{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T21:33:29Z","timestamp":1774992809888,"version":"3.50.1"},"reference-count":111,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T00:00:00Z","timestamp":1722816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Irish Research Council","award":["GOIPG\/2021\/954"],"award-info":[{"award-number":["GOIPG\/2021\/954"]}]},{"name":"Irish Research Council","award":["GOIPD\/2023\/1294"],"award-info":[{"award-number":["GOIPD\/2023\/1294"]}]},{"name":"Trinity College Dublin Postgraduate research scholarships (AJB, JPMcK)","award":["GOIPG\/2021\/954"],"award-info":[{"award-number":["GOIPG\/2021\/954"]}]},{"name":"Trinity College Dublin Postgraduate research scholarships (AJB, JPMcK)","award":["GOIPD\/2023\/1294"],"award-info":[{"award-number":["GOIPD\/2023\/1294"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels\u2013Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and N-substituted maleimides, to afford a series of 9-(E)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(E)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes 23f, 23h, 24a, 24g, 25f and 27. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as 20a, 20f, 23a and 25n with IC50 values in the ranges of 0.17\u20132.69 \u00b5M (HG-3) and 0.35\u20131.97 \u00b5M (PGA-1). The pro-apoptotic effects of the potent compounds 20a, 20f, 23a and 25n were demonstrated in CLL cell lines HG-3 (82\u201395%) and PGA-1 (87\u201397%) at 10 \u00b5M, with low toxicity (12\u201316%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC50 values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, 20a, 20f, 23a and 25n, was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. 25n also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI50 value of 0.245 \u00b5M. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL.<\/jats:p>","DOI":"10.3390\/ph17081034","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T18:21:40Z","timestamp":1722882100000},"page":"1034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and Biochemical Evaluation of Ethanoanthracenes and Related Compounds: Antiproliferative and Pro-Apoptotic Effects in Chronic Lymphocytic Leukemia (CLL)"],"prefix":"10.3390","volume":"17","author":[{"given":"James","family":"McKeown","sequence":"first","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4\/5, Dublin 2, D02 PN40 Dublin, Ireland"},{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Byrne","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4\/5, Dublin 2, D02 PN40 Dublin, Ireland"},{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Bright","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Charleton","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4\/5, Dublin 2, D02 PN40 Dublin, Ireland"},{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shubhangi","family":"Kandwal","sequence":"additional","affiliation":[{"name":"Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland"},{"name":"Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland"},{"name":"DCU Life Sciences Institute, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7787-8653","authenticated-orcid":false,"given":"Ivan","family":"\u010cmelo","sequence":"additional","affiliation":[{"name":"Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland"},{"name":"DCU Life Sciences Institute, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendan","family":"Twamley","sequence":"additional","affiliation":[{"name":"School of Chemistry, Trinity College Dublin, Dublin 2, D02 P3X2 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3276-1341","authenticated-orcid":false,"given":"Anthony","family":"McElligott","sequence":"additional","affiliation":[{"name":"Discipline of Haematology, School of Medicine, Trinity Translational Medicine Institute, St. James\u2019s Hospital and Trinity College, Dublin 8, D08 W9RT Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darren","family":"Fayne","sequence":"additional","affiliation":[{"name":"Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland"},{"name":"DCU Life Sciences Institute, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5660-4944","authenticated-orcid":false,"given":"Niamh","family":"O\u2019Boyle","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4\/5, Dublin 2, D02 PN40 Dublin, Ireland"},{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Williams","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8930-5753","authenticated-orcid":false,"given":"Mary","family":"Meegan","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4\/5, Dublin 2, D02 PN40 Dublin, Ireland"},{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,5]]},"reference":[{"key":"ref_1","unstructured":"Cancer Stat Facts: Leukemia\u2014Chronic Lymphocytic Leukemia (CLL) (2024, April 26). 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