{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T21:03:22Z","timestamp":1785359002033,"version":"3.55.0"},"reference-count":36,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","award":["PIP\u2010CONICET 0183,\u00a0PIP\u2010CONICET 11220200102951,\u00a0PIP\u2010CONICET 11220150100443CO"],"award-info":[{"award-number":["PIP\u2010CONICET 0183,\u00a0PIP\u2010CONICET 11220200102951,\u00a0PIP\u2010CONICET 11220150100443CO"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005363","name":"Universidad de Buenos Aires","doi-asserted-by":"publisher","award":["20020170100403BA"],"award-info":[{"award-number":["20020170100403BA"]}],"id":[{"id":"10.13039\/501100005363","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,7,29]]},"abstract":"<jats:p>Parkinson's disease (PD) is driven by a combination of dopaminergic neuron loss, \u03b1\u2010synuclein (\u03b1\u2010Syn) aggregation, and oxidative stress, underscoring the need for multi\u2010target therapies. We previously developed Pegasus (DAD9), a dopamine\u2013doxycycline conjugate designed to couple dopaminergic activity with the neuroprotective properties of tetracyclines while limiting dopamine's oxidative reactivity. In this study, we explore a critical but less\u2010examined element of this scaffold: the linker. By incorporating a sulfur atom and progressively extending the tether, we introduced subtle modifications to modulate molecular flexibility, electronic properties, and physicochemical parameters without disrupting the main pharmacophoric domains. The synthesis of these highly functionalized hybrids required a tailored strategy, highlighting the inherent challenges of working with such complex conjugates. Across the series, all compounds retained their ability to interfere with \u03b1\u2010Syn aggregation, showed no effect on cell viability, and lacked antibacterial activity. While modest variations in physicochemical properties were observed, anti\u2010aggregative potency remained comparable across the linker\u2010modified series. Together, these results indicate that the scaffold tolerates linker modification within the explored chemical space, supporting a role for the linker as a modulatory element rather than a primary driver of the main \u03b1\u2010Syn\u2010related functional activity.<\/jats:p>","DOI":"10.1002\/cmdc.70402","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T02:29:01Z","timestamp":1785205741000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expanding the DAD9\u2010Pegasus Scaffold: Synthesis and Functional Evaluation of Sulfur\u2010Containing Dopamine\u2013Tetracycline Conjugates for Parkinson's Disease"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2804-0789","authenticated-orcid":false,"given":"Agust\u00edn Osvaldo","family":"Pernicone","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica Facultad de Ciencias Exactas y Naturales Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) Centro de Investigaci\u00f3n en Hidratos de Carbono (CIHIDECAR) Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1892-9351","authenticated-orcid":false,"given":"Valentina","family":"Budeguer Isa","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET)\u2010 Universidad Nacional de Tucum\u00e1n (UNT)\u2010Ministerio de Salud P\u00fablica de Tucum\u00e1n\u2010SIPROSA  San Miguel de Tucum\u00e1n Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2235-6960","authenticated-orcid":false,"given":"Mar\u00eda Laura","family":"Guay\u00e1n","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET)\u2010 Universidad Nacional de Tucum\u00e1n (UNT)\u2010Ministerio de Salud P\u00fablica de Tucum\u00e1n\u2010SIPROSA  San Miguel de Tucum\u00e1n Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4859-4840","authenticated-orcid":false,"given":"Mar\u00eda del Milagro","family":"Teran","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET)\u2010 Universidad Nacional de Tucum\u00e1n (UNT)\u2010Ministerio de Salud P\u00fablica de Tucum\u00e1n\u2010SIPROSA  San Miguel de Tucum\u00e1n Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agust\u00edn","family":"Stagnetto","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET)\u2010 Universidad Nacional de Tucum\u00e1n (UNT)\u2010Ministerio de Salud P\u00fablica de Tucum\u00e1n\u2010SIPROSA  San Miguel de Tucum\u00e1n Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0710-3025","authenticated-orcid":false,"given":"Alvaro Luna","family":"Mercado","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET)\u2010 Universidad Nacional de Tucum\u00e1n (UNT)\u2010Ministerio de Salud P\u00fablica de Tucum\u00e1n\u2010SIPROSA  San Miguel de Tucum\u00e1n Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5462-1238","authenticated-orcid":false,"given":"Diego","family":"Ploper","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET)\u2010 Universidad Nacional de Tucum\u00e1n (UNT)\u2010Ministerio de Salud P\u00fablica de Tucum\u00e1n\u2010SIPROSA  San Miguel de Tucum\u00e1n Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3763-3181","authenticated-orcid":false,"given":"Ver\u00f3nica Elena","family":"Manzano","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica Facultad de Ciencias Exactas y Naturales Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) Centro de Investigaci\u00f3n en Hidratos de Carbono (CIHIDECAR) Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3504-7952","authenticated-orcid":false,"given":"Rosana","family":"Cheh\u00edn","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET)\u2010 Universidad Nacional de Tucum\u00e1n (UNT)\u2010Ministerio de Salud P\u00fablica de Tucum\u00e1n\u2010SIPROSA  San Miguel de Tucum\u00e1n Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0952-608X","authenticated-orcid":false,"given":"Oscar","family":"Varela","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica Facultad de Ciencias Exactas y Naturales Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) Centro de Investigaci\u00f3n en Hidratos de Carbono (CIHIDECAR) Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"issue":"1","key":"e_1_2_10_2_1","first-page":"S3\u2013S8","article-title":"The Emerging Evidence of the Parkinson Pandemic","volume":"8","author":"Dorsey E. R.","year":"2018","journal-title":"Journal of Parkinson's Disease"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.3299"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-239901"},{"issue":"1","key":"e_1_2_10_5_1","first-page":"S51\u2013S69","article-title":"The Synucleinopathies: Twenty Years On","volume":"7","author":"Goedert M.","year":"2017","journal-title":"Journal of Parkinson's Disease"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.62"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063522"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4641"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27607"},{"issue":"2","key":"e_1_2_10_10_1","first-page":"S32\u2013S44","article-title":"Problems with Long\u2010Term Levodopa Therapy for Parkinson's Disease","volume":"17","author":"Marsden C. D.","year":"1994","journal-title":"Clinical Neuropharmacology"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2013.12.009"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201402291"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(00)02380-2"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-15991-w"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep41755"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2017.12.002"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2022.105229"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.4c00169"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26094251"},{"key":"e_1_2_10_20_1","first-page":"1","volume-title":"Handbook of Neurotoxicity","author":"Segura\u2010Aguilar J.","year":"2022"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/0008-6215(92)84093-8"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20102001\u201018769"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.2c01059"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/polym14204457"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2OB02262A"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2007.11.064"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/03602458008066533"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.28.3662"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00443a033"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2005.06.046"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00772a043"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.65.2.232\u2010260.2001"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010017\u20100149\u20100"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2023.2293158"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11172759"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105256"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076\u20106879(99)09020\u20105"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70402","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.70402","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70402","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T20:28:11Z","timestamp":1785356891000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.70402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":36,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2026,7,29]]}},"alternative-id":["10.1002\/cmdc.70402"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.70402","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"assertion":[{"value":"2026-04-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70402"}}