Lipophilic modification of salirasib modulates the antiproliferative and antimigratory activity.

Autor: Ballari MS; Instituto de Química Rosario (IQUIR), Universidad Nacional de Rosario-CONICET, Suipacha 531 S2002LRK, Rosario, Argentina., O J Porta E; Instituto de Química Rosario (IQUIR), Universidad Nacional de Rosario-CONICET, Suipacha 531 S2002LRK, Rosario, Argentina., Zalazar EA; Instituto de Inmunología Clínica y Experimental de Rosario (IDICER), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Suipacha 590 S2000LRJ, Rosario, Argentina., Etichetti CMB; Instituto de Fisiología Experimental de Rosario (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531 2000 Rosario, Argentina., Padrón JM; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, Apartado 456 E-38071, La Laguna, Spain. Electronic address: jmpadron@ull.edu.es., Girardini JE; Instituto de Inmunología Clínica y Experimental de Rosario (IDICER), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Suipacha 590 S2000LRJ, Rosario, Argentina. Electronic address: girardini@idicer-conicet.gob.ar., Labadie GR; Instituto de Química Rosario (IQUIR), Universidad Nacional de Rosario-CONICET, Suipacha 531 S2002LRK, Rosario, Argentina; Departamento de Química Orgánica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina. Electronic address: labadie@iquir-conicet.gov.ar.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2023 Sep 07; Vol. 92, pp. 117417. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1016/j.bmc.2023.117417
Abstrakt: Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker. A combination of bioassay, cheminformatics, docking, and in silico ADME-Tox was also performed. SAR analysis that analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, three compounds display superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behavior of the collection on migration and invasion, a key process in tumor metastasis, was also studied. Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: