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Single and multiple inhibitors of the biosynthesis of 5-, 12-, 15-lipoxygenase products derived from cinnamyl-3,4-dihydroxy-α-cyanocinnamate: Synthesis and structure-activity relationship.
Touaibia, Mohamed; Chiasson, Audrey Isabel; Robichaud, Samuel; Doiron, Jérémie A; Hébert, Mathieu P A; Surette, Marc E.
Afiliación
  • Touaibia M; Chemistry and Biochemistry Department, Université de Moncton, Moncton, New Brunswick, Canada.
  • Chiasson AI; Chemistry and Biochemistry Department, Université de Moncton, Moncton, New Brunswick, Canada.
  • Robichaud S; Chemistry and Biochemistry Department, Université de Moncton, Moncton, New Brunswick, Canada.
  • Doiron JA; Chemistry and Biochemistry Department, Université de Moncton, Moncton, New Brunswick, Canada.
  • Hébert MPA; New Brunswick Center for Precision Medicine, Université de Moncton, Moncton, New Brunswick, Canada.
  • Surette ME; Chemistry and Biochemistry Department, Université de Moncton, Moncton, New Brunswick, Canada.
Drug Dev Res ; 85(3): e22181, 2024 May.
Article en En | MEDLINE | ID: mdl-38619209
ABSTRACT
The involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure-activity study was carried out, which led to the discovery of several novel compounds (16a-c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5-, 12- and 15-LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA-approved 5-LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α-position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12- and 15-LO products. Compounds 16a, 17a far surpassed baicalein, a known 12-LO inhibitor, as inhibitors of 12-LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α-position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15-LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5-LO active site.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Araquidonato 15-Lipooxigenasa / Cinamatos / Hidroxiurea Idioma: En Revista: Drug Dev Res Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Araquidonato 15-Lipooxigenasa / Cinamatos / Hidroxiurea Idioma: En Revista: Drug Dev Res Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos