{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:55:33Z","timestamp":1760230533874,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portugal 2020 through FEDER in the frame of POCI and in the scope of the projects: MultiBiorefinery","award":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"]}]},{"name":"CICECO\u2014Aveiro Institute of Materials","award":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"]}]},{"name":"LAQV-REQUIMTE","award":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"]}]},{"name":"FCT\/MCTES","award":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"]}]},{"name":"Joana Sousa and H\u00e9lio Albuquerque acknowledge the EpigenGlicON project","award":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016403","UIDB\/50011\/2020","UIDP\/50011\/2020","UIDB\/50006\/2020","POCI-01-0145-FEDER-029767"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Betulinic acid (BA) was used as starting building block to create a library of novel BA-derived compounds containing O- and N-heterocycles. Firstly, BA was converted into methyl betulonate (BoOMe), which was used as intermediate in the developed methodologies. 1,2-Oxazine-fused BoOMe compounds were obtained in 12\u201325% global yields through a Michael addition of nitromethane to methyl (E)-2-benzylidenebetulonate derivatives, followed by nitro group reduction and intramolecular cyclization. Remarkably, the triterpene acts as a diastereoselective inducer in the conjugate addition of nitromethane, originating only one diastereomer out of four possible ones. Furthermore, other oxygen and nitrogen-containing heterocycles were installed at the A-ring of BoOMe, affording 2-amino-3-cyano-4H-pyran-fused BoOMe, diarylpyridine-fused BoOMe and 1,2,3-triazole\u2013BoOMe compounds, using simple and straightforward synthetic methodologies. Finally, BA was revealed to be a versatile starting material, allowing the creation of a molecular diversification of compounds containing a triterpenic scaffold and O- and N-heterocycles.<\/jats:p>","DOI":"10.3390\/molecules27154904","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T04:04:00Z","timestamp":1659326640000},"page":"4904","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Decoration of A-Ring of a Lupane-Type Triterpenoid with Different Oxygen and Nitrogen Heterocycles"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1412-4197","authenticated-orcid":false,"given":"Joana L. C.","family":"Sousa","sequence":"first","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5905-3316","authenticated-orcid":false,"given":"H\u00e9lio M. T.","family":"Albuquerque","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, 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\u2014Aveiro Institute of Materials, 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":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,31]]},"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":"568","DOI":"10.1021\/acsmedchemlett.6b00010","article-title":"Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity","volume":"7","author":"Liu","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1177\/095632020801900301","article-title":"Bevirimat: A Novel Maturation Inhibitor for the Treatment of HIV-1 Infection","volume":"19","author":"Martin","year":"2008","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e01876-21","DOI":"10.1128\/AAC.01876-21","article-title":"GSK3640254 Is a Novel HIV-1 Maturation Inhibitor with an Optimized Virology Profile","volume":"66","author":"Dicker","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sousa, J.L.C., Freire, C.S.R., Silvestre, A.J.D., and Silva, A.M.S. (2019). Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds. Molecules, 24.","DOI":"10.3390\/molecules24020355"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1039\/C5NP00015G","article-title":"Pentacyclic triterpenoids with nitrogen- and sulfur-containing heterocycles: Synthesis and medicinal significance","volume":"32","author":"Kvasnica","year":"2015","journal-title":"Nat. Prod. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1002\/ajoc.201800163","article-title":"Synthesis of Betulinic Acid Derivatives with Modified A-Rings and their Application as Potential Drug Candidates","volume":"7","author":"Borkova","year":"2018","journal-title":"Asian J. Org. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"636","DOI":"10.2174\/0929867324666171009122612","article-title":"Click Reactions in Chemistry of Triterpenes\u2014Advances Towards Development of Potential Therapeutics","volume":"25","author":"Pokorny","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2174\/1570193X15666180531092843","article-title":"A Review on Current Synthetic Strategies of Oxazines","volume":"16","author":"Gaonkar","year":"2019","journal-title":"Mini-Rev. Org. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2174\/1385272824999201008154659","article-title":"Syntheses, Biological and Material Significance of Dihydro 1,3 oxazine Derivatives: An Overview","volume":"25","author":"Lathwal","year":"2021","journal-title":"Curr. Org. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1016\/j.tetlet.2007.02.032","article-title":"Design, synthesis and biological evaluation of new oxazines with potential antiparasitic activity","volume":"48","author":"Gamenara","year":"2007","journal-title":"Tetrahedron Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.tiv.2017.07.021","article-title":"Cyclohexene-fused 1,3-oxazines with selective antibacterial and antiparasitic action and low cytotoxic effects","volume":"44","author":"Pelaez","year":"2017","journal-title":"Toxicol. In Vitro"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/cptc.201900276","article-title":"A Synthetic Strategy for the Structural Modification of Photoactivatable BODIPY-Oxazine Dyads","volume":"4","author":"Thapaliya","year":"2020","journal-title":"ChemPhotoChem"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11773","DOI":"10.1021\/la201062h","article-title":"Fast and Stable Photochromic Oxazines for Fluorescence Switching","volume":"27","author":"Deniz","year":"2011","journal-title":"Langmuir"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"36977","DOI":"10.1039\/C7RA05441F","article-title":"The value of pyrans as anticancer scaffolds in medicinal chemistry","volume":"7","author":"Kumar","year":"2017","journal-title":"RSC Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11594","DOI":"10.1038\/s41598-020-68076-1","article-title":"Ultrasound-assisted multicomponent synthesis of 4H-pyrans in water and DNA binding studies","volume":"10","author":"Gimeno","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10257","DOI":"10.1021\/jm501100b","article-title":"Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals","volume":"57","author":"Vitaku","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14046","DOI":"10.1021\/acs.jmedchem.1c01215","article-title":"Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design","volume":"64","author":"Subbaiah","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1039\/C3MD00282A","article-title":"Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes","volume":"5","author":"Haavikko","year":"2014","journal-title":"MedChemComm"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12290","DOI":"10.1021\/acs.jmedchem.0c00530","article-title":"Amide Bond Bioisosteres: Strategies, Synthesis, and Successes","volume":"63","author":"Kumari","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sousa, J.L.C., Gon\u00e7alves, C., Ferreira, R.M., Cardoso, S.M., Freire, C.S.R., Silvestre, A.J.D., and Silva, A.M.S. (2021). Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants. Antioxidants, 10.","DOI":"10.3390\/antiox10020148"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1055\/s-0034-1380144","article-title":"Efficient Synthesis of Highly Enantioenriched \u03941-Pyrrolines","volume":"26","author":"Resende","year":"2015","journal-title":"Synlett"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3449","DOI":"10.1002\/ejoc.201000273","article-title":"Highly Enantioselective 1,4-Michael Additions of Nucleophiles to Unsaturated Aryl Ketones with Organocatalysis by Bifunctional Cinchona Alkaloids","volume":"2010","author":"Oliva","year":"2010","journal-title":"Eur. J. Org. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3797","DOI":"10.1021\/jo200112r","article-title":"Organocatalytic Conjugate Addition of Malononitrile to Conformationally Restricted Dienones","volume":"76","author":"Hu","year":"2011","journal-title":"J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Albuquerque, H.M.T., Santos, C.M.M., Balanay, M.P., Cavaleiro, J.A.S., and Silva, A.M.S. (2017). 1,6-Conjugate Additions of Carbon Nucleophiles to 2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones. Eur. J. Org. Chem., 5293\u20135305.","DOI":"10.1002\/ejoc.201700944"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s11030-019-09994-9","article-title":"Synthesis and pharmacological properties of polysubstituted 2-amino-4H-pyran-3-carbonitrile derivatives","volume":"24","author":"Tashrifi","year":"2020","journal-title":"Mol. Divers."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5312","DOI":"10.1002\/cptc.202000134","article-title":"Unsymmetrical 2,4,6-Triarylpyridines as Versatile Scaffolds for Deep-Blue and Dual-Emission Fluorophores","volume":"4","author":"Fontes","year":"2020","journal-title":"ChemPhotoChem"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4732","DOI":"10.1002\/ejoc.201500448","article-title":"(E)-2-(4-Arylbut-1-en-3-yn-1-yl)chromones as Synthons for the Synthesis of Xanthone-1,2,3-triazole Dyads","volume":"2015","author":"Albuquerque","year":"2015","journal-title":"Eur. J. Org. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/15\/4904\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:29Z","timestamp":1760140829000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/15\/4904"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,31]]},"references-count":29,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["molecules27154904"],"URL":"https:\/\/doi.org\/10.3390\/molecules27154904","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2022,7,31]]}}}