Untitled

Abstract

Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents.

Partition-Variant Desferrithiocin Analogues: Organ Targeting and Increased Iron Clearance

“…Recall that the desferrithiocin analogues form 2:1 complexes with Fe(III); accordingly, the ligand-to-metal ratios from 0.5 to 2 are measured for ligands 1 − 8 (Figure ). The 4‘-substituted ( 1 − 4 ), 3‘-hydroxy ( 5 and 6 ), and 3‘-methoxy ( 7 and 8 ) analogues slowed Fe(III) reduction considerably, even at a 0.5:1 ratio, as did the parent compound DFT (data not shown). , The results with the parent ligand are consistent with those reported in this same assay 31,34 and in a cultured cell system . These results indicate that an enhancement of Fenton chemistry is unlikely to account for the toxicity of desferrithiocin and some of its derivatives.…”

“…The Fe(III) liberated can be reduced back to Fe(II) via a variety of biological reductants (e.g., ascorbate), a problematic cycle. The hydroxyl radical reacts very quickly with a variety of cellular constituents and can initiate free radicals and radical-mediated chain processes that damage DNA and membranes, as well as produce carcinogens. ,, Radical traps can help to attenuate the already ongoing free-radical- mediated damage; for example, N,N ‘ - bis(2-hydroxybenzyl)ethylenediamine- N,N ‘ - diacetic acid (HBED) and desferrioxamine B (DFO) , are excellent radical traps.…”

Synthesis and evaluation of L-cystathionine as a standard for amino acid analysis

“…[23][24][25] (3S)-3-(tert-Butoxycarbonyl)amino-4-iodobutanoic acid tert-butyl ester (13) was obtained as a white solid in a total yield of 45% from N-tert-butoxycarbonyl-L-aspartic acid β-tert-butyl ester (10) in accordance with methods described in the literature. [28][29][30][31] NMR and ESI-MS data for compounds 4, 8, and 13 were identical to literature data. (3S)-3-(tert-Butoxycarbonyl)amino-4-iodobutanoic acid tert-butyl ester (13 S-[(2R)-3-(tert-Butoxy)-2-(tert-butoxycarbonyl)amino-3-oxypropyl]-N-tert-butoxycarbonyl-L-homocysteine tert-butyl ester (9).…”

“…5) following the method described for the synthesis of 8 (45% total yield). [28][29][30][31] The coupling of iodide 13 with cysteine derivative 4 proceeded under the same conditions as those used for 9, affording 4-[(2R)-3-tert-butoxy-2-(tert-butoxycarbonyl)amino-3-oxopropyl]thio-[(3S)-3-(tert-butoxycarbonyl)amino] butanoic acid tert-butyl ester (14) in 97% yield. Deprotection of 14 was performed using a 4 N HCl/dioxane solution to afford 15·2HCl in approximately quantitative yield.…”

An Improved Synthesis of (3S,12S)-N ¹ ,N 14-Diethyl-3,12-dihydroxy-homospermine, a Polyamine Analogue Therapeutic Agent

“…[4][5][6][7][8] In the course of our clinical studies with these analogues as antineoplastics, we found N 1 ,N 14 -diethylhomospermine (DEHSPM), a polyamine analogue designed and synthesized in these laboratories, to be a very potent gastrointestinal antitransit and antisecretory agent. 9,10 In one attempt to ameliorate some metabolic problems associated with DEHSPM, 11 we raised the oxidation state of two of the methylene groups of DEHSPM by introducing a single hydroxyl in the (R) configuration at each of the external aminobutyl fragments, resulting in (3R,12R)-N 1 ,N 14 -diethyl-3,12-dihydroxyhomospermine[(R,R)-(HO) 2 DEHSPM, (R,R)-1]. 12 Three synthetic routes to chiral N 1 ,N 14 -diethyl-3,12-dihydroxyhomospermines [(HO) 2 DEHSPMs] have been published from this laboratory.…”