{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T22:33:05Z","timestamp":1794349985576,"version":"4.9.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T00:00:00Z","timestamp":1560729600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T00:00:00Z","timestamp":1560729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery\/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a &gt;10\u2009g scale with &gt;99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce \u03b1-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery\/development even for the cases of complex natural products.<\/jats:p>","DOI":"10.1038\/s41598-019-45001-9","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T06:03:05Z","timestamp":1560751385000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["A landmark in drug discovery based on complex natural product synthesis"],"prefix":"10.1038","volume":"9","author":[{"given":"Satoshi","family":"Kawano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6991-9221","authenticated-orcid":false,"given":"Kenzo","family":"Yahata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunobu","family":"Kira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Akagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Asano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Iso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiyoshi","family":"Matsuura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Ohashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunobu","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minetaka","family":"Isomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeo","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Fukuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Miyashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Kaburagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Yokoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Asano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Owa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshito","family":"Kishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,6,17]]},"reference":[{"key":"45001_CR1","doi-asserted-by":"publisher","first-page":"4796","DOI":"10.1021\/ja00302a042","volume":"107","author":"D Uemura","year":"1985","unstructured":"Uemura, D. et al. Norhalichondrin A: an antitumor polyether macrolide from a marine sponge. Journal of the American Chemical Society 107, 4796\u20134798 (1985).","journal-title":"Journal of the American Chemical Society"},{"key":"45001_CR2","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1351\/pac198658050701","volume":"58","author":"Y Hirata","year":"1986","unstructured":"Hirata, Y. & Uemura, D. Halichondrins - antitumor polyether macrolides from a marine sponge. Pure and Applied Chemistry 58, 701 (1986).","journal-title":"Pure and Applied Chemistry"},{"key":"45001_CR3","doi-asserted-by":"publisher","first-page":"3339","DOI":"10.1021\/jm00115a027","volume":"34","author":"GR Pettit","year":"1991","unstructured":"Pettit, G. R. et al. Isolation and structure of the cell growth inhibitory constituents from the western Pacific marine sponge Axinella sp. Journal of medicinal chemistry 34, 3339\u20133340 (1991).","journal-title":"Journal of medicinal chemistry"},{"key":"45001_CR4","doi-asserted-by":"publisher","first-page":"2538","DOI":"10.1021\/jo00061a030","volume":"58","author":"GR Pettit","year":"1993","unstructured":"Pettit, G. R. et al. Isolation and structure of halistatin 1 from the eastern Indian Ocean marine sponge Phakellia carteri. The Journal of organic chemistry 58, 2538\u20132543 (1993).","journal-title":"The Journal of organic chemistry"},{"key":"45001_CR5","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1021\/jo962231n","volume":"62","author":"M Litaudon","year":"1997","unstructured":"Litaudon, M. et al. Antitumor Polyether Macrolides:\u2009 New and Hemisynthetic Halichondrins from the New Zealand Deep-Water Sponge Lissodendoryx sp. The Journal of organic chemistry 62, 1868\u20131871 (1997).","journal-title":"The Journal of organic chemistry"},{"key":"45001_CR6","doi-asserted-by":"publisher","first-page":"9435","DOI":"10.1016\/S0040-4039(00)78563-7","volume":"35","author":"M Litaudon","year":"1994","unstructured":"Litaudon, M., Hart, J. B., Blunt, J. W., Lake, R. J. & Munro, M. H. Isohomohalichondrin B, a new antitumour polyether macrolide from the New Zealand deep-water sponge Lissodendoryx sp. Tetrahedron Letters 35, 9435\u20139438 (1994).","journal-title":"Tetrahedron Letters"},{"key":"45001_CR7","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.1016\/j.bmc.2008.10.093","volume":"17","author":"SJH Hickford","year":"2009","unstructured":"Hickford, S. J. H., Blunt, J. W. & Munro, M. H. G. Antitumour polyether macrolides: Four new halichondrins from the New Zealand deep-water marine sponge Lissodendoryx sp. Bioorganic & Medicinal Chemistry 17, 2199\u20132203 (2009).","journal-title":"Bioorganic & Medicinal Chemistry"},{"key":"45001_CR8","first-page":"371","volume":"123","author":"GR Pettit","year":"1993","unstructured":"Pettit, G. R. et al. Anti neoplastic agents. CCLII. Isolation and structure of Halistatin 2 from the Comoros marine sponge Axinella carteri. Gazzetta Chimica Italiana 123, 371\u2013377 (1993).","journal-title":"Gazzetta Chimica Italiana"},{"key":"45001_CR9","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/0006-2952(93)90079-C","volume":"45","author":"RF Luduen\u0304a","year":"1993","unstructured":"Luduen\u0304a, R. F., Roach, M. C., Prasad, V. & Pettit, G. R. Interaction of halichondrin B and homohalichondrin B with bovine brain tubulin. Biochemical Pharmacology 45, 421\u2013427 (1993).","journal-title":"Biochemical Pharmacology"},{"key":"45001_CR10","first-page":"757","volume":"44","author":"R Bai","year":"1993","unstructured":"Bai, R., Cichacz, Z. A., Herald, C. L., Pettit, G. R. & Hamel, E. Spongistatin 1, a highly cytotoxic, sponge-derived, marine natural product that inhibits mitosis, microtubule assembly, and the binding of vinblastine to tubulin. Molecular pharmacology 44, 757\u2013766 (1993).","journal-title":"Molecular pharmacology"},{"key":"45001_CR11","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/0163-7258(92)90028-X","volume":"55","author":"E Hamel","year":"1992","unstructured":"Hamel, E. Natural products which interact with tubulin in the vinca domain: Maytansine, rhizoxin, phomopsin a, dolastatins 10 and 15 and halichondrin B. Pharmacology & Therapeutics 55, 31\u201351 (1992).","journal-title":"Pharmacology & Therapeutics"},{"key":"45001_CR12","first-page":"119","volume":"1","author":"O Fodstad","year":"1996","unstructured":"Fodstad, O., Breistol, K., Pettit, G. R., Shoemaker, R. H. & Boyd, M. R. Comparative antitumor activities of halichondrins and vinblastine against human tumor xenografts. Journal of experimental therapeutics & oncology 1, 119\u2013125 (1996).","journal-title":"Journal of experimental therapeutics & oncology"},{"key":"45001_CR13","doi-asserted-by":"publisher","first-page":"3162","DOI":"10.1021\/ja00034a086","volume":"114","author":"TD Aicher","year":"1992","unstructured":"Aicher, T. D. et al. Total synthesis of halichondrin B and norhalichondrin B. Journal of the American Chemical Society 114, 3162\u20133164 (1992).","journal-title":"Journal of the American Chemical Society"},{"key":"45001_CR14","doi-asserted-by":"publisher","first-page":"10796","DOI":"10.1002\/anie.201705523","volume":"56","author":"K Yahata","year":"2017","unstructured":"Yahata, K., Ye, N., Ai, Y., Iso, K. & Kishi, Y. Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium\/Nickel\u2010Mediated One\u2010Pot Ketone Synthesis as the Final Coupling Reaction. Angewandte Chemie International Edition 56, 10796\u201310800 (2017).","journal-title":"Angewandte Chemie International Edition"},{"key":"45001_CR15","unstructured":"Fukuyama, T. et al. Synthesis of Halichondrins. WO 2019010363 (2019)."},{"key":"45001_CR16","unstructured":"Kishi, Y., Yan, W., Li, J., Li, Z. & Yahata, K. Chromium-Mediated Coupling And Application to the Synthesis of Halichondrins. WO 2016176560 (2016)."},{"key":"45001_CR17","doi-asserted-by":"publisher","first-page":"15387","DOI":"10.1021\/ja905843e","volume":"131","author":"H Guo","year":"2009","unstructured":"Guo, H. et al. Toolbox approach to the search for effective ligands for catalytic asymmetric Cr-mediated coupling reactions. J Am Chem Soc 131, 15387\u201315393 (2009).","journal-title":"J Am Chem Soc"},{"key":"45001_CR18","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1177\/117693510700300028","volume":"3","author":"JT Huzil","year":"2007","unstructured":"Huzil, J. T., Chen, K., Kurgan, L. & Tuszynski, J. A. The roles of beta-tubulin mutations and isotype expression in acquired drug resistance. Cancer informatics 3, 159\u2013181 (2007).","journal-title":"Cancer informatics"},{"key":"45001_CR19","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/nrc2803","volume":"10","author":"M Kavallaris","year":"2010","unstructured":"Kavallaris, M. Microtubules and resistance to tubulin-binding agents. Nature Reviews Cancer 10, 194 (2010).","journal-title":"Nature Reviews Cancer"},{"key":"45001_CR20","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1053\/j.seminoncol.2014.03.003","volume":"41","author":"JM Curry","year":"2014","unstructured":"Curry, J. M. et al. Tumor microenvironment in head and neck squamous cell carcinoma. Seminars in oncology 41, 217\u2013234 (2014).","journal-title":"Seminars in oncology"},{"key":"45001_CR21","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1111\/j.1349-7006.2009.01357.x","volume":"101","author":"M Vered","year":"2010","unstructured":"Vered, M. et al. Tumor-host histopathologic variables, stromal myofibroblasts and risk score, are significantly associated with recurrent disease in tongue cancer. Cancer science 101, 274\u2013280 (2010).","journal-title":"Cancer science"},{"key":"45001_CR22","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-016-0412-6","volume":"17","author":"S Schmitz","year":"2016","unstructured":"Schmitz, S. & Machiels, J. P. Targeting the Tumor Environment in Squamous Cell Carcinoma of the Head and Neck. Current treatment options in oncology 17, 37 (2016).","journal-title":"Current treatment options in oncology"},{"key":"45001_CR23","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1080\/19336918.2015.1008332","volume":"9","author":"T Yoshida","year":"2015","unstructured":"Yoshida, T., Akatsuka, T. & Imanaka-Yoshida, K. Tenascin-C and integrins in cancer. Cell Adhesion & Migration 9, 96\u2013104 (2015).","journal-title":"Cell Adhesion & Migration"},{"key":"45001_CR24","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1002\/iub.493","volume":"63","author":"ES White","year":"2011","unstructured":"White, E. S. & Muro, A. F. Fibronectin splice variants: understanding their multiple roles in health and disease using engineered mouse models. IUBMB life 63, 538\u2013546 (2011).","journal-title":"IUBMB life"},{"key":"45001_CR25","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1038\/nrc3792","volume":"14","author":"FJ Sulzmaier","year":"2014","unstructured":"Sulzmaier, F. J., Jean, C. & Schlaepfer, D. D. FAK in cancer: mechanistic findings and clinical applications. Nature reviews. Cancer 14, 598\u2013610 (2014).","journal-title":"Nature reviews. Cancer"},{"key":"45001_CR26","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1083\/jcb.201206050","volume":"198","author":"S Stehbens","year":"2012","unstructured":"Stehbens, S. & Wittmann, T. Targeting and transport: How microtubules control focal adhesion dynamics. The Journal of cell biology 198, 481 (2012).","journal-title":"The Journal of cell biology"},{"key":"45001_CR27","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.1158\/1535-7163.MCT-09-0366","volume":"8","author":"EA Perez","year":"2009","unstructured":"Perez, E. A. Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Molecular cancer therapeutics 8, 2086 (2009).","journal-title":"Molecular cancer therapeutics"},{"key":"45001_CR28","doi-asserted-by":"publisher","first-page":"203","DOI":"10.4161\/cam.20377","volume":"6","author":"M Otranto","year":"2012","unstructured":"Otranto, M. et al. The role of the myofibroblast in tumor stroma remodeling. Cell adhesion & migration 6, 203\u2013219 (2012).","journal-title":"Cell adhesion & migration"},{"key":"45001_CR29","doi-asserted-by":"crossref","unstructured":"Augsten, M. Cancer-Associated Fibroblasts as Another Polarized Cell Type of the Tumor Microenvironment. Frontiers in oncology 4, 62 (2014).","DOI":"10.3389\/fonc.2014.00062"},{"key":"45001_CR30","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/jop.12452","volume":"46","author":"N-N Lin","year":"2017","unstructured":"Lin, N.-N. et al. Significance of oral cancer-associated fibroblasts in angiogenesis, lymphangiogenesis, and tumor invasion in oral squamous cell carcinoma. Journal of Oral Pathology & Medicine 46, 21\u201330 (2017).","journal-title":"Journal of Oral Pathology & Medicine"},{"key":"45001_CR31","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1016\/j.jcms.2014.05.002","volume":"42","author":"T Dettenborn","year":"2014","unstructured":"Dettenborn, T. et al. Prognostic features in angiosarcoma of the head and neck: a retrospective monocenter study. Journal of cranio-maxillo-facial surgery: official publication of the European Association for Cranio-Maxillo-Facial Surgery 42, 1623\u20131628 (2014).","journal-title":"Journal of cranio-maxillo-facial surgery: official publication of the European Association for Cranio-Maxillo-Facial Surgery"},{"key":"45001_CR32","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1158\/1535-7163.MCT-13-0748","volume":"13","author":"T-H Shin","year":"2014","unstructured":"Shin, T.-H. et al. Enhancement of the Tumor Penetration of Monoclonal Antibody by Fusion of a Neuropilin-Targeting Peptide Improves the Antitumor Efficacy. Molecular cancer therapeutics 13, 651 (2014).","journal-title":"Molecular cancer therapeutics"},{"key":"45001_CR33","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-015-0662-4","volume":"18","author":"T Tanei","year":"2016","unstructured":"Tanei, T. et al. Antitumor activity of Cetuximab in combination with Ixabepilone on triple negative breast cancer stem cells. Breast Cancer Research 18, 6 (2016).","journal-title":"Breast Cancer Research"},{"key":"45001_CR34","first-page":"3615","volume":"33","author":"S Bruheim","year":"2013","unstructured":"Bruheim, S., Sandvold, M. L., Maelandsmo, G. M. & Fodstad, O. Antitumor activity of elacytarabine combined with bevacizumab, cetuximab and trastuzumab in human NSCLC xenografts. Anticancer research 33, 3615\u20133621 (2013).","journal-title":"Anticancer research"},{"key":"45001_CR35","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.ccell.2015.12.008","volume":"29","author":"JY Li","year":"2016","unstructured":"Li, J. Y. et al. A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy. Cancer cell 29, 117\u2013129 (2016).","journal-title":"Cancer cell"},{"key":"45001_CR36","doi-asserted-by":"publisher","first-page":"9280","DOI":"10.1158\/0008-5472.CAN-08-1776","volume":"68","author":"GD Lewis Phillips","year":"2008","unstructured":"Lewis Phillips, G. D. et al. Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody\u2013Cytotoxic Drug Conjugate. Cancer research 68, 9280 (2008).","journal-title":"Cancer research"},{"key":"45001_CR37","doi-asserted-by":"publisher","first-page":"2330","DOI":"10.3892\/ijo.2016.3482","volume":"48","author":"T Ogura","year":"2016","unstructured":"Ogura, T., Tanaka, Y., Tamaki, H. & Harada, M. Docetaxel induces Bcl-2- and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells. Int J Oncol 48, 2330\u20132338 (2016).","journal-title":"Int J Oncol"},{"key":"45001_CR38","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1158\/1535-7163.MCT-14-0820","volume":"14","author":"EB Reilly","year":"2015","unstructured":"Reilly, E. B. et al. Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody. Molecular cancer therapeutics 14, 1141 (2015).","journal-title":"Molecular cancer therapeutics"},{"key":"45001_CR39","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1158\/2159-8290.CD-15-1412","volume":"6","author":"Y Wang","year":"2016","unstructured":"Wang, Y. et al. Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression. Cancer discovery 6, 1022\u20131035 (2016).","journal-title":"Cancer discovery"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-45001-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-45001-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-45001-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T05:23:50Z","timestamp":1671254630000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-45001-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,17]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["45001"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-45001-9","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.735996414.793564680","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,17]]},"assertion":[{"value":"8 January 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"8656"}}