2. Academic Validation
  3. Synthesis, Biological Evaluation, and Molecular Docking Study of 3-Amino and 3-Hydroxy- seco A Derivatives of α-Amyrin and 3-Epilupeol as Inhibitors of COX-2 Activity and NF-kB Activation

Synthesis, Biological Evaluation, and Molecular Docking Study of 3-Amino and 3-Hydroxy- seco A Derivatives of α-Amyrin and 3-Epilupeol as Inhibitors of COX-2 Activity and NF-kB Activation

  • J Nat Prod. 2022 Apr 22;85(4):787-803. doi: 10.1021/acs.jnatprod.1c00827.
Antonio Romero-Estrada 1 2,  Alicia Boto 3,  Judith González-Christen 4,  Ivan Romero-Estudillo 1 5,  María Luisa Garduño-Ramírez 1,  Rodrigo Said Razo-Hernández 6,  Silvia Marquina 1,  Amalia Maldonado-Magaña 7,  María C Columba-Palomares 4,  Jessica Nayelli Sánchez-Carranza 4,  Laura Alvarez 1
Affiliations

Affiliations

  • 1 Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca 62209, Morelos, México.
  • 2 Departamento de Madera, Celulosa y Papel, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Km 15.5 Carretera Guadalajara-Nogales, Col. Las Agujas, Zapopan 45100, Jalisco, México.
  • 3 Instituto de Productos Naturales y Agrobiología del CSIC, Avenuda Astrofísico Francisco Sánchez 3, 38206-La Laguna, Tenerife, Spain.
  • 4 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca 62209 Morelos, México.
  • 5 CONACYT-Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca 62209 Morelos, México.
  • 6 Centro de Investigación en Dinámica Celular-IICBA, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca 62209, Morelos, México.
  • 7 Instituto Tecnológico de Milpa Alta. Independencia Sur No. 36, Col. San Salvador Cuauhténco, Alcaldía Milpa Alta CDMX 12300, México.
PMID: 35175765 DOI: 10.1021/acs.jnatprod.1c00827
Abstract

In this study, a series of novel 3-seco-A derivatives of the natural Triterpenes α-amyrin (1) and 3-epilupeol (2) were synthesized by a one-pot radical scission-oxidation procedure and evaluated in vitro and in vivo for their capacity to inhibit the inflammatory process. For the in vitro studies, the trans-4-hydroxy-l-proline methyl ester derivatives (1f and 2f) were consistently effective in inhibiting NO, IL-6, and TNF-α secretion, as well as inhibition of NF-κB activation, in RAW cells stimulated by LPS. The further in vivo anti-inflammatory study revealed that the trans-4-hydroxy-l-proline methyl ester derivatives (1f and 2f), together with 1g, were the most effective in inhibiting TPA-induced edema. Interestingly, the α-amyrin derivatives were the most potent inhibitors of COX-2, but inhibited COX-1 only to some extent. The hydroxyl derivative (1c) was selective for COX-2 inhibition (66.3 ± 1.1% at 17.5 μM) without affecting the COX-1 isoform and did not present toxicity. Molecular docking studies revealed that these compounds bind with their polar region in the cavity over Arg-120, and their lipophilic part is orientated to the HEM cofactor similarly to the natural substrate arachidonic acid in the catalytic site of COX-2. These results indicated that seco-A ursane derivatives could be considered promising candidates for the future development of selective NF-κB and COX-2 inhibitors.

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