{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T06:42:56Z","timestamp":1765089776911,"version":"build-2065373602"},"reference-count":97,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2007,11,12]],"date-time":"2007-11-12T00:00:00Z","timestamp":1194825600000},"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>Many drugs suffer from an extensive first-pass metabolism leading to druginactivation and\/or production of toxic metabolites, which makes them attractive targets forprodrug design. The classical prodrug approach, which involves enzyme-sensitive covalentlinkage between the parent drug and a carrier moiety, is a well established strategy toovercome bioavailability\/toxicity issues. However, the development of prodrugs that canregenerate the parent drug through non-enzymatic pathways has emerged as an alternativeapproach in which prodrug activation is not influenced by inter- and intraindividualvariability that affects enzymatic activity. Cyclization-activated prodrugs have beencapturing the attention of medicinal chemists since the middle-1980s, and reached maturityin prodrug design in the late 1990s. Many different strategies have been exploited in recentyears concerning the development of intramoleculary-activated prodrugs spanning fromanalgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role intwo-step prodrug activation, where an initial enzymatic cleavage step is followed by acyclization-elimination reaction that releases the active drug. This wor<\/jats:p>","DOI":"10.3390\/12112484","type":"journal-article","created":{"date-parts":[[2008,10,25]],"date-time":"2008-10-25T13:32:11Z","timestamp":1224941531000},"page":"2484-2506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Cyclization-activated Prodrugs"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6018-4724","authenticated-orcid":false,"given":"Paula","family":"Gomes","sequence":"first","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o em Qu\u00edmica da Universidade do Porto, Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, Porto, Portugal"}]},{"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o em Qu\u00edmica da Universidade do Porto, Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, Porto, Portugal"}]},{"given":"Rui","family":"Moreira","sequence":"additional","affiliation":[{"name":"Centro de Estudos de Ci\u00eancias Farmac\u00eauticas, Faculdade de Farm\u00e1cia, Universidade de Lisboa, Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2007,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1124\/jpet.104.073205","article-title":"The impact of \u0394G on the oral bioavailability of low bioavailable therapeutic agents","volume":"312","author":"Salama","year":"2005","journal-title":"J. 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