dc.contributor.author | Gorle, Anil Kumar | |
dc.contributor.author | Rajaratnam, Premraj | |
dc.contributor.author | Chang, Chih-Wei | |
dc.contributor.author | von Itzstein, Mark | |
dc.contributor.author | Berners-Price, Susan J | |
dc.contributor.author | Farrell, Nicholas P | |
dc.date.accessioned | 2020-06-29T02:57:34Z | |
dc.date.available | 2020-06-29T02:57:34Z | |
dc.date.issued | 2019 | |
dc.identifier.issn | 0020-1669 | |
dc.identifier.doi | 10.1021/acs.inorgchem.8b03035 | |
dc.identifier.uri | http://hdl.handle.net/10072/385427 | |
dc.description.abstract | We report herein a detailed NMR study of the aquation and subsequent covalent binding of the trinuclear clinical agent [{ trans-PtCl(15NH3)2}2{μ- trans-Pt(15NH3)2(15NH2(CH2)615NH2)2}]4+ (1, 1,0,1/ t, t, t or Triplatin) with three d-glucosamine residues containing varied O-sulfate and N-sulfate or N-acetyl substitutions, which represent monosaccharide fragments present within the repeating disaccharide sequences of cell surface heparan sulfate (HS). The monosaccharides GlcNS(6S), GlcNS, and GlcNAc(6S) were synthesized in good yield from a common 4,6-diol α-methyl glucopyranoside intermediate. The reactions of 15N-1 with sodium sulfate, GlcNS(6S), GlcNS, and GlcNAc(6S) were followed by 2D [1H,15N] heteronuclear single quantum coherence (HSQC) NMR spectroscopy using conditions (298 K, pH ≈5.4) similar to those previously used for other anionic systems, allowing for a direct comparison. The equilibrium constants (p K1) for the aquation of 1 in the presence of GlcNS(6S) and GlcNS were slightly higher compared to that of the aquation in a sulfate solution, while a comparable p K1 value was observed in the presence of GlcNAc(6S). A comparison of the rate constants for sulfate displacement of the aqua ligand showed preferential binding to 2- N-sulfate compared to 6- O-sulfate but a more rapid liberation. For disulfated GlcNS(6S), equilibrium conditions were achieved rapidly (9 h) and strongly favored the dichloro form, with <2% sulfato species observed. The value of kL1 was up to 15-fold lower than that for binding to sulfate, whereas the rate constant for the reverse ligation ( k-L1) was comparable. Equilibrium conditions were achieved much more slowly (∼ 100 h) for the reactions of 1 with GlcNS and GlcNAc(6S), attributed to covalent binding also to the N-donor of the sulfamate (GlcNS) group and the O-donor of the N-acetyl [GlcNAc(6S)] group. The rate constants ( kL2) were 20-40-fold lower than that for binding to the 2- N- or 6- O-sulfate, but the binding was less reversible, so that their equilibrium concentrations (5-8%) were comparable to the 2- N- or 6- O-sulfate-bound species. The results emphasize the relevance of glycans in bioinorganic chemistry and underpin a fundamental molecular description of the HS-Pt interactions that alter the profile of platinum agents from cytotoxic to metastatic in a systematic manner. | |
dc.description.peerreviewed | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | American Chemical Society | |
dc.relation.ispartoflocation | United States | |
dc.relation.ispartofpagefrom | 7146 | |
dc.relation.ispartofpageto | 7155 | |
dc.relation.ispartofissue | 11 | |
dc.relation.ispartofjournal | Inorganic Chemistry | |
dc.relation.ispartofvolume | 58 | |
dc.relation.uri | http://purl.org/au-research/grants/ARC/DP150100308 | |
dc.relation.grantID | DP150100308 | |
dc.relation.funders | ARC | |
dc.subject.fieldofresearch | Inorganic chemistry | |
dc.subject.fieldofresearch | Physical chemistry | |
dc.subject.fieldofresearch | Other chemical sciences | |
dc.subject.fieldofresearch | Macromolecular and materials chemistry | |
dc.subject.fieldofresearchcode | 3402 | |
dc.subject.fieldofresearchcode | 3406 | |
dc.subject.fieldofresearchcode | 3499 | |
dc.subject.fieldofresearchcode | 3403 | |
dc.title | Glycans as Ligands in Bioinorganic Chemistry. Probing the Interaction of a Trinuclear Platinum Anticancer Complex with Defined Monosaccharide Fragments of Heparan Sulfate | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
dc.description.version | Accepted Manuscript (AM) | |
gro.rights.copyright | This document is the Postprint: Accepted Manuscript version of a Published Work that appeared in final form in Inorganic Chemistry, copyright 2019 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.inorgchem.8b03035 | |
gro.hasfulltext | Full Text | |
gro.griffith.author | von Itzstein, Mark | |
gro.griffith.author | Berners-Price, Sue J. | |