Ballari, MS;
O. J. Porta, E;
Zalazar, EA;
Etichetti, CMB;
Padrón, JM;
Girardini, JE;
Labadie, GR;
(2023)
Lipophilic modification of salirasib modulates the antiproliferative and antimigratory activity.
Bioorganic and Medicinal Chemistry
, 92
, Article 117417. 10.1016/j.bmc.2023.117417.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Lipophilic modification of salirasib modulates the antiproliferative and antimigratory activity |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bmc.2023.117417 |
| Publisher version: | http://dx.doi.org/10.1016/j.bmc.2023.117417 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | 1, 2, 3-triazoles, Antineoplastic Agents, Cancer, Cell Line, Cell Migration, Cell Proliferation, Cheminformatics, Docking, Farnesol, Salicylates, Salirasib, SAR studies, Tumor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10185881 |
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