{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:02:03Z","timestamp":1789142523033,"version":"build-2803163510"},"reference-count":47,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2025,10,6]]},"abstract":"<jats:p>Dolastatins are a class of naturally occurring antimitotic peptides that have inspired the development of some of the most active and widely used anticancer agents. Here, we report on the development of synthetic methodologies for the preparation of parallel libraries of small peptides inspired by dolastatin 15 and its analogs cemadotin and tasidotin. The approaches rely on the use of either one or multiple Ugi\u2010multicomponent reactions to generate amide <jats:italic>N<\/jats:italic>\u2010substituted dolastatin\u2010like skeletons, which allow the exploration of tertiary amide chemical spaces that have not been assessed previously. Evaluation of the anticancer activity in a variety of cancer cells showed that introducing a tertiary amide at the <jats:italic>C<\/jats:italic>\u2010terminal fragment or by replacement of a proline residue does not lead to an increment in the anti\u2010proliferative activity. The microtubule\u2010disrupting capacity of the new dolastatin analogs was studied and compared with other potent antimitotic agents, thereby shedding light on mechanistic details of their anti\u2010proliferative activity.<\/jats:p>","DOI":"10.1002\/cmdc.202500580","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T17:59:27Z","timestamp":1755885567000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploration of the Tertiary Amide Chemical Space of Dolastatin 15 Analogs Reveals New Insights into the Structure\u2013Anticancer Activity Relationship"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3355-1610","authenticated-orcid":false,"given":"Dayana","family":"Alonso","sequence":"first","affiliation":[{"name":"Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry  Weinberg 3 D\u201006120 Halle (Saale) Germany"},{"name":"Laboratory of Synthetic and Biomolecular Chemistry Faculty of Chemistry University of Havana  Zapata &amp; G Havana 10400 Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9083-8752","authenticated-orcid":false,"given":"Leslie","family":"Reguera","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry  Weinberg 3 D\u201006120 Halle (Saale) Germany"},{"name":"Laboratory of Synthetic and Biomolecular Chemistry Faculty of Chemistry University of Havana  Zapata &amp; G Havana 10400 Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3665-6696","authenticated-orcid":false,"given":"Robert","family":"Rennert","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry  Weinberg 3 D\u201006120 Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry  Weinberg 3 D\u201006120 Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Saoud","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry  Weinberg 3 D\u201006120 Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel G.","family":"Ricardo","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry  Weinberg 3 D\u201006120 Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Vald\u00e9s","sequence":"additional","affiliation":[{"name":"Laboratory of Synthetic and Biomolecular Chemistry Faculty of Chemistry University of Havana  Zapata &amp; G Havana 10400 Cuba"},{"name":"Institute of Pharmacy and Food Chemistry University of Havana  222 Street.Nr.2317 Havana 10600 Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1687-9756","authenticated-orcid":false,"given":"Julieta","family":"Coro\u2010Bermello","sequence":"additional","affiliation":[{"name":"Laboratory of Synthetic and Biomolecular Chemistry Faculty of Chemistry University of Havana  Zapata &amp; G Havana 10400 Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2060-8235","authenticated-orcid":false,"given":"Ludger A.","family":"Wessjohann","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry  Weinberg 3 D\u201006120 Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5538-1555","authenticated-orcid":false,"given":"Daniel G.","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry Leibniz Institute of Plant Biochemistry  Weinberg 3 D\u201006120 Halle (Saale) Germany"},{"name":"Laboratory of Synthetic and Biomolecular Chemistry Faculty of Chemistry University of Havana  Zapata &amp; G Havana 10400 Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"1","volume-title":"The Chemistry of Organic Natural Products","author":"Pettit G. R.","year":"1997"},{"key":"e_1_2_8_3_1","first-page":"263","volume-title":"Anticancer Agents from Natural Products","author":"Flahive E.","year":"2011"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00256a070"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612805666230109214008"},{"key":"e_1_2_8_6_1","first-page":"529","volume":"10","author":"Pettit G. R.","year":"1995","journal-title":"Anticancer Drug Des."},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001813-200201000-00005"},{"key":"e_1_2_8_8_1","first-page":"243","volume":"13","author":"Pettit G. R.","year":"1998","journal-title":"Anticancer Drug Des."},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.1c01135"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2289"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.c19-00853"},{"key":"e_1_2_8_12_1","first-page":"3085","volume":"55","author":"de Arruda M.","year":"1995","journal-title":". Cancer Res."},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi9817414"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3065"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/9783527609628.ch13"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008430515881"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002800000152"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(02)00531-2"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2004.22.90140.7530"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0058"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.051110"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.enzmictec.2009.10.013"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-012-1925-8"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201106527"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201307628"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21377"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar8000603"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201500312"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.430350105"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(98)00034-1"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(92)90153-A"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.5b01147"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7OB00459A"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.8b00906"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-3011.1999.00130.x"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo981055a"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-00445-6"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/psc.2998"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201912095"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202401943"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1408091"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.510"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6769-10-1"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.05.016"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28041871"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202404085"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2018.06.044"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202500580","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T23:40:13Z","timestamp":1760485213000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202500580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":47,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2025,10,6]]}},"alternative-id":["10.1002\/cmdc.202500580"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202500580","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,22]]},"assertion":[{"value":"2025-07-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202500580"}}