The synthesis and iron-clearing properties of the naphthyldesferrithiocins 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4R)-carboxylic acid, 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4S)-carboxylic acid, 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4R)-carboxylic acid, and 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4S)-carboxylic acid are described. While the bile duct-cannulated rat model clearly demonstrates that the 3'-hydroxynaphthyl-2'-yl compounds are orally active iron-clearing agents and the corresponding 2'-hydroxynaphthyl-1'-yl compounds are not, in the primate model none of the benz-fused desazadesferrithiocin analogues are active. Oral versus subcutaneous administration of these ligands strongly suggests that metabolism is a key issue in their iron-clearing properties and that these benz-fused desferrithiocins are not good candidates for orally active iron-clearing drugs.
No abstract
The hydrolyses of (S)-desferrithiocin (DFT, 1), (R)-desmethyl-DFT (2), and (R)-desazadesmethyl-DFT (3) were studied at pH 2.5 and 7.2 in order to access the stability of the thiazolines at the pH of the stomach and the serum. At 37 degrees C and pH 2.5, DFT (1) (t1/2 = 18.6 h), desmethyl-DFT (2) (t1/2 = 8.74 h), and desazadesmethyl-DFT (3) (t1/2 = 31.7 h) were shown to open principally to the thiol amides with trace amounts of the corresponding thioesters, < or = 2%. The thiazolines were resistant to hydrolysis at pH 7.2. Iron(III) stabilized significantly the thiazolines in the complexes 16a/b of 3 in regard to hydrolysis at pH 2.5 (t1/2 > 20 days). The iron(III) complexes 16a/b were shown to be stable at pH 7.2. While the thiol amides 13 and 14 of 1 and 2 were isolated from the hydrolysis of the parent desferrithiocins, the thioester 4 and the thiol amide 5 of 3 were synthesized and their stability in aqueous solution, iron-clearance properties, and toxicity were evaluated. Thioester 4 was shown to rearrange to thiol amide 5 at pH 2.5 and 37 degrees C with a half-life of 4.18 h and instantaneously at pH 7.2. Thiol amide 5 is in equilibrium with 4 (5/4 = 49:1) at pH 2.5 and was shown to be stable at pH 7.2. Thioester 4 and thiol amide 5 demonstrated neither iron-clearance activity in iron-overloaded rats nor toxic side effects in mice. Hydrolysis products of the drug, which might be generated in the stomach, seem unlikely to be the source of the drug's toxicity or iron-clearing properties.
COMMUNICATIONSsolution of 5 mg of the vitaminA acetate mixture in 50pL of n-heptane (10% solution) was used for the chromatographic separation. NMR parameters: Bruker ARX 400 spectrometer, 12OpL continuous-flow probe with an rf coil arrangement for inverse I3C/'H spectroscopy: 48 transients per FID; 8 K time domain data points (TD2) with a spectral width (SW2) of 5618 Hz, acquisition time (AQ) = 0.73 s per transient, pulse width 90", solvent presaturation over 0.5 s (alternating irradiation at the heptane signals at 6 = 0.82 and 1.22 for 5 ms each); 128 FIDs (TDI) with an acquisition time per FID of 60 s were recorded during the separation. Data were treated like a 2D NMR matrix ( I , direction = retention time) and processed with UXNMR software (211; a phase-sensitive Fourier transformation was performed only in the I , direction: zero filling in I , to 32 K data points; multiplication with a sine square apodization function.Telefax: Int. code + (761) 203-5987["I This project has been supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and the BASF AG. G. G. thanks the Freiwilligen Akademischen Gesellschaft, Basel, for a Treubel Stipendium. We thank R. Schmidlin for low-temperature measurements, Prof. T. Bally and Prof. E. Haselbach (University of Fribourg, Switzerland) for access to the '"Co source.
Intriguing 4c/3e cases in the multifaceted story of cyclobutane radical cations1•2 are the two minima of the reaction coordinate calculated for the synchronous, symmetry forbidden3 [2 + 1] cycloaddition of ethylene to the ethylene radical cation with imposed Dy, symmetry (ab initio, UHF 3-21G, Figure 1). Yet, neither the "extended" ( -complex, E,rs 2.6 Á) nor the "tight" (cyclobutane-like, T, r s= 1.75 Á) configuration is a true minimum. Without extra stabilization, both structures are bound to open to a linear tetramethylene radical cation;2 rigid molecular skeletons like that of (iso)pagodanes (e.g., 1 and 3) and the valence isomeric dienes (e.g., 2 and 4) indeed provide this stabilization.4The radical cation produced from the Dih symmetrical [l.l.l.l]pagodane 1, which was impressively persistent (lifetime at room temperature ca. 2 days, Amax 610 nm), had been
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.