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Replacement of an Indole Scaffold Targeting Human 15‐Lipoxygenase‐1 Using Combinatorial Chemistry
Author(s) -
Prismawan Deka,
van der Vlag Ramon,
Guo Hao,
Dekker Frank J.,
Hirsch Anna K. H.
Publication year - 2019
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.201900040
Subject(s) - chemistry , indole test , arachidonic acid , lipoxygenase , polyunsaturated fatty acid , biochemistry , arachidonate 5 lipoxygenase , inflammation , combinatorial chemistry , enzyme , fatty acid , immunology , biology
Human 15‐lipoxygenase‐1 (15‐LOX‐1) belongs to the class of lipoxygenases, which catalyze oxygenation of polyunsaturated fatty acids, such as arachidonic and linoleic acid. Recent studies have shown that 15‐LOX‐1 plays an important role in physiological processes linked to several diseases such as airway inflammation disease, coronary artery disease, and several types of cancer such as rectal, colon, breast and prostate cancer. In this study, we aimed to extend the structural diversity of 15‐LOX‐1 inhibitors, starting from the recently identified indolyl core. In order to find new scaffolds, we employed a combinatorial approach using various aromatic aldehydes and an aliphatic hydrazide tail. This scaffold‐hopping study resulted in the identification of the 3‐pyridylring as a suitable replacement of the indolyl core with an inhibitory activity in the micromolar range ( IC 50 =16±6 μ m ) and a rapid and efficient structure–activity relationship investigation.