Synthesis of Mesylated and Tosylated α-Hydroxy-Benzylphosphonates; Their Reactivity and Cytostatic Activity.
| Autor: | Szalai Z; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary., Debrei M; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary., Ábrányi-Balogh P; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary.; Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Hungary.; National Drug Research and Development Laboratory, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Hungary., Bősze S; Hungarian Research Network (HUN-REN), HUN-REN-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, 1117 Budapest, Hungary., Oláhné Szabó R; Hungarian Research Network (HUN-REN), HUN-REN-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, 1117 Budapest, Hungary.; Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary., Karaghiosoff K; Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, Germany., Drahos L; MS Proteomics Research Group, Research Centre for Natural Sciences, 1117 Budapest, Hungary., Keglevich G; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary. |
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| Jazyk: | angličtina |
| Zdroj: | ACS omega [ACS Omega] 2024 Jul 02; Vol. 9 (28), pp. 31043-31055. Date of Electronic Publication: 2024 Jul 02 (Print Publication: 2024). |
| DOI: | 10.1021/acsomega.4c04382 |
| Abstrakt: | α-Hydroxyphosphonates and their acylated and phosphorylated derivatives may be of significant biological activity including cytotoxic effects. To extend the pool of the potentially bioactive species, new methane- and arenesulfonyloxyphosphonates were synthesized by the sulfonylation of differently substituted α-hydroxy-benzylphosphonates using methanesulfonyl chloride or p -toluenesulfonyl chloride at 25 °C in the presence of triethylamine in toluene. The new sulfonyl derivatives were obtained in 54-80% yields. In the case of the 4- or 2-methoxy substituent in the aromatic ring, surprisingly the corresponding α-chlorophosphonates were the exclusive products, whose formation was explained assuming a quinoid intermediate and supported by theoretical calculations. With a 3-methoxyphenyl substituent, the expected mesylation of the hydroxy group took place. Attempted alcoholyses of the diethyl α-methanesulfonyloxy-benzylphosphonates with different substituents in the benzyl ring at ∼140 °C in the presence of triethylamine under microwave irradiation left the P-function intact under the conditions applied, instead, the mesyloxy group was substituted by an alkoxy unit in a selective new reaction. The α-alkoxy-benzylphosphonates were isolated in 60-77% yields. While α-chloro- or α-bromo-benzylphosphonates proved to be rather inefficient in the Michaelis-Arbuzov reaction with triethyl phosphite, according to a new possibility, the α-methansulfonyloxy-benzylphosphonates underwent an efficient Arbuzov fission using the phosphite in excess at 135 °C. The arylmethylenebisphosphonates were obtained in yields of 76-81%. Bioactivity studies with the members of the phosphonate library revealed pronounced in vitro cytostatic effect of the α-hydroxy- and α-mesyloxy-3,5-di- tert -butylbenzylphosphonates on human breast carcinoma cell culture with IC Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.) |
| Databáze: | MEDLINE |
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