{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T11:55:32Z","timestamp":1764244532251,"version":"3.46.0"},"reference-count":36,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Commission MSCA Staff Exchanges project GreenCosmIn \u201cGreen chemistry and biotechnology approaches for the development of nature-based cosmetics\u201d","award":["101131346"],"award-info":[{"award-number":["101131346"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>\u03a4riterpenic acids represent a prominent class of bioactive compounds, with a wide range of biological properties, including anti-inflammatory, antiviral, and anticancer effects. Among them, 24Z-isomasticadienonic acid (IMNA), a major constituent of Chios Mastic Gum, has attracted little attention compared with other well-studied triterpenes such as oleanolic or betulinic acid, largely because its isolation in sufficient purity and quantity was only recently achieved. In this study, a series of IMNA analogs was synthesized through targeted modifications at the A-ring. These included the introduction of heteroatoms at position 2, the incorporation of heterocyclic rings such as an oxazole and a thiazole, and rearrangements of the ring structure. The new compounds were evaluated for their antiproliferative activity against a diverse panel of cancer cell lines (Capan-1, HCT-116, LN-229, NCI-H460, DND-41, HL-60, K-562, Z-138). Among the synthesized analogs, compounds 3, 7 and 9 demonstrated selective anticancer activity toward the Capan-1 cell line, whereas compounds 6 and 10 exhibited broad-spectrum cytotoxic effects across multiple cancer cell lines. Overall, these findings highlight IMNA as a promising scaffold for anticancer drug design and demonstrate the value of A-ring modifications in improving activity and selectivity.<\/jats:p>","DOI":"10.3390\/molecules30234572","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T11:50:13Z","timestamp":1764244213000},"page":"4572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and Synthesis of Structurally Modified Analogs of 24Z-Isomasticadienonic Acid with Enhanced Anti-Proliferative Activity"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4628-8719","authenticated-orcid":false,"given":"Panagiota","family":"Stamou","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7898-0868","authenticated-orcid":false,"given":"Leentje","family":"Persoons","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, Box 1048, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3256-5850","authenticated-orcid":false,"given":"Dominique","family":"Schols","sequence":"additional","affiliation":[{"name":"Molecular, Structural and Translational Virology Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, Box 1049, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3872-6558","authenticated-orcid":false,"given":"Steven","family":"De Jonghe","sequence":"additional","affiliation":[{"name":"Molecular, Structural and Translational Virology Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, Box 1049, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leandros A.","family":"Skaltsounis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmacognosy and Natural Products Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9901-5223","authenticated-orcid":false,"given":"Ioannis K.","family":"Kostakis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural Products as Sources of New Drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0163-7258(03)00042-1","article-title":"Natural Products for Cancer Prevention: A Global Perspective","volume":"99","author":"Reddy","year":"2003","journal-title":"Pharmacol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural Products in Drug Discovery: Advances and Opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s11101-010-9172-2","article-title":"Anti-HIV Activity of Natural Triterpenoids and Hemisynthetic Derivatives 2004\u20132009","volume":"10","author":"Cassels","year":"2011","journal-title":"Phytochem. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"465","DOI":"10.3109\/09546634.2015.1021663","article-title":"Triterpenes with Healing Activity: A Systematic Review","volume":"26","author":"Agra","year":"2015","journal-title":"J. Dermatol. Treat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.canlet.2012.02.037","article-title":"Targeted Inhibition of Tumor Proliferation, Survival, and Metastasis by Pentacyclic Triterpenoids: Potential Role in Prevention and Therapy of Cancer","volume":"320","author":"Shanmugam","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1055\/s-2006-957748","article-title":"Anti-Inflammatory Actions of Pentacyclic Triterpenes","volume":"63","author":"Safayhi","year":"1997","journal-title":"Planta Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1055\/s-0028-1097349","article-title":"Moronic Acid, a Simple Triterpenoid Keto Acid with Antimicrobial Activity Isolated from Ozoroa Mucronata","volume":"37","author":"Nakanishi","year":"1979","journal-title":"Planta Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0378-8741(95)90032-2","article-title":"Pharmacology of Oleanolic Acid and Ursolic Acid","volume":"49","author":"Liu","year":"1995","journal-title":"J. Ethnopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20614","DOI":"10.3390\/molecules201119721","article-title":"Ursolic Acid-A Pentacyclic Triterpenoid with a Wide Spectrum of Pharmacological Activities","volume":"20","year":"2015","journal-title":"Molecules"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3892\/ijo_00000402","article-title":"Betulinic Acid Treatment Promotes Apoptosis in Hepatoblastoma Cells","volume":"35","author":"Kappler","year":"2009","journal-title":"Int. J. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1021\/jm900872z","article-title":"Structure\u2212Activity Relationship Study of Betulinic Acid, A Novel and Selective TGR5 Agonist, and Its Synthetic Derivatives: Potential Impact in Diabetes","volume":"53","author":"Genet","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Xu, T., Pang, Q., Zhou, D., Zhang, A., Luo, S., Wang, Y., and Yan, X. (2014). Proteomic Investigation into Betulinic Acid-Induced Apoptosis of Human Cervical Cancer HeLa Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105768"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1158\/1078-0432.CCR-12-3630","article-title":"Lamin B1 Is a Novel Therapeutic Target of Betulinic Acid in Pancreatic Cancer","volume":"19","author":"Li","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7239","DOI":"10.1016\/j.bmc.2013.09.066","article-title":"Dimethylaminopyridine Derivatives of Lupane Triterpenoids Cause Mitochondrial Disruption and Induce the Permeability Transition","volume":"21","author":"Bernardo","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ejmech.2016.05.029","article-title":"Lupane and 18\u03b1-Oleanane Derivatives Substituted in the Position 2, Their Cytotoxicity and Influence on Cancer Cells","volume":"121","author":"Borkova","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2174\/1574892815666201002162315","article-title":"Terpenes with Antitumor Activity: A Patent Review","volume":"15","author":"Serafini","year":"2020","journal-title":"Recent Pat. Anticancer Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.drudis.2013.07.018","article-title":"Triterpenoids as Reversal Agents for Anticancer Drug Resistance Treatment","volume":"19","author":"Yan","year":"2014","journal-title":"Drug Discov. Today"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.1021\/jm201540h","article-title":"Synthesis and Biological Evaluation of Heterocyclic Ring-Fused Betulinic Acid Derivatives as Novel Inhibitors of Osteoclast Differentiation and Bone Resorption","volume":"55","author":"Xu","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"127555","DOI":"10.1016\/j.molstruc.2019.127555","article-title":"Synthesis, Structure Analysis and Activity against Breast and Cervix Cancer Cells of a Triterpenoid Thiazole Derived from Ochraceolide A","volume":"1204","author":"Quijano","year":"2020","journal-title":"J. Mol. Struct."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1128\/AAC.00642-06","article-title":"In Vitro and in Vivo Activities of Chios Mastic Gum Extracts and Constituents against Helicobacter Pylori","volume":"51","author":"Paraschos","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Stamou, P., Gianniou, D.D., Trougakos, I.P., Mitakou, S., Halabalaki, M., Kostakis, I.K., and Skaltsounis, A.-L. (2024). Anti-Inflammatory Activity of the Major Triterpenic Acids of Chios Mastic Gum and Their Semi-Synthetic Analogues. Biomolecules, 14.","DOI":"10.3390\/biom14121618"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ayeleso, T.B., Matumba, M.G., and Mukwevho, E. (2017). Oleanolic Acid and Its Derivatives: Biological Activities and Therapeutic Potential in Chronic Diseases. Molecules, 22.","DOI":"10.3390\/molecules22111915"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.molmed.2004.11.001","article-title":"Betulinic Acid Derivatives as HIV-1 Antivirals","volume":"11","author":"Aiken","year":"2005","journal-title":"Trends Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mlala, S., Oyedeji, A.O., Gondwe, M., and Oyedeji, O.O. (2019). Ursolic Acid and Its Derivatives as Bioactive Agents. Molecules, 24.","DOI":"10.3390\/molecules24152751"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1055\/s-1970-21620","article-title":"The Isomerization of Olefins Part II. Thermal and Catalytic Lsomerization of Olefins Using Acids, Metals, Metal Complexes, or Boron Compounds as Catalysts","volume":"1970","author":"Hubert","year":"1970","journal-title":"Synthesis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5774","DOI":"10.1016\/j.bmc.2012.08.010","article-title":"Synthesis of Novel Ursolic Acid Heterocyclic Derivatives with Improved Abilities of Antiproliferation and Induction of P53, P21waf1 and NOXA in Pancreatic Cancer Cells","volume":"20","author":"Leal","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4692","DOI":"10.1021\/jm5002293","article-title":"Tryptophan Hydroxylase 1 (Tph-1)-Targeted Bone Anabolic Agents for Osteoporosis","volume":"57","author":"Fu","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1039\/c2md20051a","article-title":"Synthesis, Anti-Proliferative and Proapoptotic Activity of Novel Oleanolic Acid Azaheterocyclic Derivatives","volume":"3","author":"Kang","year":"2012","journal-title":"MedChemComm"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.bmcl.2016.12.071","article-title":"Discovery of FZU-03,010 as a Self-Assembling Anticancer Amphiphile for Acute Myeloid Leukemia","volume":"27","author":"Chen","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, R., Yang, W., Fan, Y., Dehaen, W., Li, Y., Li, H., Wang, W., Zheng, Q., and Huai, Q. (2019). Design and Synthesis of the Novel Oleanolic Acid-Cinnamic Acid Ester Derivatives and Glycyrrhetinic Acid-Cinnamic Acid Ester Derivatives with Cytotoxic Properties. Bioorg. Chem., 88.","DOI":"10.1016\/j.bioorg.2019.102951"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"114784","DOI":"10.1016\/j.ejmech.2022.114784","article-title":"Design, Synthesis, and Biological Evaluation of Ocotillol Derivatives Fused with 2-Aminothiazole via A-Ring as Modulators of P-Glycoprotein-Mediated Multidrug Resistance","volume":"243","author":"Wang","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/cmdc.201600626","article-title":"Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid","volume":"12","author":"Borkova","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19057","DOI":"10.1039\/c3ra42929f","article-title":"Stereoselectivity of A-Ring Contraction for 3-Oxotriterpenoids","volume":"3","author":"Kacharov","year":"2013","journal-title":"RSC Adv."},{"key":"ref_36","first-page":"555788","article-title":"Lead Tetraacetate in Organic Synthesis","volume":"10","author":"Banerjee","year":"2021","journal-title":"Org. Med. Chem. Int. J."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/23\/4572\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T11:51:40Z","timestamp":1764244300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/23\/4572"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":36,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["molecules30234572"],"URL":"https:\/\/doi.org\/10.3390\/molecules30234572","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]}}}