Half-Sandwich Type Platinum-Group Metal Complexes of <i>C</i>-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities
While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-grou...
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MDPI AG
2023-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/7/3058 |
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| author | István Kacsir Adrienn Sipos Evelin Major Nikolett Bajusz Attila Bényei Péter Buglyó László Somsák Gábor Kardos Péter Bai Éva Bokor |
| author_facet | István Kacsir Adrienn Sipos Evelin Major Nikolett Bajusz Attila Bényei Péter Buglyó László Somsák Gábor Kardos Péter Bai Éva Bokor |
| author_sort | István Kacsir |
| collection | DOAJ |
| description | While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a <i>C</i>-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to <i>O</i>-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above <i>C</i>-glucosaminyl heterocycles in their <i>O</i>-perbenzylated, <i>O</i>-perbenzoylated and <i>O</i>-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with <i>p</i>-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with <i>p</i>-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, <i>O</i>-benzyl groups were superior to <i>O</i>-benzoyl groups. The IC<sub>50</sub> values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive <i>Staphylococcus aureus</i> and <i>Enterococcus</i> clinical isolates in the low micromolar range. |
| first_indexed | 2024-03-11T05:29:29Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T05:29:29Z |
| publishDate | 2023-03-01 |
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| series | Molecules |
| spelling | doaj.art-30af28179b93455b82bd4840db51a6892023-11-17T17:12:54ZengMDPI AGMolecules1420-30492023-03-01287305810.3390/molecules28073058Half-Sandwich Type Platinum-Group Metal Complexes of <i>C</i>-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial ActivitiesIstván Kacsir0Adrienn Sipos1Evelin Major2Nikolett Bajusz3Attila Bényei4Péter Buglyó5László Somsák6Gábor Kardos7Péter Bai8Éva Bokor9Department of Organic Chemistry, University of Debrecen, P.O. Box 400, H-4002 Debrecen, HungaryDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem Tér 1., H-4032 Debrecen, HungaryDepartment of Metagenomics, University of Debrecen, H-4032 Debrecen, HungaryDepartment of Metagenomics, University of Debrecen, H-4032 Debrecen, HungaryDepartment of Physical Chemistry, Faculty of Sciences and Technology, University of Debrecen, Egyetem Tér 1., H-4032 Debrecen, HungaryDepartment of Inorganic & Analytical Chemistry, Faculty of Sciences and Technology, University of Debrecen, Egyetem Tér 1., H-4032 Debrecen, HungaryDepartment of Organic Chemistry, University of Debrecen, P.O. Box 400, H-4002 Debrecen, HungaryDepartment of Metagenomics, University of Debrecen, H-4032 Debrecen, HungaryDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem Tér 1., H-4032 Debrecen, HungaryDepartment of Organic Chemistry, University of Debrecen, P.O. Box 400, H-4002 Debrecen, HungaryWhile platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a <i>C</i>-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to <i>O</i>-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above <i>C</i>-glucosaminyl heterocycles in their <i>O</i>-perbenzylated, <i>O</i>-perbenzoylated and <i>O</i>-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with <i>p</i>-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with <i>p</i>-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, <i>O</i>-benzyl groups were superior to <i>O</i>-benzoyl groups. The IC<sub>50</sub> values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive <i>Staphylococcus aureus</i> and <i>Enterococcus</i> clinical isolates in the low micromolar range.https://www.mdpi.com/1420-3049/28/7/3058rutheniumosmiumiridiumrhodiumhalf-sandwich complex<i>C</i>-glucosaminyl heterocycles |
| spellingShingle | István Kacsir Adrienn Sipos Evelin Major Nikolett Bajusz Attila Bényei Péter Buglyó László Somsák Gábor Kardos Péter Bai Éva Bokor Half-Sandwich Type Platinum-Group Metal Complexes of <i>C</i>-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities Molecules ruthenium osmium iridium rhodium half-sandwich complex <i>C</i>-glucosaminyl heterocycles |
| title | Half-Sandwich Type Platinum-Group Metal Complexes of <i>C</i>-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities |
| title_full | Half-Sandwich Type Platinum-Group Metal Complexes of <i>C</i>-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities |
| title_fullStr | Half-Sandwich Type Platinum-Group Metal Complexes of <i>C</i>-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities |
| title_full_unstemmed | Half-Sandwich Type Platinum-Group Metal Complexes of <i>C</i>-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities |
| title_short | Half-Sandwich Type Platinum-Group Metal Complexes of <i>C</i>-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities |
| title_sort | half sandwich type platinum group metal complexes of i c i glucosaminyl azines synthesis and antineoplastic and antimicrobial activities |
| topic | ruthenium osmium iridium rhodium half-sandwich complex <i>C</i>-glucosaminyl heterocycles |
| url | https://www.mdpi.com/1420-3049/28/7/3058 |
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