Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs
| Autor: | Erica J. Peterson, Arun V. Everest-Dass, Mark von Itzstein, Nicholas Farrell, Kazuaki Takabe, Susan J. Berners-Price, Eriko Katsuta, Thomas Haselhorst, James D. Hampton, Anil K. Gorle, Samantha J. Katner, Jennifer E. Koblinski |
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| Rok vydání: | 2020 |
| Předmět: |
Magnetic Resonance Spectroscopy
Organoplatinum Compounds Stereochemistry Iduronic Acid Molecular Conformation Iduronic acid Antineoplastic Agents 010402 general chemistry 01 natural sciences Catalysis Article Adduct chemistry.chemical_compound Sulfation Cell Movement Cell Line Tumor Humans Density Functional Theory Glycosaminoglycans Platinum chemistry.chemical_classification 010405 organic chemistry Chemistry Glycosidic bond General Chemistry Nuclear magnetic resonance spectroscopy Heparan sulfate Small molecule 0104 chemical sciences Platinum Compound Heparitin Sulfate |
| Zdroj: | Angew Chem Int Ed Engl |
| ISSN: | 1521-3773 |
| Popis: | (1)H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution-inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the (1)C(4):(2)S(0) forms of the FPX residue IdoA(2S) is altered from ≈ 35:65 (free FPX) to ≈ 75:25 in the adduct; the first demonstration of a small molecule affecting conformational changes on a HS oligosaccharide. Functional consequences of such binding are suggested to be inhibition of HS cleavage in MDA-MB-231 triple-negative breast cancer (TNBC) cells. We further describe inhibition of metastasis by TriplatinNC in the TNBC 4T1 syngeneic tumour model. Our work provides insight into a novel approach for design of platinum drugs (and coordination compounds in general) with intrinsic anti-metastatic potential. |
| Databáze: | OpenAIRE |
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