(9Z)- and (11Z)-8-methylretinals for artificial visual pigment studies:: Stereoselective synthesis, structure, and binding models

被引:17
作者
Alvarez, R
Domínguez, M
Pazos, Y
Sussman, F
de Lera, AR [1 ]
机构
[1] Univ Vigo, Dept Quim Organ, Fac Ciencias, Vigo 36200, Spain
[2] Univ Santiago de Compostela, Dept Quim Organ, Fac Quim, Santiago De Compostela 15700, Spain
关键词
cross-coupling; docking models; membrane proteins; receptors;
D O I
10.1002/chem.200304847
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Artificial visual pigment formation was studied by using 8-methyl-substituted retinals in an effort to understand the effect that alkyl substitution of the chromophore side chain has on the visual cycle. The stereoselective synthesis of the 9-cis and 11-cis isomers of 8-methylretinal, as well as the 5-demethylated analogues is also described. The key bond formations consist of a thallium-accelerated Suzuki cross-coupling reaction between cyclohexenyl-boronic acids and dienyliodides (C6-C7), and a highly stereocontrolled Horner-Wadsworth-Emmons or Wittig condensation (C11-C12). The cyclo-hexenylboronic acid was prepared by trapping the precursor cyclohexenyl-lithium species with B(OiPr)(3) or B(OMe)(3). The cyclohexenyllithium species is itself obtained by nBuLi-induced elimination of a trisylhydrazone (Shapiro reaction), or depending upon the steric hindrance of the ring, by iodine-metal exchange. In binding experiments with the apoprotein opsin, only 9-cis-5-demethyl-8-methylretinal yielded an artificial pigment; 9-cis-8-methylretinal simply provided residual binding, while evidence of artificial pigment formation was not found for the 11-cis analogues. Molecular-mechanics-based docking simulations with the crystal structure of rhodopsin have allowed us to rationalize the lack of binding displayed by the 11-cis analogues. Our results indicate that these isomers are highly strained, especially when bound, due to steric clashes with the receptor, and that these interactions are undoubtedly alleviated when 9-cis-5-demethyl-8-methylretinal binds opsin.
引用
收藏
页码:5821 / 5831
页数:11
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