Functionalized Homologues and Positional Isomers of Rabbit 15-
Lipoxygenase RS75091 Inhibitor

Alexander      Zhuravlev; Alexey      Golovanov; Valery      Toporkov; Hartmut      Kuhn; Igor      Ivanov
doi:10.2174/1573406417666210604112009
Abstract

Background: RS75091 is a cinnamic acid derivative that has been used for the crystallization of the rabbit ALOX15-inhibitor complex. The atomic coordinates of the resolved ALOX15- inhibitor complex were later on used to define the binding sites of other mammalian lipoxygenase orthologs, for which no direct structural data with ligand has been reported so far.
Introduction: The putative binding pocket of the human ALOX5 was reconstructed on the basis of its structural alignment with rabbit ALOX15-RS75091 inhibitor. However, considering the possible conformational changes the enzyme may undergo in solution, it remains unclear whether the existing models adequately mirror the architecture of ALOX5 active site.
Methods: In this study, we prepared a series of RS75091 derivatives using a Sonogashira coupling reaction of regioisomeric bromocinnamates with protected acetylenic alcohols and tested their inhibitory properties on rabbit ALOX15.
Results: A bulky pentafluorophenyl moiety linked to either ortho- or metha-ethynylcinnamates via aliphatic spacer does not significantly impair the inhibitory properties of RS75091.
Conclusion: Hydroxylated 2- and 3-alkynylcinnamates may be suitable candidates for incorporation of an aromatic linker group like tetrafluorophenylazides for photoaffinity labeling assays.
Keywords: RS7091 inhibitor, cinnamic acid derivatives, Sonogashira-coupling, lipoxygenases, photoaffinity probes, ALOXs.
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Graphical Abstract

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DOI https://dx.doi.org/10.2174/1573406417666210604112009	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638
Medicinal Chemistry

Functionalized Homologues and Positional Isomers of Rabbit 15- Lipoxygenase RS75091 Inhibitor

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