Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik Reaction
<b>Background:</b> 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. <b>Methods:</b> Methylenebisphosphonates may be obtained by the Michae...
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2025-01-01
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| author | Zsuzsanna Szalai Janka Bednárik Boldizsár Szigfrid Tóth Angéla Takács Szilárd Tekula László Kőhidai Konstantin Karaghiosoff László Drahos György Keglevich |
| author_facet | Zsuzsanna Szalai Janka Bednárik Boldizsár Szigfrid Tóth Angéla Takács Szilárd Tekula László Kőhidai Konstantin Karaghiosoff László Drahos György Keglevich |
| author_sort | Zsuzsanna Szalai |
| collection | DOAJ |
| description | <b>Background:</b> 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. <b>Methods:</b> Methylenebisphosphonates may be obtained by the Michaelis–Arbuzov reaction of suitably α-substituted methylphosphonates and trialkyl phosphites or phosphinous esters, while the hydroxy-methylene variations are prepared by the Pudovik reaction of α-oxophosphonates and different >P(O)H reagents, such as diethyl phosphite and diarylphosphine oxides. <b>Results:</b> After converting α-hydroxy-benzylphosphonates and -phosphine oxides to the α-halogeno- and α-sulfonyloxy derivatives, they were utilized in the Michaelis–Arbuzov reaction with trialkyl phosphites and ethyl diphenylphosphinite to afford the corresponding bisphosphonate, bis(phosphine oxide) and phosphonate–phosphine oxide derivatives. The Pudovik approach led to α-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. <b>Conclusions:</b> 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. |
| format | Article |
| id | doaj-art-22aaac3011194b17be1428f57e2fd104 |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-22aaac3011194b17be1428f57e2fd1042025-01-24T13:45:21ZengMDPI AGPharmaceuticals1424-82472025-01-011819110.3390/ph18010091Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik ReactionZsuzsanna Szalai0Janka Bednárik1Boldizsár Szigfrid Tóth2Angéla Takács3Szilárd Tekula4László Kőhidai5Konstantin Karaghiosoff6László Drahos7György Keglevich8Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, HungaryDepartment of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, HungaryDepartment of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, HungaryDepartment of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, HungaryDepartment of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, HungaryDepartment of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, HungaryDepartment Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, GermanyMS Proteomics Research Group, Research Centre for Natural Sciences, 1117 Budapest, HungaryDepartment of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary<b>Background:</b> 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. <b>Methods:</b> Methylenebisphosphonates may be obtained by the Michaelis–Arbuzov reaction of suitably α-substituted methylphosphonates and trialkyl phosphites or phosphinous esters, while the hydroxy-methylene variations are prepared by the Pudovik reaction of α-oxophosphonates and different >P(O)H reagents, such as diethyl phosphite and diarylphosphine oxides. <b>Results:</b> After converting α-hydroxy-benzylphosphonates and -phosphine oxides to the α-halogeno- and α-sulfonyloxy derivatives, they were utilized in the Michaelis–Arbuzov reaction with trialkyl phosphites and ethyl diphenylphosphinite to afford the corresponding bisphosphonate, bis(phosphine oxide) and phosphonate–phosphine oxide derivatives. The Pudovik approach led to α-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. <b>Conclusions:</b> 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.https://www.mdpi.com/1424-8247/18/1/91bisphosphonatesdronatesArbuzov reactionPudovik reactionX-ray structurebiological activity |
| spellingShingle | Zsuzsanna Szalai Janka Bednárik Boldizsár Szigfrid Tóth Angéla Takács Szilárd Tekula László Kőhidai Konstantin Karaghiosoff László Drahos György Keglevich Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik Reaction Pharmaceuticals bisphosphonates dronates Arbuzov reaction Pudovik reaction X-ray structure biological activity |
| title | Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik Reaction |
| title_full | Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik Reaction |
| title_fullStr | Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik Reaction |
| title_full_unstemmed | Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik Reaction |
| title_short | Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis–Arbuzov or the Pudovik Reaction |
| title_sort | cytotoxic activity of bisphosphonic derivatives obtained by the michaelis arbuzov or the pudovik reaction |
| topic | bisphosphonates dronates Arbuzov reaction Pudovik reaction X-ray structure biological activity |
| url | https://www.mdpi.com/1424-8247/18/1/91 |
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