Functionalized Homologues and Positional Isomers of Rabbit 15- Lipoxygenase RS75091 Inhibitor.
ALOXs
RS7091 inhibitor
Sonogashira-coupling
cinnamic acid derivatives
lipoxygenases
photoaffinity probes
Journal
Medicinal chemistry (Shariqah (United Arab Emirates))
ISSN: 1875-6638
Titre abrégé: Med Chem
Pays: Netherlands
ID NLM: 101240303
Informations de publication
Date de publication:
2022
2022
Historique:
received:
05
11
2020
revised:
12
03
2021
accepted:
05
04
2021
pubmed:
8
6
2021
medline:
3
3
2022
entrez:
7
6
2021
Statut:
ppublish
Résumé
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. 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. 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. A bulky pentafluorophenyl moiety linked to either ortho- or metha-ethynylcinnamates via aliphatic spacer does not significantly impair the inhibitory properties of RS75091. Hydroxylated 2- and 3-alkynylcinnamates may be suitable candidates for incorporation of an aromatic linker group like tetrafluorophenylazides for photoaffinity labeling assays.
Sections du résumé
BACKGROUND
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
BACKGROUND
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
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
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
CONCLUSIONS
Hydroxylated 2- and 3-alkynylcinnamates may be suitable candidates for incorporation of an aromatic linker group like tetrafluorophenylazides for photoaffinity labeling assays.
Identifiants
pubmed: 34097594
pii: MC-EPUB-115971
doi: 10.2174/1573406417666210604112009
doi:
Substances chimiques
Lipoxygenase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
406-416Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : KU 961/14-1
Organisme : Russian Foundation for Basic Research
ID : 19-04-00082
Organisme : Russian Ministry of Science and High Education
ID : 0706-2020-0019
Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.