{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T05:11:08Z","timestamp":1771650668692,"version":"3.50.1"},"reference-count":95,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,1,19]],"date-time":"2019-01-19T00:00:00Z","timestamp":1547856000000},"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>Betulinic acid (BA) and its natural analogues betulin (BN), betulonic (BoA), and 23-hydroxybetulinic (HBA) acids are lupane-type pentacyclic triterpenoids. They are present in many plants and display important biological activities. This review focuses on the chemical transformations used to functionalize BA\/BN\/BoA\/HBA in order to obtain new derivatives with improved biological activity, covering the period since 2013 to 2018. It is divided by the main chemical transformations reported in the literature, including amination, esterification, alkylation, sulfonation, copper(I)-catalyzed alkyne-azide cycloaddition, palladium-catalyzed cross-coupling, hydroxylation, and aldol condensation reactions. In addition, the synthesis of heterocycle-fused BA\/HBA derivatives and polymer\u2012BA conjugates are also addressed. The new derivatives are mainly used as antitumor agents, but there are other biological applications such as antimalarial activity, drug delivery, bioimaging, among others.<\/jats:p>","DOI":"10.3390\/molecules24020355","type":"journal-article","created":{"date-parts":[[2019,1,22]],"date-time":"2019-01-22T03:08:22Z","timestamp":1548126502000},"page":"355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1412-4197","authenticated-orcid":false,"given":"Joana L. C.","family":"Sousa","sequence":"first","affiliation":[{"name":"QOPNA &amp; LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"},{"name":"CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Carmen S. R.","family":"Freire","sequence":"additional","affiliation":[{"name":"CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5403-8416","authenticated-orcid":false,"given":"Armando J. D.","family":"Silvestre","sequence":"additional","affiliation":[{"name":"CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2861-8286","authenticated-orcid":false,"given":"Artur M. S.","family":"Silva","sequence":"additional","affiliation":[{"name":"QOPNA &amp; LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4236\/pp.2012.32018","article-title":"Biological Activity of Betulinic Acid: A Review","volume":"3","author":"Moghaddam","year":"2012","journal-title":"Pharmacol. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1055\/s-0043-123472","article-title":"New Pharmacological Opportunities for Betulinic Acid","volume":"84","year":"2018","journal-title":"Planta Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejps.2006.04.006","article-title":"Pharmacological properties of the ubiquitous natural product betulin","volume":"29","author":"Sami","year":"2006","journal-title":"Eur. J. Pharm. 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