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Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?

Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?

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TITZ, Alexander, John PATTON, André ALKER, Michele PORRO, Oliver SCHWARDT, Michael HENNIG, Eric FRANCOTTE, John MAGNANI, Beat ERNST, 2008. Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?. In: Bioorganic & Medicinal Chemistry. 16(2), pp. 1046-1056. ISSN 0968-0896. eISSN 1464-3391

@article{Titz2008adama-17125, title={Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?}, year={2008}, doi={10.1016/j.bmc.2007.07.025}, number={2}, volume={16}, issn={0968-0896}, journal={Bioorganic & Medicinal Chemistry}, pages={1046--1056}, author={Titz, Alexander and Patton, John and Alker, André and Porro, Michele and Schwardt, Oliver and Hennig, Michael and Francotte, Eric and Magnani, John and Ernst, Beat} }

Porro, Michele Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists? Hennig, Michael Alker, André Publ. in: Bioorganic & Medicinal Chemistry ; 16 (2008), 2. - pp. 1046-1056 Patton, John 2011-11-29T10:32:54Z eng Magnani, John Ernst, Beat Porro, Michele Francotte, Eric Francotte, Eric Schwardt, Oliver Ernst, Beat 2008 deposit-license Patton, John Alker, André Schwardt, Oliver 2011-11-29T10:32:54Z Titz, Alexander Titz, Alexander The selectins play a key role in the inflammatory process, that is, the recruitment of leukocytes from blood vessels into inflamed tissue. Because excessive infiltration of leukocytes can induce acute or chronic reactions, the control of leukocyte extravasation is of great pharmaceutical interest. All physiological ligands of the selectins contain the tetrasaccharide epitope sialyl Lewisx, which therefore became the lead structure in selectin antagonist research. Previous studies indicated that an important factor for the affinity of sLex is the fact that in solution its pharmacophores are already conformationally pre-organized in the bioactive orientation. In mimics where the GlcNAc- and the NeuNAc-moieties of sLex were replaced by (R, R)-cyclohexane-1,2-diol and (S)-cyclohexyllactic acid, respectively, an optimized pre-organization of the pharmacophores could be realized, leading to antagonists with improved affinities. To further optimize the pre-organization of the carboxylic acid, a pharmacophore essential for binding, the replacement of NeuNAc by bulky (R)- and (S)-adamantyl-lactic acid was studied. Although antagonist (S)-7 showed a slightly reduced affinity, the expected beneficial effect of the (S)-configuration at C-2 of the lactate could be confirmed. Magnani, John Hennig, Michael

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