Abstract
Quinolines, indolizines, and coumarins are well known structural elements in many biologically active molecules. In this report, we have developed straightforward methods to incorporate quinoline, indolizine, and coumarin structures into galactoside derivatives under robust reaction conditions for the discovery of glycomimetic inhibitors of the galectin family of proteins that are involved in immunological and tumor-promoting biological processes. Evaluation of the quinoline, indolizine and coumarin-derivatised galactosides as inhibitors of the human galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9N, and 9C revealed quinoline derivatives that selectively bound galectin-8N, a galectin with key roles in lymphangiogenesis, tumor progression, and autophagy, with up to nearly 60-fold affinity improvements relative to methyl β-d-galactopyranoside. Molecular dynamics simulations proposed an interaction mode in which Arg59 had moved 2.5 Å and in which an inhibitor carboxylate and quinoline nitrogen formed structure-stabilizing water-mediated hydrogen bonds. The compounds were demonstrated to be non-toxic in an MTT assay with several breast cancer cell lines and one normal cell line. The improved affinity, selectivity, and low cytotoxicity suggest that the quinoline-galactoside derivatives provide an attractive starting point for the development of galectin-8N inhibitors potentially interfering with pathological lymphangiogenesis, autophagy, and tumor progression.
Highlights
Galectins are an ancient family of glycan binding proteins found in most organisms, including 15 mammalian members.[1]
As galectins bind galactose-containing glycoconjugates and have been demonstrated to be inhibited by synthetic galactosides derivatized with aromatic structures at C-3,14 we hypothesized that combining quinolines, indolizines, and coumarins with a β-D-galactoside core structure could lead to the discovery of new compounds with enhanced galectin affinities and selectivities
The quinoline- (1a–1i), indolizine- (2a–2e), and coumarin- (3a–3e) derived galactosides were evaluated as inhibitors against the human galectin-1, -2, -3. -4N- and C-terminal domains, -7, 8N-and C-terminal domains, and -9N- and C-terminal domains in a competitive protein-binding assay based on fluorescence anisotropy.[25,26,27]
Summary
Survival, neoplastic metamorphosis, angiogenesis, and tumour metastasis. There is a pressing need for molecules towards the discovery of galectin-blocking drug leads.[6,7,8,9]. Quinolines, indolizines, and coumarins and substituted derivatives thereof are common structures in medicinal and synthetic organic chemistry and frequently display distinct biological activities.[10,11,12,13] As galectins bind galactose-containing glycoconjugates and have been demonstrated to be inhibited by synthetic galactosides derivatized with aromatic structures at C-3,14 we hypothesized that combining quinolines, indolizines, and coumarins with a β-D-galactoside core structure could lead to the discovery of new compounds with enhanced galectin affinities and selectivities. We report the design and synthesis of a series of quinoline-, indolizine-, and coumarin-carrying galactoside derivatives and their evaluation as inhibitors of galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9N, and 9C, as well as of their cytotoxic properties
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