- Design and synthesis of an aminobenzo-15-crown-5-labeled estradiol tethered with disulfide linkage
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A novel measuring method (electroimmunoassay) of 17β-estradiol (E 2) in urine or blood was proposed on the basis of a competition between E2 and a labeled E2 against an immobilizing antibody. To evaluate the principle, 3-{4-[17β-hydroxy-1,3,5(10)- estratrien-3-yloxy]butyldisulfanyl}-N-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14, 17-pentaoxabenzocyclopentadecen-2-yl) succinamic acid (1) was designed and synthesized as a novel aminobenzo-15-crown-5-containing E2 tethered with disulfide linkage. Two thiol-intermediates 5b and 19c were efficiently synthesized from mercaptosuccinic acid 7 and 4,4′-dithiodibutyric acid 12, respectively. Formations of disulfide linkages from less reactive thiols were examined and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) could be employed for the formation of an unsymmetrical disulfide 20c from 5b and 19c. Then, removal of TMS- and allyl-protecting groups in 20c successfully afforded the crown ether-containing E2 1. Graphical Abstract
- Harusawa, Shinya,Yoshida, Kazufumi,Kojima, Chihiro,Araki, Lisa,Kurihara, Takushi
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- Reversibility of the thia-Michael reaction of cytotoxic C5-curcuminoid and structure-activity relationship of bis-thiol-adducts thereof
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C5-curcuminoids [a.k.a. bis(arylmethylidene)acetones] are curcumin analogues bearing a reactive cross-conjugated dienone structure essential for eliciting cytotoxicity. To gain insight into the mode of action of C5-curcuminoids, we investigated the reversibility of the thia-Michael reaction of 1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one, named GO-Y030 which is the most potent cytotoxic C5-curcuminoid, using spectroscopic methods. A panel of GO-Y030-bis-thiol-adducts were synthesized and the structure-reactivity relationship regarding the retro thia-Michael reaction as well as the cell growth inhibitory activity against human colon cancer HCT116 were evaluated. Some C5-curcuminoid thiol-adducts exhibited comparable cytotoxicity with GO-Y030, demonstrating their potential use as prodrugs. These results imply that C5-curcuminoids elicit cytotoxicity by covalently interacting with various biothiols via a reversible thia-Michael reaction.
- Kohyama, Aki,Fukuda, Michihiro,Sugiyama, Shunsuke,Yamakoshi, Hiroyuki,Kanoh, Naoki,Ishioka, Chikashi,Shibata, Hiroyuki,Iwabuchi, Yoshiharu
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- Efficient synthesis of unsymmetrical disulfides
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A novel way of synthesizing unsymmetrical disulfides from thiols with DDQ is presented here. This procedure ran in a straightforward manner to give high product yields. Unsymmetrical disulfides were directly synthesized from the corresponding mixture of thiols in equimolar amounts under mild conditions.
- Vandavasi, Jaya Kishore,Hu, Wan-Ping,Chen, Chung-Yu,Wang, Jeh-Jeng
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experimental part
p. 8895 - 8901
(2011/11/30)
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- Kinetics of the Aqueous Periodate Oxidation of Aliphatic Disulfides and Thioethers
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Water-soluble aliphatic disulfides are oxidatively cleaved by borate-buffered periodate at 23 deg C.The reaction conditions were selected because they are used for the oxidation of methionine in protein modification, and we wanted to test the reactivity of the disulfide linkage in various bifunctional molecules under these conditions.A colorimetric method was developed which uses 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) to determine the concentrations of periodate.The γ-substituted amine-disulfide 1b consumes 4 equiv of periodate at a rate which is accelerated 100-fold over that of 4,4'-dithiodibutanol (1c) and forms the cyclic sulfinamide 3 an sulfonamide 4.To account for the stoichiometry and acceleration, we have proposed intermediates in which a nucleophilic sulfur atom attacks an oxygen atom of periodate to give an anhydride or complex rather than invoking direct oxygen atom transfer.The γ- and δ-hydroxy disulfides 1a and 1c consume 5 equiv of periodate and are oxidized to the sulfonic acids.The rate of DL-methionine (2a) oxidation in water is reported, along with the oxidations of dibutyl sulfide (2c) and of 1,5-dithiacyclooctane (2d) in 50percent aqueous ethanol.The oxidation of 2d is only 2.1 times faster than the oxidation of 2c, showing that the transannular sulfur atom in 2d does not participate in the oxidation.A comparison of the rate of periodate oxidation of disulfides, thioethers, and ethylene glycol under the same conditions shows that it is possible for these processes to be competitive.
- Evans, Brian J.,Takahashi Doi, Joyce,Musker, W. Kenneth
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p. 2580 - 2586
(2007/10/02)
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- Oxidative Cleavage and Cyclization of Disulfide Carboxylic Acids and Alcohols by Aqueous Iodine: A Facile Route to Five-Membered Ring Sultines
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The kinetics and mechanism of the oxidative cleavage by aqueous iodine of disulfide carboxylic acids and alcohols are presented.There is evidence for intramolecular interaction of the oxygen nucleophiles.The sole product of the iodine oxidation of 3,3'-dithiodipropanol is the sultine 1,2-oxathiolane 2-oxide, which is formed after the rate-determining step, apparently via rapid cyclization of the sulfenyl iodide.The anchimeric assistance provided by the neighboring carboxylate group in the reaction of 3,3'-dithiodipropanoic acid is responsible for the pH profile of the rate of oxidative cleavage.At a given pH, the rate law for the reaction is -d/dt = kI3->(0.0905->-1 + 0.0019->-2).The inverse second term in iodide ion not has been observed previously in kinetic studies of disulfide reactions and is interpreted as evidence for a disulfide-iodonium complex.
- Doi, Joyce Takahashi,Luehr, Gary W.,Musker, W. Kenneth
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p. 5716 - 5719
(2007/10/02)
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