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- Almqvist, Fredrik, et al.
(författare)
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Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)
- 2004
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Ingår i: Organic & Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 2:21, s. 3085-3090
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Tidskriftsartikel (refereegranskat)abstract
- The formylated spirobyclic alcohol 8a was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound 8c, carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone 12. Microtubule stabilization was not observed for 8c, indicating that the model needs to be adjusted.
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- Manner, Sophie, et al.
(författare)
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Asymmetric baker's yeast reductions of bridgehead-substituted bicyclo[2.2.2]octane-2,6-dione derivatives followed by conversion into catalytically active BODOLs for the diethylzinc addition to benzaldehyde.
- 2010
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Ingår i: Tetrahedron. - : Elsevier Ltd.. - 0957-4166 .- 1362-511X. ; 21:11-12, s. 1374-1381
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Tidskriftsartikel (refereegranskat)abstract
- 4-Substituted bicyclo[2.2.2]octane-2,6-diones I [R = acetyl, benzyl, allyl, etc.] have been synthesized and tested as substrates in the enantioselective redn. with baker's yeast to give the corresponding hydroxy ketones II [R = acetyl, benzyl, allyl, etc.]. It was found that the deriv. bearing a TIPSO group at the 4-position was not reduced at all while that with a TBDMSO group gave 87% yield and 46% ee. Other 4-oxy functionalized derivs. were reduced with varying yields (36-87%) and ees (10-82%). The best result was obtained for the 4-Oallyl deriv. (80% yield, 82% ee). The hydroxy ketones carrying the benzyloxy and allyloxy groups at the 4-position were converted into the corresponding BODOLs III [R = allyl, benzyl], which were tested as catalysts in the diethylzinc addn. to benzaldehyde. In this reaction the ees were 90% and 89%, resp., which showed that BODOLs substituted at the 4-position are essentially as good catalysts in this reaction as those bearing a hydrogen. [on SciFinder(R)]
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- Volk, Anna-Luisa, et al.
(författare)
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Bispecific Antibody Molecule Inhibits Tumor Cell Proliferation More Efficiently Than the Two-Molecule Combination
- 2021
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Ingår i: Drugs in R&D. - : Adis. - 1174-5886 .- 1179-6901. ; 21:2, s. 157-168
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Tidskriftsartikel (refereegranskat)abstract
- Background: Monoclonal antibodies (mAbs) have proved to be a valuable tool for the treatment of different cancer types. However, clinical use of an increasing number of mAbs, have also highlighted limitations with monotherapy for cancers, in particular for such with more complex mechanisms, requiring action on additional molecules or pathways, or for cancers quickly acquiring resistance following monotherapy. An example for the latter is the mAb trastuzumab, FDA approved for treatment of metastatic gastric carcinoma. To circumvent this, researchers have reported synergistic, anti-proliferative effects by combination targeting of HER2 and EGFR by trastuzumab and the EGFR-targeting mAb Cetuximab overcoming trastuzumab resistance. Methods: Maintaining the proven functionality of trastuzumab, we have designed bi-specific antibody molecules, called AffiMabs, by fusing an EGFR-targeting Affibody molecule to trastuzumab’s heavy or light chains. Having confirmed binding to EGFR and Her2 and cytotoxicity of our AffiMabs, we analyzed apoptosis rate, receptor surface levels, phosphorylation levels of receptors and associated signaling pathways as well as differentially expressed genes on transcriptome level with the aim to elucidate the mode of action of our AffiMabs. Results: The AffiMabs are able to simultaneously bind HER2 and EGFR and show increased cytotoxic effect compared to the original trastuzumab therapeutic molecule and, more importantly, even to the combination of trastuzumab and EGFR-targeting Affibody molecule. Analyzing the mode of action, we could show that bi-specific AffiMabs lead to reduced surface receptor levels and a downregulation of cell cycle associated genes on transcriptome level. Conclusion: Our study shows that transcriptome analysis can be used to validate the choice of receptor targets and guide the design of novel multi-specific molecules. The inherent modularity of the AffiMab format renders it readily applicable to other receptor targets.
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