| 1. |
- Ekebergh, Andreas, 1984, et al.
(författare)
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Exploring a cascade Heck-Suzuki reaction based route to kinase inhibitors using design of experiments
- 2015
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 13:11, s. 3382-3392
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Tidskriftsartikel (refereegranskat)abstract
- Design of Experiments (DoE) has been used to optimize a diversity oriented palladium catalyzed cascade Heck-Suzuki reaction for the construction of 3-alkenyl substituted cyclopenta[b]indole compounds. The obtained DoE model revealed a reaction highly dependent on the ligand. Guided by the model, an optimal ligand was chosen that selectively delivered the desired products in high yields. The conditions were applicable with a variety of boronic acids and were used to synthesize a library of 3-alkenyl derivatized compounds. Focusing on inhibition of kinases relevant for combating melanoma, the library was used in an initial structure-activity survey. In line with the observed kinase inhibition, cellular studies revealed one of the more promising derivatives to inhibit cell proliferation via an apoptotic mechanism.
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| 2. |
- Lingblom, Christine, 1984
(författare)
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Functional and Phenotypic Studies of Eosinophilic Granulocytes in Patients with Eosinophilic Esophagitis
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Eosinophilic Esophagitis (EoE) is a chronic inflammatory disorder of unknown etiology, in which the esophagus is infiltrated by eosinophils and T cells. Topical corticosteroids are one of the treatment options for patients with EoE. The function of eosinophils in EoE is unknown, here we hypothesize that eosinophils serve as immunoregulatory cells. The eosinophils in the blood of untreated adult patients with EoE have a distinct phenotype. The aims of this thesis were to explore whether the eosinophilic phenotype of untreated patients with EoE can be reverted to the healthy phenotype by topical corticosteroid treatment, and to examine whether blood eosinophils from children with EoE have a distinct phenotype, different from that of healthy children. Moreover, we tested the hypothesis that eosinophils, similar to regulatory T cells, can diminish T cell proliferation and express FOXP3. The role of the eosinophilic protein galectin-10 in mediating immunosuppression was also investigated. This thesis demonstrates that the EoE phenotype of blood eosinophils is not restored by topical corticosteroid treatment, except with respect to CD18. We also show that eosinophils from patients with EoE have an immunoregulatory phenotype, i.e., increased levels of FOXP3 and galectin-10. Moreover, eosinophils from healthy subjects and patients with EoE are able to suppress T cell proliferation in vitro, in part via galectin-10. We show that eosinophils exposed to activated T cells release galectin-10 via DNA nets and appear to transfer this protein to T cells through synapses. Two subsets of eosinophils emerge after co-culturing. Finally, we demonstrate that the blood eosinophils of children with EoE have a distinct phenotype, different from that of healthy children and that of adults with EoE. Importantly, we reveal marked age-related differences regarding the molecular patterns displayed by the blood eosinophils of healthy donors. Our finding that eosinophils from patients with EoE have upregulated immunoregulatory molecules could indicate that the function of eosinophils in EoE is to reduce a T cell-mediated inflammation in the esophagus.
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