Structure-activity relationship studies of novel heteroretinoids: induction of apoptosis in the HL-60 cell line by a novel isoxazole-containing heteroretinoid.
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Simoni D, Invidiata FP, Rondanin R, Grimaudo S, Cannizzo G, Barbusca E, Porretto F, D'Alessandro N, Tolomeo M
Structure-activity relationship studies of novel heteroretinoids: induction of apoptosis in the HL-60 cell line by a novel isoxazole-containing heteroretinoid.
J Med Chem. 1999 Dec 2;42(24):4961-9.
- PubMed ID
- 10585206 [ View in PubMed]
- Abstract
In a search for retinoic acid receptor (RAR and RXR)-selective ligands, a series of isoxazole retinoids was synthesized and evaluated in vitro in transcriptional activation and competition binding assays for RARs and RXRs. In addition, these compounds were evaluated for their differentiating, cytotoxic, and apoptotic activities. In general, these derivatives showed scarcely any binding affinity and were not active in the transcriptional assay. However, among these isoxazole derivatives, the cis-isomer 14b was identified as a potent inducer of apoptosis, and its activity was found to be 6.5 and 4 times superior than that of 13-cis- and 9-cis-retinoic acids, respectively. On the other hand, compound 13b, which has the trans stereochemistry at the double bond, was found not to be active in the apoptotic assay, but it was endowed with appreciable differentiating activity. Therefore, it seems that the different stereochemistry of the double bond may be associated with a different biological activity: potent apoptotic activity for the cis-isomer but differentiating activity for the trans structure. This biological behavior was found, at least in part, for the 9-cis- and 13-cis-retinoic acids with respect to the all-trans-retinoic acid. Thus, structure 14b could offer an interesting model for the design of new compounds endowed with apoptotic activity.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Tretinoin Retinoic acid receptor alpha EC 50 (nM) 5 N/A N/A Details Tretinoin Retinoic acid receptor alpha EC 50 (nM) 102 N/A N/A Details Tretinoin Retinoic acid receptor alpha Kd (nM) 16 N/A N/A Details Tretinoin Retinoic acid receptor beta EC 50 (nM) 1.5 N/A N/A Details Tretinoin Retinoic acid receptor beta EC 50 (nM) 3.3 N/A N/A Details Tretinoin Retinoic acid receptor beta Kd (nM) 7 N/A N/A Details Tretinoin Retinoic acid receptor gamma EC 50 (nM) 0.5 N/A N/A Details Tretinoin Retinoic acid receptor gamma EC 50 (nM) 6 N/A N/A Details Tretinoin Retinoic acid receptor gamma Kd (nM) 3 N/A N/A Details Tretinoin Retinoic acid receptor RXR-alpha EC 50 (nM) 13 N/A N/A Details