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

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 18; no. 3; p. 406
• Main Authors: Zhuravlev, Alexander, Golovanov, Alexey, Toporkov, Valery, Kuhn, Hartmut, Ivanov, Igor
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2022
• Subjects: Animals; Binding Sites; Catalytic Domain; Lipoxygenase Inhibitors - pharmacology; Rabbits; Substrate Specificity; lipoxygenases; ALOXs; RS7091 inhibitor; cinnamic acid derivatives; Sonogashira-coupling; photoaffinity probes
• ISSN: 1875-6638
• DOI: 10.2174/1573406417666210604112009

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.