{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:53:22Z","timestamp":1791874402993,"version":"4.3.4"},"reference-count":24,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase II\u03b1. To further extend the structure\u2013activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3\u20136 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure\u2013activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase II\u03b1-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation.<\/jats:p>","DOI":"10.3390\/molecules26030557","type":"journal-article","created":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T03:31:30Z","timestamp":1611286290000},"page":"557","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Bicyclic Basic Merbarone Analogues as Antiproliferative Agents"],"prefix":"10.3390","volume":"26","author":[{"given":"Andrea","family":"Spallarossa","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7003-7891","authenticated-orcid":false,"given":"Matteo","family":"Lusardi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Caneva","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Profumo","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale Policlinico San Martino, Proteomics and Mass Spectrometry Unit, L.go R. Benzi 10, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2949-9215","authenticated-orcid":false,"given":"Camillo","family":"Rosano","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale Policlinico San Martino, Proteomics and Mass Spectrometry Unit, L.go R. Benzi 10, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ponassi","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale Policlinico San Martino, Proteomics and Mass Spectrometry Unit, L.go R. Benzi 10, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1146\/annurev.bi.65.070196.003223","article-title":"DNA topoisomerases","volume":"65","author":"Wang","year":"1996","journal-title":"Annu. Rev. 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