br Conclusion In this brief Letter we report an

Conclusion In this brief Letter, we report an easy method for the preparation of the antileukemic natural product 1. Using a biomimetic strategy,1, 8 in which the aromatic residues are attached to a lysine moiety prior to the reduction of the central carboxylate group, a step-economical synthesis of 1 has been achieved. In terms of yield, the presented method is more efficient than the procedure, in which the reduction reaction precedes the installation of the aromatic moieties. A facile access to 1 will now certainly foster further research activities in the pharmacological field.
Experimental section
Acknowledgments Financial support from the Bundesministerium für Bildung und Forschung (BMBF) – Germany within the programme InfectControl 2020 (grant# 03ZZ0803A) is gratefully acknowledged.
Introduction 5-Lipoxygenase (5-LO) catalyzes the first part of the leukotriene (LT) biosynthesis. 5-LO interacts with different proteins like coactosin-like protein (CLP) [1,2] and after cell stimulation it translocates to the nuclear membrane, where it colocalizes with the 5-LO-activating protein (FLAP) [3,4] and the cytosolic phospholipase A2 (cPLA2) [5] which releases arachidonic Midostaurin (AA) from the membrane. In the first reaction step, AA is oxidized into 5-hydroperoxyeicosatetraenoic acid (5-HpETE) which can be reduced to 5-hydroxyeicosatetraenoic acid (5-HETE) by peroxidases. In a second step, 5-HpETE is converted into the instable epoxide leukotriene A4 (LTA4) by 5-LO. Then, LTA4 can be either metabolized to LTB4 by LTA4 hydrolase or by LTC4 synthase into the cysteinyl-leukotriene LTC4 which is then further degraded to LTD4 and LTE4[6–9]. LTs have been associated with many diseases like asthma [10], atherosclerosis [11,12], sepsis [13], rheumatoid arthritis (RA) [14,15] and various types of cancer such as colon cancer [16], prostate cancer [17] or lung cancer [18]. 5-LO is expressed in certain cell types like neutrophils, basophils, eosinophils, mast cells, macrophages/monocytes, and B-lymphocytes, whereas platelets are 5-LO negative [19–21]. For several years, the presence of 5-LO in T cells was controversially discussed but recent findings support the existence of 5-LO in primary T cells [20,22]. Previous work showed that resting 5-LO can be located either in the cytosol or in the nucleus, depending on the cell type. In eosinophils and leukocytes of peripheral blood, 5-LO is cytosolic, whereas in alveolar macrophages and mouse bone marrow-derived mast cells (BMMC) it was predominantly found in the nucleus [3,23–26]. The control of nuclear import and export of 5-LO is yet not fully understood. Jones et al. found nuclear localization sequences (NLS) which are localized both on the N-terminal C2-like regulatory domain and the C-terminal catalytic domain of 5-LO. The relevant amino acids for the nuclear import are R112, K158 and R518 [27,28]. Besides the NLS, 5-LO also exhibits a nuclear export sequence (NES). Hanaka et al. showed an inhibition of nuclear export after treatment with the export inhibitor leptomycin B [29,30]. The nuclear import and export of 5-LO in intact cells also depends on the phosphorylation status. By now, several different phosphorylation sites are known [31]. S271 can be phosphorylated by mitogen-activated protein kinase 2 (MK2), S663 by extracellular signal-regulated kinases (ERKs) and S523 by protein kinase A (PKA) [32–34]. It is known that phosphorylation at S271 and S663 results in increased intranuclear 5-LO and increased LT formation. In contrast, phosphorylation at S523 has an inhibitory effect on LT biosynthesis and 5-LO remains cytosolic [35–37]. Furthermore, additional phosphorylations of 5-LO by tyrosine kinases were detected in-vitro [31]. It is known that alternative splicing is very important for preserving the complexity of the human proteome and that the majority of human genes are alternatively spliced. The resulting alternative mRNA transcripts play pivotal roles in physiological processes, development and in many diseases. In addition, it was shown that these transcripts have varying biological properties in enzymatic capacity, protein interaction and cellular localization [38,39].