torikai, Makoto Ebine, Tohru Oishi, Synthesis of 6/6/6-tricyclic ether system via Achmatowicz and intramolecular oxa-michael reactions, Heterocycles, 10.3987/COM-17-S(T)10, 97, 1, 158-162, 2018.01, Synthesis of 6/6/6-tricyclic ethers possessing 1,3-diaxial methyl groups was examined via Achmatowicz reaction and intramolecular oxa-Michael reaction. A key precursor was prepared via coupling of an aldehyde with a furyllithium derivative followed by radical deoxygenation of the resulting secondary alcohol. The intramolecular oxa-Michael reaction proceeded in a stereoselective manner to afford cis-fused product as a single isomer..
4. Sota Katayama, Tomoyuki Koge, Satoko Katsuragi, Shuji Akai, Tohru Oishi, Flow synthesis of (3R)- and (3S)-(E)-1-iodohexa-1,5-dien-3-ol
Chiral building blocks for natural product synthesis, Chemistry Letters, 10.1246/cl.180475, 47, 9, 1116-1118, 2018.01, 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 and batch conditions via successive half reduction followed by Grignard reaction. Kinetic resolution of the racemic alcohol was achieved under flow conditions by using lipase packed in a column to afford (3S)-(E)-1-iodohexa-1,5-dien-3-ol and corresponding (3R)-acetate. Removal of the acetyl group was also carried out under flow conditions by using ion exchange resin packed in a column and (3R)-(E)-1-iodohexa-1,5-dien-3-ol was obtained after simple evaporation of the eluent..
5. Naoya Osato, Hisaaki Onoue, Yoshiki Toma, Kohei Torikai, Makoto Ebine, Masayuki Satake, Tohru Oishi, Convergent syntheses of the WXYZ ring of maitotoxin and the HIJK ring of brevisulcenal-F, Chemistry Letters, 10.1246/cl.171056, 47, 3, 265-268, 2018.01, 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..
6. Hiroshi Tsuchikawa, Yuichi Umegawa, Michio Murata, Tohru Oishi, A synthetic approach to the channel complex structure of antibiotic in a membrane
Backbone
19
F-labeled amphotericin B for solidstate NMR analysis, Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry, 10.5059/yukigoseikyokaishi.76.1197, 76, 11, 1197-1205, 2018.01, Over 40 years have passed since a well-known hypothesis of a channel-like amphotericin B (AmB) assembly with ergosterol (Erg) was proposed as the mode of action accounting for its selective fungal toxicity. However, no reliable or direct experimental evidence had been obtained until recently mainly because of significant difficulties in structural analysis of the self-assembly of small molecules specifically formed inside a membrane. In this study, we describe the accomplishments in the chemical synthesis of two AmB derivatives with fluorine labeling in the molecular skeleton for applying solid-state NMR techniques. The interatomic distance measurements using these chemically prepared probes have successfully shown the detailed AmB-Erg bimolecular interaction in the channel structure for the first time. The latest solid-state NMR analysis backed by synthetic chemistry is expected to achieve a breakthrough in elucidating the long-unsolved AmB channel architecture..
7. Tomohiro Watanabe, Hajime Shibata, Makoto Ebine, Hiroshi Tsuchikawa, Nobuaki Matsumori, Michio Murata, Manabu Yoshida, Masaaki Morisawa, Shu Lin, Kosei Yamauchi, Ken Sakai, Tohru Oishi, Synthesis and complete structure determination of a sperm-activating and -attracting factor isolated from the ascidian ascidia sydneiensis, Journal of Natural Products, 10.1021/acs.jnatprod.7b01052, 81, 4, 985-997, 2018.04, 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 25S; thus the complete structure was determined and the first synthesis of Assydn-SAAF was achieved..
8. Yuma Wakamiya, Makoto Ebine, Mariko Murayama, Hiroyuki Omizu, Nobuaki Matsumori, Michio Murata, Tohru Oishi, Synthesis and Stereochemical Revision of the C31–C67 Fragment of Amphidinol 3, Angewandte Chemie - International Edition, 10.1002/anie.201712167, 57, 21, 6060-6064, 2018.05, 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..
9. Milandip Karak, Tohru Oishi, Kohei Torikai, Synthesis of anti-tubercular marine alkaloids denigrins A and B, Tetrahedron Letters, 10.1016/j.tetlet.2018.06.013, 59, 29, 2800-2803, 2018.07, 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..
10. Milandip Karak, Yohei Joh, Masahiko Suenaga, Tohru Oishi, Kohei Torikai, 1,2- trans Glycosylation via Neighboring Group Participation of 2- O-Alkoxymethyl Groups
Application to One-Pot Oligosaccharide Synthesis, Organic Letters, 10.1021/acs.orglett.9b00220, 2019.01, 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..
11. Takuya Sato, Yohei Joh, Tohru Oishi, Kohei Torikai, 1-Naphthylmethyl and 1-naphthylmethoxymethyl protecting groups
New members of the benzyl- and benzyloxymethyl-type family, Tetrahedron Letters, 10.1016/j.tetlet.2017.04.046, 58, 23, 2178-2181, 2017.01, 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..
12. Kohei Torikai, Rintaro Koga, Xiaohui Liu, Kaoru Umehara, Tatsuya Kitano, Kenji Watanabe, Tohru Oishi, Hiroshi Noguchi, Yasuyuki Shimohigashi, Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents, Bioorganic and Medicinal Chemistry, 10.1016/j.bmc.2017.07.067, 25, 20, 5216-5237, 2017.01, 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)..
13. Hisaaki Onoue, Riho Marubayashi, Erina Ishikawa, Keiichi Konoki, Kohei Torikai, Makoto Ebine, Michio Murata, Tohru Oishi, Syntheses and Biological Activities of the LMNO, ent-LMNO, and NOPQR(S) Ring Systems of Maitotoxin, Journal of Organic Chemistry, 10.1021/acs.joc.7b01658, 82, 18, 9595-9618, 2017.01, 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% inhibition, respectively, at 300 μM, whereas the NOPQR(S) ring system elicited no inhibitory activity..
14. Yasuo Nakagawa, Yuichi Umegawa, Naohiro Matsushita, Tomoya Yamamoto, Hiroshi Tsuchikawa, Shinya Hanashima, Tohru Oishi, Nobuaki Matsumori, Michio Murata, 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, Biochemistry, 10.1021/acs.biochem.6b00193, 55, 24, 3392-3402, 2016.06, 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 19F-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 13C{19F} 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..
15. Rintaro Koga, Tohru Oishi, Kohei Torikai, Tuned Classical Thermal Aromatization Furnishing an Estrogenic Benzoacridine, Synlett, 10.1055/s-0035-1560521 , 26, 20, 2801-2805, 2015.12, 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 biol. active compds. Exploration of this 12-​arylbenzoacridine library furnished a 4'-​OH deriv. as an estrogenic compd..
16. Takuya Sato, Tohru Oishi, Torikai, K., 2-​Naphthylmethoxymethyl as a Mildly Introducible and Oxidatively Removable Benzyloxymethyl-​Type Protecting Group, Org. Lett., 10.1021/acs.orglett.5b01408, 17, 12, 3110-3113, 2015.06, The 2-​naphthylmethoxymethyl (NAPOM) group was developed as a protecting group for alcs., phenols, carboxylic acids, and thiols. The NAPOM group can be introduced in extremely mild conditions using 2-​naphthylmethoxymethyl chloride either with diisopropylethylamine as a base or with 2,​6-​lutidine as a base in the presence of tetrabutylammonium iodide at room temp.; under the latter conditions, a monoacetylated diol was protected with minimal concomitant acyl migration. Selective removal of the NAPOM protecting group in the presence of 2-​naphthylmethyl and p-​methoxybenzyl (PMB) groups and, conversely, selective removal of a PMB group in the presence of a NAPOM group were realized. The solvent compatibility of the installation and removal of the NAPOM group was studied; most solvents were compatible with its installation, while deprotections in THF and DMF gave product in reduced yields..
17. Takeshi Tsuruda, Makoto Ebine, Aya Umeda, Tohru Oishi, Stereoselective Synthesis of the C1-C29 Part of Amphidinol 3., J. Org. Chem., 10.1021/jo502322m, 80, 2, 859–871, 2015.01, 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..
18. Yasuo Nakagawa, Yuichi Umegawa, Kenichi Nonomura, Naohiro Matsushita, Tetsuro Takano, Hiroshi Tsuchika, Shinya Hanashima, Tohru Oishi, Nobuaki Matsumori, Michio Murata, Axial Hydrogen at C7 Position and Bumpy Tetracyclic Core Markedly Reduce Sterol's Affinity to Amphotericin B in Membrane, Biochemistry, 10.1021/bi5012942, 54, 2, 303–312, 2015.01, 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 13C{19F} 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..
19. Yasuo Nakagawa, Yuichi Umegawa, Kenichi Nonomura, Naohiro Matsushita, Tetsuro Takano, Hiroshi Tsuchika, Shinya Hanashima, Tohru Oishi, Nobuaki Matsumori, Michio Murata, Axial Hydrogen at C7 Position and Bumpy Tetracyclic Core Markedly Reduce Sterol's Affinity to Amphotericin B in Membrane., Biochemistry, 10.1021/bi3009399, 51, 42, 8363–8370, 2014.12, Lipid rafts have attracted much attention because of their significant functional roles in membrane-​assocd. 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 the authors show accurate local motions encompassing an entire sphingomyelin mol., which were captured by measuring quadrupole splittings for 19 kinds of site-​specifically deuterated sphingomyelins (i.e., mol. 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. Also (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 temp. dependent than that of lower regions probably due to intermol. hydrogen bond formation among SM mols. These insights into the at.-​level dynamics of sphingomyelin provide crit. clues to understanding the mechanism of raft formation. .
20. Hisaaki Onoue, Tomomi Baba, Keiichi Konoki, Kohei TORIKAI, Makoto EBINE, Tohru Oishi, Synthesis and Biological Activity of the QRS Ring System of Maitotoxin. , Chem. Lett., 10.1246/cl.140789, 43, 12, 1904-1906, 2014.09, 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 ring comprised of a 6/6/7 tricyclic system was synthesized through stereoselective construction of the five contiguous stereogenic centers on the Q ring via i) coupling of a Weinreb amide and a furyllithium, followed by ii) Noyori asymmetric transfer hydrogenation, iii) Achmatowicz reaction, iv) chemoselective methylation of a methyl acetal in the presence of a carbonyl group by treatment with Me2Zn/BF3·OEt2, v) highly diastereoselective dihydroxylation, and vi) ring expansion of a six-membered to a seven-membered ring ketone. The synthetic specimen inhibited MTX-induced Ca2+ influx with an IC50 value of 44 microM..
21. Masahiro Kunitake, Takahiro Oshima, Keiichi Konoki, Michio Murata, Tohru Oishi, Synthesis and Biological Activity of the C’D’E’F’ Ring System of Maitotoxin. , J. Org. Chem. , 10.1021/jo5005235, 79, 11, 4948-4962, 2014.03, Stereoselective synthesis of the C’D’E’F’ ring system of maitotoxin was achieved starting from the E’ ring through successive formation of the D’ and C’ rings based on SmI2-mediated reductive cyclization. Construction of the F’ ring was accomplished via Suzuki-Miyaura cross coupling with a side chain fragment and Pd(II)-catalyzed cyclization of an allylic alcohol. The C’D’E’F’ ring system inhibited MTX-induced Ca2+ influx in rat glioma C6 cells with an IC50 value of 59 microM.
22. Kazuki Kajitani, Tomomi KOSHIYAMA, Akihiro Hori, Ryo Ohtani, Akio Mishima, Kohei TORIKAI, Makoto EBINE, Tohru Oishi, Susumu Kitagawa, Masaaki OHBA, Guest responsivity of a two−dimensional coordination polymer incorporating a cholesterol−based co−ligand. , Dalton Trans. 2013,, 10.1039/C3DT51465J, 42, 31, 15893−15897, 2013.07, To implement specific guest responsivity, a hydrophobic cholesterol-based co-ligand, cholest-5-en-3-yl-4-isonicotinate (Cholpy), was incorporated into a two-dimensional Hofmann-type Co(II)Ni(II) coordination polymer. The chemically programmed structure successfully demonstrated the unique guest response with remarkable chromatic changes..
23. Ebine, Makoto; Kanemoto, Mitsunori; Manabe, Yoshiyuki; Konno, Yosuke; Sakai, Ken; Matsumori, Nobuaki; Murata, Michio; Oishi, Tohru , Synthesis and Structure Revision of the C43-​C67 Part of Amphidinol 3, Organic Letters , 10.1021/ol401176a, 15, 11, 2846-2849, 2013.05, Stereoselective synthesis of the C43-​C67 part of amphidinol 3 (AM3) and its C51-​epimer, I (R1 = OH, R2 = H; R1 = H, R2 = OH)​, was achieved starting from a common intermediate corresponding to the tetrahydropyran moiety of AM3, via asym. oxidns. and Julia-​Kocienski olefination. By comparing NMR data of the synthetic specimens with those of AM3, the abs. configuration at C51 of AM3 was revised from R to S. .
24. Matsumori, Nobuaki; Hiradate, Yuki; Shibata, Hajime; Oishi, Tohru; Shimma, Shuichi; Toyoda, Michisato; Hayashi, Fumiaki; Yoshida, Manabu; Murata, Michio; Morisawa, Masaaki , A Novel Sperm-​Activating and Attracting Factor from the Ascidian Ascidia sydneiensis, Organic Letters , 10.1021/ol303172n, 15, 2, 294-297, 2013.01, A novel SAAF was isolated from the title ascidian. The structure was elucidated using the entire sample of 4 nmol, suggesting that the position of the OH group confers genus-​specificity to sperm chemotaxis in ascidians. This study not only provides insight into the chem. tactics in sperm chemotaxis but demonstrates that the innovative techniques allow structure detn. of natural products in trace amts. .
25. Yoshiyuki Manabe, Makoto EBINE, Nobuaki Matsumori, Michio Murata, Tohru Oishi, Confirmation of the Absolute Configuration at C45 of Amphidinol 3. , J. Nat. Prod. , 10.1021/np300604w, 75, 11, 303–312, 2012.11, Amphidinol 3 (AM3), a membrane-active agent isolated from the dinoflagellate Amphidinium klebsii, consists of a long carbon chain containing twenty five stereogenic centers. Although the absolute configuration of AM3 was determined by extensive NMR analysis and degradation of the natural product, the partial structure corresponding to the tetrahydropyran ring system was found to be antipodal to that of karlotoxin 2, a structurally related compound recently isolated from the dinoflagellate Karlodinium veneficum. By extensive degradation of the natural product and conversion of the resulting alcohol to an MTPA ester, the absolute configuration at C45 of AM3 was confirmed to be R, supporting the originally proposed structure..
26. Nobuaki Matsumori, Tomokazu Yasuda, Hiroki Okazaki, Takashi Suzuki, Toshiyuki Yamaguchi, Tetsuro Takano, Hiroshi Tsuchika, Mototsugu Doi, Tohru Oishi, Michio Murata, Comprehensive Molecular Motion Capture for Sphingomyelin by Site−Specific Deuterium Labeling. , Biochemistry, 10.1021/bi3009399, 51, 42, 8363–8370, 2012.09, Lipid rafts have attracted much attention because of their significant functional roles in membrane-​assocd. 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 the authors show accurate local motions encompassing an entire sphingomyelin mol., which were captured by measuring quadrupole splittings for 19 kinds of site-​specifically deuterated sphingomyelins (i.e., mol. 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. Also (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 temp. dependent than that of lower regions probably due to intermol. hydrogen bond formation among SM mols. These insights into the at.-​level dynamics of sphingomyelin provide crit. clues to understanding the mechanism of raft formation. .
27. Tohru Oishi, Keiichi Konoki, Masahiro Kunitake, Rie Tamate, Kohei TORIKAI, Futoshi Hasegawa, Nobuaki Matsumori, Michio Murata, Artificial ladder−shaped polyethers that inhibit maitotoxin−induced Ca2+ influx in rat glioma C6 cells. , Bioorg. Med. Chem. Lett., 10.1016/j.bmcl.2012.04.053, 22, 11, 3619−3622, 2012.06, Maitotoxin (MTX) is a ladder-​shaped polyether produced by the epiphytic dinoflagellate Gambierdiscus toxicus. It is known to elicit potent toxicity against mammals and induce influx of Ca2+ into cells. An artificial ladder-​shaped polyether possessing a 6​/7​/6​/6​/7​/6​/6 heptacyclic ring system, which was designed for elucidating interactions with transmembrane proteins, was found to be the most potent inhibitor against MTX-​induced Ca2+ influx that has ever been reported. .
28. Toshiyuki Yamaguchi, Takashi Suzuki, Tomokazu Yasuda, Tohru Oishi, Nobuaki Matsumori, Michio Murata, NMR−based conformational analysis of sphingomyelin in bicelles. , Bioorg. Med. Chem. , 10.1016/j.bmc.2011.11.001, 20, 1, 270−278, 2012.01, Sphingomyelin (SM) is a common sphingolipid in mammalian membranes and is known to be substantially involved in cellular events such as the formation of lipid rafts. Despite its biol. significance, conformation of SM in a membrane environment remains unclear because the noncryst. property and anisotropic environment of lipid bilayers hampers the application of x-​ray crystallog. and NMR measurements. In this study, to elucidate the conformation of SM in membranes, the authors utilized bicelles as a substitute for a lipid bilayer membrane. First, the authors demonstrated through 31P NMR, 2H NMR, and dynamic light scattering expts. that SM forms both oriented and isotropic bicelles by changing the ratio of SM​/dihexanoyl phosphatidylcholine. Then, the authors detd. the conformation of SM in isotropic bicelles on the basis of coupling consts. and NOE correlations in 1H NMR and found that the C2-​C6 and amide groups of SM take a relatively rigid conformation in bicelles. .
29. Yuichi Umegawa, Yasuo Nakagawa, Kazuaki Tahara, Hiroshi Tsuchika, Nobuaki Matsumori, Tohru Oishi, Michio Murata, Head−to−Tail Interaction between Amphotericin B and Ergosterol Occurs in Hydrated Phospholipid Membrane. , Biochemistry , 10.1021/bi2012542, 51, 1, 83−89, 2011.11, 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 mol. interactions between AmB and ergosterol in hydrated phospholipid bilayers using the rotational echo double resonance (REDOR) spectra. We first performed 13C{19F}​REDOR expts. with C14-​19F-​labeled AmB and biosynthetically 13C-​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, 13C-​labeled ergosterol at the di-​Me 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 di-​Me terminus of ergosterol in membrane, 13C{31P}​REDOR were carried out using the labeled ergosterol and the phosphorus atom of a POPC headgroup. Significant REDOR dephasing was obsd. 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. .
30. Nobuaki Matsumori, Norio Tanada, Kohei Nozu, Hiroki Okazaki, Tohru Oishi, Michio Murata , Design and Synthesis of Sphingomyelin-Cholesterol Conjugates and Their Formation of Ordered Membranes, Chemistry--A European Journal , 10.1002/chem.201100849, 17, 31, 8568-8575, 2011.07, A lipid raft is a cholesterol (Chol)-rich microdomain floating in a sea of lipid bilayers. Although Chol is thought to interact preferentially with sphingolipids such as sphingomyelin (SM), rather than with glycerophospholipids, the origin of the specific interaction has remained unresolved, primarily because of the high mobility of lipid mols. and weak intermol. interactions. In this study, we synthesized SM-Chol conjugates with functionally designed linker portions to restrain Chol mobility and examd. their formation of ordered membranes by a detergent insoly. assay, fluorescence anisotropy expts., and fluorescence-quenching assay. In all of the tests, membranes prepd. from the conjugates showed properties of ordered domains comparable to a SM-Chol (1:1) membrane. To gain insight into the structure of bilayers composed from the conjugates, we performed mol. dynamics simulations with 64 mols. of the conjugates, which suggested that the conjugates form a stable bilayer structure by bending at the linker portion and, mostly, reproduce the hydrogen bonds between the SM and Chol portions. These results imply that the mol. recognition between SM and Chol in an ordered domain is essentially reproduced by the conjugated mols. and, thus, demonstrates that these conjugate mols. could potentially serve as mol. probes for understanding mol. recognition in lipid rafts.

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31. Keisuke Maruyoshi, Toshiyuki Yamaguchi, Tetsuo Demura, Nobuaki Matsumori, Tohru Oishi, Michio Murata , Conformations of spermine in adenosine triphosphate complex: The structural basis for weak bimolecular interactions of major cellular electrolytes
, Chemistry--A European Journal , 10.1002/chem.201002759, 17, 17, 4788-4795, 2011.03, Selectively 2H- and 13C-labeled spermines (SPM) were efficiently synthesized and analyzed by NMR spectroscopy to det. the spin-spin coupling consts. for 6 conformationally relevant bonds. SPM that is composed of 3 alkyl moieties, a butanylene, and 2 propanylene chains underwent a conformational change when interacting with multivalent anions (e.g., ATP, ATP-Mg2+, and tripolyphosphate). Upon interaction with ATP, the C-C bonds, which affect the distance between the neighboring pairs of NH4+ groups (i.e., N1/N5 and N5/N5'), increased 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 differed from that of the spermidine (SPD)-ATP complex. This implied that SPM may preferentially recognize the adenylyl group of ATP rather than the tripolyphosphate moiety. This may account for the higher affinity of SPM to ATP-Mg2+ than with that of SPD, which chiefly interacts with β- and γ-phosphates and is easily replaced by Mg2+. These results may provide a clue for the further understanding of the structural basis of polyamine biol. functions. .
32. Respati T. Swasono, Mitsunori Kanemoto, Nobuaki Matsumori, Tohru Oishi, Michio Murata , Structural reevaluations of amphidinol 3, a potent antifungal compound from dinoflagellate
, Heterocycles , 10.3987/COM-10-S(E)86, 82, 2, 1359-1369, 2011.01, Among other homologues, amphidinol 3 (AM3) is the most potent antifungal compd. isolated from the dinoflagellate Amphidinium klebsii. AM3 undergoes conformational changes in org. solvents while it takes relatively fixed configuration in a membrane model. By using NMR data of peracetyl AM3, we were able to confirm the configuration of C50-C51 of AM3 which remained uncertain in our previous study. .
33. Yusuke Kasai, Nobuaki Matsumori, Hiroyuki Ueno, Kenichi Nonomura, Shinya Yano, Murata Michio, Tohru Oishi , Synthesis of 6-F-ergosterol and its influence on membrane-permeabilization of amphotericin B and amphidinol 3, Organic & Biomolecular Chemistry , 10.1039/c0ob00685h, 9, 5, 1437-1442, 2011.01, Two well-known antifungals, amphotericin B (AmB) and amphidinol 3 (AM3), are thought to exert antifungal activity by forming ion-permeable channels or pores together with sterol mols. However, detailed mol. recognitions for AmB-sterol and AM3-sterol in lipid bilayers have yet to be detd. Toward 19F NMR-based investigation of the mol. recognition underlying their potent antifungal activity, we synthesized 6-fluoro-ergosterol I in five steps via ring opening of (5α,6α)-epoxide of ergosterol acetate using a novel combination of TiF4 and n-Bu4N+Ph3SiF2-. Then we evaluated its activity of promoting pore formation of AmB and AM3, and found that pore formation of AmB was barely promoted by 6-F-ergosterol in clear contrast to the dramatic promotion effect of unmodified ergosterol, whereas AM3 activity was markedly enhanced in the presence of 6-F-ergosterol, which was comparable to that of unmodified ergosterol. These results indicate that the introduction of an F atom at C6 position of ergosterol plays an inhibitory role in interacting with AmB, but it is not the case with AM3..
34. Respati Swasono, Ryota Mouri, Nagy Morsy, Nobuaki Matsumori, Tohru Oishi, Michio Murata, Sterol Effect on Interaction between Amphidinol 3 and Liposomal Membrane as Evidenced by Surface Plasmon Resonance., Bioorg. Med. Chem. Lett., 1016/j.bmcl.2010.02.025, 20, 7, 2215-2218, 2010.04, The affinity of amphidinol 3 (AM3) to phospholipid membranes in the presence and absence of sterol was examd. by surface plasmon resonance (SPR) expts. The results showed that AM3 has 1000 and 5300 times higher affinity for cholesterol- and ergosterol-​contg. liposomes, resp., than those without sterol. The two-​state reaction model well reproduced the sensor grams, which indicated that the interaction is composed of two steps, which correspond to binding to the membrane and internalization to form stable complexes. .
35. Respati Swasono, Ryota Mouri, Nagy Morsy, Nobuaki Matsumori, Tohru Oishi, Michio Murata, Sterol Effect on Interaction between Amphidinol 3 and Liposomal Membrane as Evidenced by Surface Plasmon Resonance., Bioorg. Med. Chem. Lett., 10.1016/j.bmcl.2010.02.025, 20, 2215-2218, 2010.01.
36. Satoru Ujihara, Tohru Oishi, Ryota Mouri, Rie Tamate, Keiichi Konoki, Nobuaki Matsumori, Michio Murata, Yasukatsu Oshima, Naoyuki Sugiyama, Masaru Tomita, Yasushi Ishihama, Detection of Rap1A as a yessotoxin binding protein from blood cell membranes., Bioorg. Med. Chem. Lett., 10.1016/j.bmcl.2010.09.080, 20, 6443-6446, 2010.01.
37. Tohru Oishi, Kouichiro Ootou, Hajime Shibata, Michio Murata, Second-Generation Synthesis of Endogenous Sperm-Activating and Attracting Factor (SAAF) Isolated from the Ascidian Ciona intestinalis., Tetrahedron Lett., 10.1016/j.tetlet.2010.03.011, 51, 2600-2602, 2010.01.
38. Tohru Oishi, Tomoyoshi Imaizumi, Michio Murata, Reductive Etherification under Microfluidic Conditions: Application to Practical Synthesis of the FGHIJ-Ring System of Yessotoxin., Chem. Lett., 10.1246/cl.2010.108, 39, 2, 108-109, 2010.01.
39. Keiichi Konoki, Masaki Hashimoto, Kaori Honda, Kazuo Tachibana, Rie Tamate, Futoshi Hasegawa, Tohru Oishi, Michio Murata, Maitotoxin-Photoactive Probe Binds to Membrane Proteins in Blood Cells., Heterocycles, 79, 1007-1017, 2009.01.
40. Keisuke Maruyoshi, Kaori Nonaka, Takeshi Sagane, Tetsuo Demura, Toshiyuki Yamaguchi, Nobuaki Matsumori, Tohru Oishi, Michio Murata, Conformational Change of Spermidine upon Interaction with Adenosine Triphosphate in Aqueous Solution., Chem. Eur. J., 15, 1618-1626, 2009.01.
41. Michio Murata, Yusuke Kasai, Yuichi Umegawa, Naohiro Matsushita, Hiroshi Tsuchikawa, Nobuaki Matsumori, Tohru Oishi, Ion Channel Complex of Antibiotics as Viewed by NMR., Pure Appl. Chem., 81, 1123–1129, 2009.01.
42. Mitsunori Kanemoto, Michio Murata, Tohru Oishi, Stereoselective Synthesis of the C31-C40/C43-C52 Unit of Amphidinol 3, J. Org. Chem., 74, 8810–8813, 2009.01.
43. Naohiro Matsushita, Yukiko Matsuo, Hiroshi Tsuchikawa, Nobuaki Matsumori, Michio Murata, Tohru Oishi, Synthesis of 25-13C-Amphotericin B Methyl Ester: A Molecular Probe for Solid-state NMR Measurements., Chem. Lett., 38, 114-115, 2009.01.
44. Nobuaki Matsumori, Kazuaki Tahara, Hiroko Yamamoto, Atsushi Morooka, Mototsugu Doi, Tohru Oishi, Michio Murata, Direct Interaction between Amphotericin B and Ergosterol in Lipid Bilayers As Revealed by 2H NMR Spectroscopy., J. Am. Chem. Soc., 131, 11855–11860, 2009.01.
45. Ryota Mouri, Tohru Oishi, Kohei Torikai, Satoru Ujihara, Nobuaki Matsumori, Michio Murata, Yasukatsu Oshima, Surface Plasmon Resonance-Based Detection of Ladder-Shaped Polyethers by Inhibition Detection Method., Bioorg. Med. Chem. Lett., 19, 2824-2828, 2009.01.
46. Eri Kondoh, Aru Konno, Kazuo Inaba, Tohru Oishi, Michio Murata, Manabu Yoshida, Valosin-Containing Protein/p97 Interacts with Sperm-Activating and Sperm-Attracting Factor (SAAF) in the Ascidian Egg and Modulates Sperm-Attracting Activity., Dev. Growth Differ., 50, 665-673, 2008.01.
47. Kohei Torikai, Koji Watanabe, Hiroaki Minato, Tomoyoshi Imaizumi, Michio Murata, Tohru Oishi, Convergent Synthesis of the A-J Ring System of Yessotoxin., Synlett, 2368-2372, 2008.01.
48. Manabu Yoshida, Kogiku Shiba, Kaoru Yoshida, Hiroshi Tsuchikawa, Ouichirou Ootou, Tohru Oishi, Michio Murata, Ascidian Sperm Activating and Attracting Factor: Importance of Sulfate Groups for the Activities and Implication of Its Putative Receptor., FEBS Lett., 582, 3429-3433, 2008.01.
49. Nagy Morsy, Keiichi Konoki, Toshihiro Houdai, Nobuaki Matsumori, Tohru Oishi, Michio Murata, Saburo Aimoto, Roles of Integral Protein in Membrane Permeabilization by Amphidinols., Biochim. Biophys. Acta, Biomembranes, 1778, 1453-1459, 2008.01.
50. Nagy Morsy, Toshihiro Houdai, Keiichi Konoki, Nobuaki Matsumori, Tohru Oishi, Michio Murata, Effects of Lipid Constituents on Membrane-Permeabilizing Activity of Amphidinols., Bioorg. Med. Chem., 16, 3084-3090, 2008.01.
51. Nobuaki Matsumori, Yusuke Kasai, Tohru Oishi, Michio Murata, Kaoru Nomura, Orientation of Fluorinated Cholesterol in Lipid Bilayers Analyzed by 19F Tensor Calculation and Solid-State NMR., J. Am. Chem. Soc., 130, 4757-4766, 2008.01.
52. Ryota Mouri, Keiichi Konoki, Nobuaki Matsumori, Tohru Oishi, Michio Murata, Complex Formation of Amphotericin B in Sterol-Containing Membranes As Evidenced by Surface Plasmon Resonance., Biochemistry, 47, 7807-7815, 2008.01.
53. Satoru Ujihara, Tohru Oishi, Kohei Torikai, Keiichi Konoki, Nobuaki Matsumori, Michio Murata, Yasukatsu Oshima, Saburo Aimoto, Interaction of Ladder-Shaped Polyethers with Transmembrane -Helix of Glycophorin A as Evidenced by Saturation Transfer Difference NMR and Surface Plasmon Resonance. , Bioorg. Med. Chem. Lett., 18, 6115-6118, 2008.01.
54. Tohru Oishi, Futoshi Hasegawa, Kohei Torikai, Keiichi Konoki, Nobuaki Matsumori, Michio Murata, Convergent Synthesis and Biological Activity of the WXYZA’B’C’ Ring System of Maitotoxin. Tohru Oishi, Futoshi Hasegawa, Kohei Torikai, Keiichi Konoki, Nobuaki Matsumori, Michio Murata Org. Lett. 2008, 10, 3599-3602., Org. Lett., 10, 3599-3602, 2008.01.
55. Tohru Oishi, Mitsunori Kanemoto, Respati Swasono, Nobuaki Matsumori, Michio Murata, Combinatorial Synthesis of the 1,5-Polyol System Based on Cross Metathesis: Structure Revision of Amphidinol 3., Org. Lett., 10, 5203-5206, 2008.01.
56. Yuichi Umegawa, Nobuaki Matsumori, Tohru Oishi, Michio Murata., Ergosterol Increases the Intermolecular Distance of Amphotericin B in the Membrane-Bound Assembly As Evidenced by Solid-State NMR., Biochemistry, 47, 13463-13469, 2008.01.
57. Yusuke Kasai, Nobuaki Matsumori, Yuichi Umegawa, Shigeru Matsuoka, Hiroyuki Ueno, Hiroki Ikeuchi, Tohru Oishi, Michio Murata, Self-Assembled Amphotericin B is Probably Surrounded by Ergosterol: Bimolecular Interactions as Evidenced by Solid-State NMR and CD Spectra., Chem. Eur. J., 14, 1178-1185, 2008.01.