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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

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

Author(s): Alexander Zhuravlev, Alexey Golovanov, Valery Toporkov, Hartmut Kuhn and Igor Ivanov*

Volume 18, Issue 3, 2022

Published on: 04 June, 2021

Page: [406 - 416] Pages: 11

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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