{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:05:32Z","timestamp":1787065532204,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["K134318"],"award-info":[{"award-number":["K134318"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Methylenebisphosphonic derivatives including hydroxy-methylenebisphosphonic species may be of potential biological activity, and a part of them is used in the treatment of bone diseases. Methods: Methylenebisphosphonates may be obtained by the Michaelis\u2013Arbuzov reaction of suitably \u03b1-substituted methylphosphonates and trialkyl phosphites or phosphinous esters, while the hydroxy-methylene variations are prepared by the Pudovik reaction of \u03b1-oxophosphonates and different &gt;P(O)H reagents, such as diethyl phosphite and diarylphosphine oxides. Results: After converting \u03b1-hydroxy-benzylphosphonates and -phosphine oxides to the \u03b1-halogeno- and \u03b1-sulfonyloxy derivatives, they were utilized in the Michaelis\u2013Arbuzov reaction with trialkyl phosphites and ethyl diphenylphosphinite to afford the corresponding bisphosphonate, bis(phosphine oxide) and phosphonate\u2013phosphine oxide derivatives. The Pudovik approach led to \u03b1-hydroxy-methylenebisphosphonic species and to their rearranged products. A part of the derivatives revealed a significant cytotoxic effect on pancreatic adenocarcinoma or multiple myeloma cells. Conclusions: The new families of compounds synthesized by our novel approaches may be of practical importance due to the significant cytotoxic activity on the cell cultures investigated. Compounds lacking hydroxy groups showed anti-myeloma activity or limited effect on pancreatic cancer (PANC-1) cells unless substituted with para-trifluoromethyl group. Hydroxy-containing bisphosphonates and their rearranged derivatives demonstrated varying effects depending on structural modifications. While myeloma (U266) cells indicated greater sensitivity overall, the most significant reductions in cell viability were observed in PANC-1 cancer cells, raising potential therapeutic applications of bisphosphonates beyond myeloma-associated bone disease, particularly for malignancies like pancreatic ductal adenocarcinoma.<\/jats:p>","DOI":"10.3390\/ph18010091","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T11:31:31Z","timestamp":1736767891000},"page":"91","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis\u2013Arbuzov or the Pudovik Reaction"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3559-6011","authenticated-orcid":false,"given":"Zsuzsanna","family":"Szalai","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janka","family":"Bedn\u00e1rik","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boldizs\u00e1r Szigfrid","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9la","family":"Tak\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szil\u00e1rd","family":"Tekula","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"K\u0151hidai","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8855-730X","authenticated-orcid":false,"given":"Konstantin","family":"Karaghiosoff","sequence":"additional","affiliation":[{"name":"Department Chemie, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Butenandtstr. 5-13, D-81377 M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9589-6652","authenticated-orcid":false,"given":"L\u00e1szl\u00f3","family":"Drahos","sequence":"additional","affiliation":[{"name":"MS Proteomics Research Group, Research Centre for Natural Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5366-472X","authenticated-orcid":false,"given":"Gy\u00f6rgy","family":"Keglevich","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fischer, J., and Ganellin, C.R. 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