{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:44:43Z","timestamp":1761237883445,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2012,3,5]],"date-time":"2012-03-05T00:00:00Z","timestamp":1330905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>MG 50-3-1 (3, trisodium 1-amino-4-{4-[4-chloro-6-(2-sulfophenylamino)-1,3,5-triazin-2-ylamino]-2-sulfophenylamino}-9,10-dioxo-9,10-dihydroanthracene 2-sulfonate) is the most potent and selective antagonist (IC50 4.6 nM) for \u201cP2Y1-like\u201d nucleotide-activated membrane receptors in guinea-pig taenia coli responsible for smooth muscle relaxation. Full characterization of the compound, however, e.g., at the human P2Y1 receptor, which is a novel potential target for antithrombotic drugs, as well as other P2 receptor subtypes, has been hampered due to difficulties in synthesizing the compound in sufficient quantity. MG 50-3-1 would be highly useful as a biological tool for detailed investigation of signal transduction in the gut. We have now developed a convenient, fast, mild, and efficient convergent synthesis of 3 based on retrosynthetic analysis. A new, regioselective Ullmann coupling reaction under microwave irradiation was successfully developed to obtain 1-amino-4-(4-amino-2-sulfophenylamino)-9,10-dioxo-9,10-dihydro\u00adanthracene 2-sulfonate (8). Four different copper catalysts (Cu, CuCl, CuCl2, and CuSO4) were investigated at different pH values of sodium phosphate buffer, and in water in the absence or presence of base. Results showed that CuSO4 in water in the presence of triethylamine provided the best conditions for the regioselective Ullmann coupling reaction yielding the key intermediate compound 8. A new synthon (sodium 2-(4,6-dichloro-1,3,5-triazin-2-ylamino)benzenesulfonate, 13) which can easily be obtained on a gram scale was prepared, and 13 was successfully coupled with 8 yielding the target compound 3.<\/jats:p>","DOI":"10.3390\/molecules17032599","type":"journal-article","created":{"date-parts":[[2012,3,5]],"date-time":"2012-03-05T19:43:27Z","timestamp":1330976607000},"page":"2599-2615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Convergent Synthesis of the Potent P2Y Receptor Antagonist MG 50-3-1 Based on a Regioselective Ullmann Coupling Reaction"],"prefix":"10.3390","volume":"17","author":[{"given":"Younis","family":"Baqi","sequence":"first","affiliation":[{"name":"PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0013-6624","authenticated-orcid":false,"given":"Christa E.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2012,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1152\/physrev.00043.2006","article-title":"Physiology and pathophysiology of purinergic neurotransmission","volume":"87","author":"Burnstock","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1124\/pr.58.1.5","article-title":"Pathophysiology and therapeutic potential of purinergic signaling","volume":"58","author":"Burnstock","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.2174\/1381612023392937","article-title":"P2-pyrimidinergic receptors and their ligands","volume":"8","year":"2002","journal-title":"Curr. Pharm. Des."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"289","DOI":"10.2174\/092986706775476052","article-title":"P2 receptors activated by uracil nucleotides\u2014An update","volume":"13","author":"Brunschweiger","year":"2006","journal-title":"Curr. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.bcp.2005.10.033","article-title":"The challenge of drug discovery of a GPCR target: Analysis of preclinical pharmacology of histamine H3 antagonists\/inverse agonists","volume":"71","author":"Hancock","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1161\/hq0302.105360","article-title":"Purinergic signaling and vascular cell proliferation and death","volume":"22","author":"Burnstock","year":"2002","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1160\/TH07-11-0673","article-title":"P2 receptors, platelet function and pharmacological implications","volume":"99","author":"Gachet","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.pharmthera.2005.03.009","article-title":"The platelet P2 receptors as molecular targets for old and new antiplatelet drugs","volume":"108","author":"Gachet","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1146\/annurev.pharmtox.46.120604.141207","article-title":"Regulation of platelet functions by P2 receptors","volume":"46","author":"Gachet","year":"2006","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1093\/eurheartj\/ehi851","article-title":"P2Y12 receptor antagonists: A rapidly expanding group of antiplatelet agents","volume":"27","author":"Cattaneo","year":"2006","journal-title":"Eur. Heart J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1161\/01.ATV.0000145980.39477.a9","article-title":"Aspirin and clopidogrel efficacy, safety, and the issue of drug resistance Arterioscler","volume":"24","author":"Cattaneo","year":"2004","journal-title":"Thromb. Vasc. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1097\/CRD.0b013e3182099d86","article-title":"Ticagrelor: A novel reversible oral antiplatelet agent","volume":"19","author":"Nawarskas","year":"2011","journal-title":"Cardiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1172\/JCI8399","article-title":"Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor-null mice","volume":"104","author":"Hechler","year":"1999","journal-title":"J. Clin. Invest."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1038\/13522","article-title":"Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice","volume":"5","author":"Fabre","year":"1999","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1124\/jpet.107.131169","article-title":"Involvement of P2Y1 and P2Y11 purinoceptors in parasympathetic inhibition of colonic smooth muscle","volume":"324","author":"King","year":"2008","journal-title":"Pharmacol. Exp. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0165-6147(92)90032-2","article-title":"Pharmacology and electrophysiology of ATP-activated ion channels","volume":"13","author":"Bean","year":"1992","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1111\/j.1476-5381.1991.tb12265.x","article-title":"Antagonism by reactive blue 2 but not by brilliant blue G of extracellular ATP-evoked responses in PC12 phaeochromocytoma cells","volume":"102","author":"Inoue","year":"1991","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1007\/BF00370517","article-title":"Effects of ATP antagonists on purinoceptor-operated inward currents in rat phaeochromocytoma cells","volume":"418","author":"Nakazawa","year":"1991","journal-title":"Pfl\u00fcgers Arch."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S1537-1891(03)00030-2","article-title":"Evaluation of reactive blue 2 derivatives as selective antagonists for P2Y receptors","volume":"39","author":"Brown","year":"2003","journal-title":"Vasc. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/PL00005144","article-title":"P2-receptor antagonists: IV. Blockade of P2-receptor subtypes and ecto-nucleotidases by compounds related to reactive blue 2","volume":"357","author":"Tuluc","year":"1998","journal-title":"Naunyn Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1016\/j.ejmech.2005.07.007","article-title":"Structure-activity relationships of novel P2-receptor antagonists structurally related to Reactive Blue 2","volume":"40","author":"Starke","year":"2005","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1021\/jm1012193","article-title":"Discovery of potent competitive antagonists and positive modulators of the P2X2 receptor","volume":"54","author":"Baqi","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.bmcl.2007.10.082","article-title":"Combinatorial synthesis of anilinoanthraquinone derivatives and evaluation as non nucleotide-derived P2Y2 receptor antagonists","volume":"18","author":"Weyler","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.1021\/jm9003297","article-title":"High-affinity, non nucleotide-derived competitive antagonists of platelet P2Y12 receptors","volume":"52","author":"Baqi","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1124\/jpet.109.156687","article-title":"Interaction of new, very potent non-nucleotide antagonists with Arg256 of the human platelet P2Y12-receptor","volume":"331","author":"Hoffmann","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s11302-008-9103-5","article-title":"Structure-activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases)","volume":"5","author":"Baqi","year":"2009","journal-title":"Purinerg. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1021\/jm901851t","article-title":"Development of potent and selective inhibitors of ecto-5\u2019-nucleotidase based on an anthraquinone scaffold","volume":"53","author":"Baqi","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1021\/ol070102v","article-title":"Rapid and efficient microwave-assisted copper(0)-catalyzed Ullmann coupling reaction: general access to anilinoanthraquinone derivatives","volume":"9","author":"Baqi","year":"2007","journal-title":"Org. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/nprot.2010.63","article-title":"Synthesis of alkyl- and aryl-amino-substituted anthraquinone derivatives by microwave-assisted copper(0)-catalyzed Ullmann coupling reactions","volume":"5","author":"Baqi","year":"2010","journal-title":"Nat. Protoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1021\/ja00239a032","article-title":"Mechanisms and models for copper mediated nucleophilic aromatic substitution. 2. A single catalytic species from three different oxidation states of copper in an Ullmann synthesis of triarylamines","volume":"109","author":"Paine","year":"1987","journal-title":"J. Am. Chem. Soc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4531","DOI":"10.1016\/S0040-4039(01)89057-2","article-title":"The mechanism of the Ullmann reaction. Detection of an organocopper intermediate","volume":"50","author":"Lewin","year":"1965","journal-title":"Tetrahedron Lett."},{"key":"ref_32","unstructured":"Ritter, S.C. (2007). Cu(I)-Catalyzed \u201cClick-Chemistry\u201c Design of a Chemical Photomultiplier Target-Guided Synthesis of Bidentate Metal-Complex Receptors. [Ph.D. thesis, University of Regensburg]."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ritter, S.C., and K\u00f6nig, B. (2006). Signal amplification and transduction by photo-activated catalysis. Chem. Commun., 4694\u20134696.","DOI":"10.1039\/B610696J"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/17\/3\/2599\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:49:12Z","timestamp":1760219352000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/17\/3\/2599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,3,5]]},"references-count":33,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2012,3]]}},"alternative-id":["molecules17032599"],"URL":"https:\/\/doi.org\/10.3390\/molecules17032599","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2012,3,5]]}}}