Synthesis, Physicochemical Properties, and Biological Evaluation of Hydroxypyranones and Hydroxypyridinones:  Novel Bidentate Ligands for Cell-Labeling

• Published in: Journal of medicinal chemistry Vol. 39; no. 19; pp. 3659 - 3670
• Main Authors: Ellis, Beverley L, Duhme, Anne K, Hider, Robert C, Hossain, M. Bilayet, Rizvi, Safia, van der Helm, Dick
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.09.1996; Amer Chemical Soc
• Subjects: Cells - metabolism; Chemical Phenomena; Chemistry; Chemistry, Medicinal; Chemistry, Physical; Crystallization; Crystallography, X-Ray; Drug Stability; Erythrocytes - metabolism; Exact sciences and technology; Gallium - metabolism; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Hydrogen-Ion Concentration; Indium Radioisotopes - metabolism; Iron - metabolism; Leukocytes - metabolism; Life Sciences & Biomedicine; Ligands; Models, Molecular; Molecular Structure; Organic chemistry; Pharmacology & Pharmacy; Preparations and properties; Pyrans - chemical synthesis; Pyrans - metabolism; Pyridones - chemical synthesis; Pyridones - metabolism; Pyrones - chemical synthesis; Pyrones - metabolism; Science & Technology; IN-111 OXINE; ETHYL MALTOL; LEUKOCYTES; PLASMA; IN-111-TROPOLONATE; RAT; COMPLEXES; CHEMISTRY; LYMPHOCYTES; GALLIUM; Human; Indium 111; Biological fluid; Radiolabelling; Nitrogen heterocycle; Leukocyte; Chemical stability; Organic ligand; Red blood cell; Oxygen heterocycle; In vitro; Blood; Metal Complexes; Blood plasma; Blood cell; Six membered ring; Concentration effect; Indium III Complexes; Indium Isotopes; Chemical synthesis; Physicochemical properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960220g

The synthesis of a range of hydroxypyranones and hydroxypyridinones with potential for the chelation of indium(III) is described. The crystal structures of two of the indium complexes are presented. The distribution coefficients of the ligands and the corresponding iron(III), gallium(III), and indium(III) complexes are reported. Good linear relationships between the distribution coefficients of the iron and gallium complexes and iron and indium complexes were obtained. In contrast a nonlinear relationship was obtained between the distribution coefficient of the free ligand and the distribution coefficient of the three groups of complexes. This latter relationship was used to identify compounds with optimal cell labeling properties. Two such compounds both 6-(alkoxymethyl)-3-hydroxy-4H-pyran-4-ones have been compared with tropolone for their ability to label human leucocytes with 111In. The leucocyte labeling efficiencies of the selected ligands were greater and the in-vitro plasma stabilities were similar to that of 111In-tropolonate. These results suggest that the new bidentate ligands may offer advantages over those currently used for cell-labeling.