- Effects of C-4 stereochemistry and C-4' hydroxylation on the iron clearing efficiency and toxicity of desferrithiocin analogues
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Additional structure-activity studies of desferrithiocin analogues are carried out. The effects of stereochemistry at C-4 on the ligands' iron clearing efficiency are reviewed and assessed using the enantiomers 4,5- dihydro-2-(2,4-dihydroxyphenyl)thiazole-4(R)-carboxylic acid and 4,5-dihydro- 2-(2,4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid. The utility of 4'- hydroxylation as a method of reducing the toxicity of desazadesferrithiocin analogues is also examined further with the synthesis and in vivo comparison of 4,5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, which is the natural product 4-methylaeruginoic acid, and 4,5-dihydro-2- (2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid. The stereochemistry at C-4 is shown to have a substantial effect on the iron clearing efficiency of desferrithiocin analogues, as does C-4'-hydroxylation on the toxicity profile. All of the compounds are evaluated in a bile-duct- cannulated rodent model to determine iron clearance efficiency and are carried forward to the iron-overloaded primate for iron clearing measurements. On the basis of the results of the present work, although 4,5- dihydro-2-(2,4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid is still the most promising candidate for clinical evaluation, 4,5-dihydro-2-(2,4- dihydroxyphenyl)4-methylthiazole-4(S)-carboxylic acid (4'- hydroxydesazadesferrithiocin) also merits further preclinical assessment.
- Bergeron, Raymond J.,Wiegand, Jan,McManis, James S.,McCosar, Bruce H.,Weimar, William R.,Brittenham, Gary M.,Smith, Richard E.
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- Synthesis and biological properties of thiazole-analogues of pyochelin, a siderophore of Pseudomonas aeruginosa
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Pyochelin is a siderophore common to all strains of Pseudomonas aeruginosa utilized by this Gram-negative bacterium to acquire iron(III). FptA is the outer membrane transporter responsible of ferric-pyochelin uptake in P. aeruginosa. We describe in this Letter the synthesis and the biological properties ( 55Fe uptake, binding to FptA) of several thiazole analogues of pyochelin. Among them we report in this Letter the two first pyochelin analogues able to bind FptA without promoting any iron uptake in P. aeruginosa.
- No?l, Sabrina,Hoegy, Fran?oise,Rivault, Freddy,Rognan, Didier,Schalk, Isabelle J.,Mislin, Ga?tan L.A.
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p. 132 - 135
(2014/01/17)
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- NOVEL COMPOUND HAVING SKIN-WHITENING, ANTI-OXIDIZING AND PPAR ACTIVITIES AND MEDICAL USE THEREFOR
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Provided are a novel compound having skin-whitening, anti-oxidizing and PPAR activities and a medical use thereof, and the compound has skin-whitening activities for the suppression of tyrosinase, and accordingly, is useful for use in skin-whitening pharmaceutical composition or cosmetic products; has anti-oxidant activities, and accordingly, is useful for the prevention and treatment of skin-aging; and has PPAR activities, and in particular, PPARα and PPARγ activities, and accordingly, is useful for use in pharmaceutical compositions or health foods which are effective for the prevention and treatment of obesity, metabolic disease, or cardiovascular disease.
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Paragraph 0296
(2014/02/16)
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