Conformational Modulation of Iduronic Acid‐Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs

Abstract

1H 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 1C4:2S0 forms of the FPX residue IdoA(2S) is altered from ca. 35:65 (free FPX) to ca. 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.

Synthetic Strategy Towards Heterodimetallic Half-Sandwich Complexes Based on a Symmetric Ditopic Ligand

“…The nature of the anticancer activity observed for multimetallic compounds is likely to be different from those found for the corresponding monometallic analogs due to altered molecular modes of action, as discussed above for BBR3464 and closely related compounds ( Ruhayel et al, 2012 ). Besides DNA, bis- and tris-Pt complexes can also bind to proteoglycans through sulfate anchoring ( Gorle et al, 2018 ; Gorle et al, 2021 ). The resulting metalloshielding stops enzyme degradation and has recently been shown to be biologically relevant in cells ( Gorle et al, 2018 ; Gorle et al, 2021 ).…”

“…Besides DNA, bis- and tris-Pt complexes can also bind to proteoglycans through sulfate anchoring ( Gorle et al, 2018 ; Gorle et al, 2021 ). The resulting metalloshielding stops enzyme degradation and has recently been shown to be biologically relevant in cells ( Gorle et al, 2018 ; Gorle et al, 2021 ). This method of template protection, a strategy analogous to complex–DNA binding, heralds a new avenue in the mechanisms of action for multimetallic compounds ( Gorle et al, 2021 ).…”