Solid-State and Solution Structure of the Salinomycin−Sodium Complex:  Stabilization of Different Conformers for an Ionophore in Different Environments

Abstract

The conformation of the ionophore−metal complex between salinomycin and sodium was determined in solid state and in solution using X-ray single-crystal structure analysis and a combined approach of 2D-NMR spectroscopy with restrained simulated annealing calculations. The solution structure of the salinomycin−Na complex was studied in two different solvents (DMSO-d 6 and CDCl3) in order to focus on conformational differences in various molecular environments. The X-ray structure of the complexed salinomycin is characterized by two separate conformers found in the asymmetric unit with a similar coordination of the central sodium ion buried in the interior, hydrophilic region of this ionophore. A quasi-macrocyclic core structure is stabilized by numerous metal−oxygen electrostatic interactions and by an intramolecular head-to-tail hydrogen bond. The NMR structure in CDCl3 is very similar to those two conformations in the solid state, while the structure in DMSO differs significantly. It could be demonstrated that previously published NMR data in CDCl3 do not define a unique conformational state with sufficient accuracy, while this was possible using our own NMR derived datasets discussed herein. For conformer classification and comparison, steric field descriptors based on the CoMFA methodology are used in conjunction with a principal component analysis to uncover the most relevant structural differences between individual salinomycin−Na structures. These studies provided insight into the specific requirements of metal binding for this important polyether ionophore, which could serve as a model system for studying ion transport across biological membranes. Different environments tend to stabilize different conformations of the outer sphere, while the complexation pattern and the geometry of the coordination sphere of the sodium ion remains unaffected.

Sorption and Degradation in Soils of Veterinary Ionophore Antibiotics: Monensin and Lasalocid

“…These groups can undergo anion exchange for soils such as A1A2 that have a considerable anion-exchange capacity (Table 1), which likely is why the highly selective phosphate anion was needed to extract sorbed lasalocid. This coordination gives ionophores the unique ability to transport metal ions across cell membranes as either undissociated acids or neutral complexes and gives the molecule a largely hydrophobic exterior [12,46,[48][49][50]. This coordination gives ionophores the unique ability to transport metal ions across cell membranes as either undissociated acids or neutral complexes and gives the molecule a largely hydrophobic exterior [12,46,[48][49][50].…”

Discovery of a 19F MRI sensitive salinomycin derivative with high cytotoxicity towards cancer cells

“…4f,5 The X-Ray crystal and molecular modelling of salinomycin show that the C20 hydroxyl group is not involved in ion chelation, and its acylation actually poses steric hindrance for ion chelation. 6 We envisioned that the inversion of the C20 configuration could relieve the steric hindrance and therefore enhance ion chelation and potency. In this way, a highly valuable conjugation site is also available for targeted delivery of salinomycin without compromising its ion chelation and potency.…”

“…Because the allylic C20 hydroxyl group is more reactive than C9 and C28 ones, 4f,6 selective tosylation of 2 provided C20 tosylate S1 in high yield (See supporting Information). However, many attempts at nucleophilic substitution of the tosylate group with an azido group resulted in the decomposition of S1 .…”

Structure, conformation, and mechanism in the membrane transport of alkali metal ions by ionophoric antibiotics

“…23 Narasin is closely related to salinomycin (2, R = H), the structure of whose sodium salt had already been studied by NMR methods, 24,25 and single crystal X-ray diffraction. 25 Variability in the conformation according to whether the molecule was studied in solution and in two different solvents has been noted. 25 We succeeded in making the Na + , K + , Rb + and Cs + salts of narasin, thus expanding the range of ions seen by us for monensin and studied for salinomycin.…”

“…25 Variability in the conformation according to whether the molecule was studied in solution and in two different solvents has been noted. 25 We succeeded in making the Na + , K + , Rb + and Cs + salts of narasin, thus expanding the range of ions seen by us for monensin and studied for salinomycin.…”