{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:59:25Z","timestamp":1760147965424,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Trento, 5X1000 campaign, project \u201cFarmaci del Mare\u201d","award":["40103306"],"award-info":[{"award-number":["40103306"]}]},{"name":"Ivana and Enrico Zobele","award":["40103306"],"award-info":[{"award-number":["40103306"]}]},{"name":"European Regional Development Fund (ERDF)","award":["40103306"],"award-info":[{"award-number":["40103306"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>The marine polyarsenical metabolite arsenicin A is the landmark of a series of natural and synthetic molecules characterized by an adamantane-like tetraarsenic cage. Arsenicin A and related polyarsenicals have been evaluated for their antitumor effects in vitro and have been proven more potent than the FDA-approved arsenic trioxide. In this context, we have expanded the chemical space of polyarsenicals related to arsenicin A by synthesizing dialkyl and dimethyl thio-analogs, the latter characterized with the support of simulated NMR spectra. In addition, the new natural arsenicin D, the scarcity of which in the Echinochalina bargibanti extract had previously limited its full structural characterization, has been identified by synthesis. The dialkyl analogs, which present the adamantane-like arsenicin A cage substituted with either two methyl, ethyl, or propyl chains, were efficiently and selectively produced and evaluated for their activity on glioblastoma stem cells (GSCs), a promising therapeutic target in glioblastoma treatment. These compounds inhibited the growth of nine GSC lines more potently than arsenic trioxide, with GI50 values in the submicromolar range, both under normoxic and hypoxic conditions, and presented high selectivity toward non-tumor cell lines. The diethyl and dipropyl analogs, which present favorable physical-chemical and ADME parameters, had the most promising results.<\/jats:p>","DOI":"10.3390\/md21030186","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T03:09:37Z","timestamp":1679281777000},"page":"186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Expanding the Chemical Space of Arsenicin A-C Related Polyarsenicals and Evaluation of Some Analogs as Inhibitors of Glioblastoma Stem Cell Growth"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4359-6951","authenticated-orcid":false,"given":"Jacopo","family":"Vigna","sequence":"first","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4950-7254","authenticated-orcid":false,"given":"Denise","family":"Sighel","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6877-4948","authenticated-orcid":false,"given":"Emanuele Filiberto","family":"Rosatti","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Defant","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3783-6069","authenticated-orcid":false,"given":"Michael","family":"Pancher","sequence":"additional","affiliation":[{"name":"High Throughput Screening (HTS) and Validation Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2621-4977","authenticated-orcid":false,"given":"Viktoryia","family":"Sidarovich","sequence":"additional","affiliation":[{"name":"High Throughput Screening (HTS) and Validation Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Quattrone","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0297-3685","authenticated-orcid":false,"given":"Ines","family":"Mancini","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8989","DOI":"10.1002\/chem.200600783","article-title":"On the First Polyarsenic Organic Compound from Nature: Arsenicin A from the New Caledonian Marine Sponge Echinochalina bargibanti","volume":"12","author":"Mancini","year":"2006","journal-title":"Chem. Eur. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"T\u00e4htinen, P., Guella, G., Saielli, G., Debitus, C., Hnawia, E., and Mancini, I. (2018). New Sulfur-Containing Polyarsenicals from the New Caledonian Sponge Echinochalina bargibanti. Mar. Drugs, 16.","DOI":"10.20944\/preprints201809.0306.v1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10445","DOI":"10.1002\/chem.200801272","article-title":"Computational NMR Spectroscopy of Organoarsenicals and the Natural Polyarsenic Compound Arsenicin A","volume":"14","author":"Saielli","year":"2008","journal-title":"Chem. Eur. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1039\/b816729j","article-title":"Vibrational analysis as a powerful tool in structure elucidation of polyarsenicals: A DFT-based investigation of arsenicin A","volume":"11","author":"Guella","year":"2009","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_5","unstructured":"Mancini, I., and Defant, A. (2013). Progress in Molecular and Subcellular Biology, Springer."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Paul, N.P., Galv\u00e1n, A.E., Yoshinaga-Sakurai, K., Rosen, B.P., and Yoshinaga, M. (2022). Arsenic in medicine: Past, present and future. Biometals, 1\u201319.","DOI":"10.1007\/s10534-022-00371-y"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chin, L., Kumana, C.R., Kwong, Y.-L., and Gill, H. (2022). The Development and Clinical Applications of Oral Arsenic Trioxide for Acute Promyelocytic Leukaemia and Other Diseases. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091945"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/med.21844","article-title":"Current Status and Future Prospects of Nanomedicine for Arsenic Trioxide Delivery to Solid Tumors","volume":"42","author":"Kerl","year":"2022","journal-title":"Med. Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s11658-020-00236-7","article-title":"Arsenic trioxide as a novel anti-glioma drug: A review","volume":"25","author":"Fang","year":"2020","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1021\/om201180d","article-title":"Resolution and Improved Synthesis of (\u00b1)-Arsenicin A: A Natural Adamantane-Type Tetraarsenical Possessing Strong Anti-Acute Promelocytic Leukemia Cell Line Activity","volume":"31","author":"Lu","year":"2012","journal-title":"Organometallics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1021\/om500829y","article-title":"Sulfur Derivatives of the Natural Polyarsenical Arsenicin a: Biologically Active, Organometallic Arsenic-Sulfur Cages Related to the Minerals Realgar and Uzonite","volume":"34","author":"Lu","year":"2015","journal-title":"Organometallics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11548","DOI":"10.1038\/s41598-017-11566-6","article-title":"Synthesis and In-vitro Anticancer Evaluation of Polyarsenicals Related to the Marine Sponge Derived Arsenicin A","volume":"7","author":"Mancini","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.addr.2021.01.012","article-title":"Frontiers in the Treatment of Glioblastoma: Past, Present and Emerging","volume":"171","author":"Janjua","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Biserova, K., Jakovlevs, A., Uljanovs, R., and Strumfa, I. (2021). Cancer Stem Cells: Significance in Origin, Pathogenesis and Treatment of Glioblastoma. Cells, 10.","DOI":"10.3390\/cells10030621"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1002\/zaac.19966220627","article-title":"Struktur von S-9,10-Dimethyl-1,3,5,7-tetraarsa-2,4,6,8-tetraoxaadamantan und 9,10-Diethyl-1,3,5,7-tetraarsa-2,4,6,8-tetraoxaadamantan","volume":"622","author":"Marx","year":"1996","journal-title":"Z. Anorg. Allg. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1007\/s00894-015-2787-x","article-title":"Critical Test of Some Computational Methods for Prediction of NMR 1H and 13C Chemical Shifts","volume":"21","author":"Toomsalu","year":"2015","journal-title":"J. Mol. Model."},{"key":"ref_17","first-page":"37","article-title":"Determination of Sulphide in Arabian Seawater using UV-Visible Spectrophotometer","volume":"58","author":"Butt","year":"2021","journal-title":"Nucleus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1039\/C8MT00231B","article-title":"Thiolation in arsenic metabolism: A chemical perspective","volume":"10","author":"Fan","year":"2018","journal-title":"Metallomics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1002\/poc.1719","article-title":"Computing the NMR Spectra of the Sponge Metabolite Arsenicin A: When Simple Becomes Difficult","volume":"23","author":"Bagno","year":"2010","journal-title":"J. Phys. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109024","DOI":"10.1016\/j.celrep.2021.109024","article-title":"Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth","volume":"35","author":"Sighel","year":"2021","journal-title":"Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/bs.podrm.2020.07.005","article-title":"Validation of in-vitro bioassay methods: Application in herbal drug research","volume":"46","author":"Indrayanto","year":"2021","journal-title":"Profiles of Drug Substances, Excipients and Related Methodology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"114979","DOI":"10.1016\/j.ejmech.2022.114979","article-title":"Streptogramin A derivatives as mitochondrial translation inhibitors to suppress glioblastoma stem cell growth","volume":"246","author":"Sighel","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/ijc.29121","article-title":"Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019","volume":"136","author":"Vecchio","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Dube, C., Gibert, M., Cruickshanks, N., Wang, B., Coughlan, M., Yang, Y., Setiady, I., Deveau, C., and Saoud, K. (2018). The p53 Pathway in Glioblastoma. Cancers, 10.","DOI":"10.3390\/cancers10090297"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1093\/neuonc\/now258","article-title":"Hypoxia in the glioblastoma microenvironment: Shaping the phenotype of cancer stem-like cells","volume":"19","author":"Colwell","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ccr.2009.03.018","article-title":"Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells","volume":"15","author":"Li","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1021\/tx200156k","article-title":"Mitochondria are the main target organelle for trivalent monomethylarsonous acid (MMA(III))-induced cytotoxicity","volume":"24","author":"Naranmandura","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1101\/gad.188292.112","article-title":"Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells","volume":"26","author":"Janiszewska","year":"2012","journal-title":"Genes Dev."},{"key":"ref_29","unstructured":"(2023, January 09). Swiss ADME. Available online: http:\/\/www.swissadme.ch\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_31","first-page":"1","article-title":"Glioblastoma stem cells: A new target for metformin and arsenic trioxide","volume":"28","author":"Carmignani","year":"2014","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_32","unstructured":"Molsft, L.L.C. (2023, March 02). Available online:https:\/\/www.molsoft.com\/."},{"key":"ref_33","unstructured":"(2023, March 02). Molinspiration. Available online: https:\/\/www.molinspiration.com\/."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1021\/cr9904009","article-title":"Quantum Mechanical Continuum Solvation Models","volume":"105","author":"Tomasi","year":"2005","journal-title":"Chem. Rev."},{"key":"ref_35","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Vreven, T., Kudin, K.N., and Burant, J.C. (2004). Gaussian, Gaussian, Inc.. Revision E.01."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1103\/PhysRevA.38.3098","article-title":"Density-Functional exchange-energy approximation with correct asymptotic behavior","volume":"38","author":"Becke","year":"1988","journal-title":"Phys. Rev. A"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1080\/00268970010018431","article-title":"Left-Right correlation energy","volume":"99","author":"Handy","year":"2001","journal-title":"J. Mol. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0009-2614(01)00581-4","article-title":"Assessment of a new local exchange functional OPTX","volume":"341","author":"Hoe","year":"2001","journal-title":"Chem. Phys. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"044108","DOI":"10.1063\/1.3185673","article-title":"Can short-range hybrids describe long-range-dependent properties?","volume":"131","author":"Henderson","year":"2009","journal-title":"J. Chem. Phys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6158","DOI":"10.1063\/1.478522","article-title":"Toward Reliable Density Functional Methods without Adjustable Parameters: The PBE0 Model","volume":"110","author":"Adamo","year":"1999","journal-title":"J. Chem. Phys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5688","DOI":"10.1063\/1.1677088","article-title":"Molecular Orbital Theory of Magnetic Shielding and Magnetic Susceptibility","volume":"56","author":"Ditchfield","year":"1972","journal-title":"J. Chem. Phys."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8251","DOI":"10.1021\/ja00179a005","article-title":"Efficient implementation of the gauge-independent atomic orbital method for NMR chemical shift calculations","volume":"112","author":"Wolinski","year":"1990","journal-title":"J. Am. Chem. Soc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/ijc.28680","article-title":"Predictability, efficacy and safety of radiosensitization of glioblastoma-initiating cells by the ATM inhibitor KU-60019","volume":"135","author":"Vecchio","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1158\/1541-7786.MCR-08-0409","article-title":"Comparative Analysis of DNA Repair in Stem and Nonstem Glioma Cell Cultures","volume":"7","author":"Ropolo","year":"2009","journal-title":"Mol. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.stem.2009.03.014","article-title":"Glioma Stem Cell Lines Expanded in Adherent Culture Have Tumor-Specific Phenotypes and Are Suitable for Chemical and Genetic Screens","volume":"4","author":"Pollard","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.stemcr.2015.09.014","article-title":"Glioblastoma stem cells respond to differentiation cues but fail to undergo commitment and terminal cell-cycle arrest","volume":"5","author":"Stricker","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Conti, L., Crisafulli, L., Caldera, V., Tortoreto, M., Brilli, E., Conforti, P., Zunino, F., Magrassi, L., Schiffer, D., and Cattaneo, E. (2012). REST Controls Self-Renewal and Tumorigenic Competence of Human Glioblastoma Cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038486"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1093\/neuonc\/now304","article-title":"The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response","volume":"19","author":"Biffoni","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1038\/nature09557","article-title":"Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells","volume":"468","author":"Pallini","year":"2010","journal-title":"Nature"}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/21\/3\/186\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:57:50Z","timestamp":1760122670000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/21\/3\/186"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,17]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["md21030186"],"URL":"https:\/\/doi.org\/10.3390\/md21030186","relation":{},"ISSN":["1660-3397"],"issn-type":[{"type":"electronic","value":"1660-3397"}],"subject":[],"published":{"date-parts":[[2023,3,17]]}}}