- Synthesis of C11-to-C14 methyl-shifted all-: Trans -retinal analogues and their activities on human aldo-keto reductases
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Human aldo-keto reductases (AKRs) are enzymes involved in the reduction, among other substrates, of all-trans-retinal to all-trans-retinol (vitamin A), thus contributing to the control of the levels of retinoids in organisms. Structure-activity relationship studies of a series of C11-to-C14 methyl-shifted (relative to natural C13-methyl) all-trans-retinal analogues as putative substrates of AKRs have been reported. The synthesis of these retinoids was based on the formation of a C10-C11 single bond of the pentaene skeleton starting from a trienyl iodide and the corresponding dienylstannanes and dienylsilanes, using the Stille-Kosugi-Migita and Hiyama-Denmark cross-coupling reactions, respectively. Since these reagents differ by the location and presence of methyl groups at the dienylorganometallic fragment, the study also provided insights into the ability of the different positional isomers to undergo cross-coupling and the sensitivity of these processes to steric hindrance. The resulting C11-to-C14 methyl-shifted all-trans-retinal analogues were found to be active substrates when tested with AKR1B1 and AKR1B10 enzymes, although relevant differences in substrate specificities were noted. For AKR1B1, all analogues exhibited higher catalytic efficiency (kcat/Km) than parent all-trans-retinal. In addition, only all-trans-11-methylretinal, the most hydrophobic derivative, showed a higher value of kcat/Km = 106 000 ± 23 200 mM-1 min-1 for AKR1B10, which is in fact the highest value from all known retinoid substrates of this enzyme. The novel structures, identified as efficient AKR substrates, may serve in the design of selective inhibitors with potential pharmacological interest. This journal is
- Alvarez, Rosana,Barracco, Vito,De Lera, Angel R.,Domínguez, Marta,Farrés, Jaume,Jiménez, Rafael,López, Susana,Parés, Xavier,Pequerul, Raquel,Rivas, Aurea
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supporting information
p. 4788 - 4801
(2020/07/13)
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- A comprehensive survey of Stille-type C(sp2)-C(sp2) single bond forming processes in the synthesis of retinoic acid and analogs
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The synthesis of the retinoid skeleton has been exhaustively explored using the Stille coupling for the formation of the side- chain single bonds. On employing the experimental catalytic conditions developed by Farina [Pd2(dba)3, AsPh3, NMP] we have modified the electronic and steric requirement of the coupling partners, alkenyl stannanes and electrophiles (alkenyl iodides and triflates). The comprehensive survey afforded appropriately matched components for every bond formation considered. Moreover, from the comparison of the reactivities of different coupling partners with different degrees of steric hindrance, the sensitivity of the Stille coupling to steric effects was confirmed. Besides providing a variety of building blocks for retinoid synthesis, the study highlights some trends that might be useful for the application of the Stille reaction to the synthesis of unsubstituted conjugated polyenes.
- Dominguez, Beatriz,Iglesias, Beatriz,De Lera, Angel R.
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p. 15071 - 15098
(2007/10/03)
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- SYNTHETIC INVESTIGATIONS IN THE CHEMISTRY OF POLYENE COMPOUNDS LII. SYNTHESIS OF RETINOIC AND DIHYDRORETINOIC ESTERS BY THE REFORMATSKII REACTION
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The esters of 7,8- and 7,14-dihydroretinoic acids were obtained by the reaction of 6-methyl-8-(2,6,6-trimethyl-1-cyclohexenyl)-3,5-octadien-2-one with bromoacetic ester in the Reformatskii reaction followed by dehydration.The 7,8- and 7,14-dihydroretinoic
- Tutorskaya, O. O.,Miropol'skaya, M. A.,Samokhvalov, G. I.
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p. 1237 - 1240
(2007/10/02)
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