Structure-activity relationship studies of novel heteroretinoids: Induction of apoptosis in the HL-60 cell line by a novel isoxazole-containing heteroretinoid

被引:50
作者
Simoni, D
Invidiata, FP
Rondanin, R
Grimaudo, S
Cannizzo, G
Barbusca, E
Porretto, F
D'Alessandro, N
Tolomeo, M
机构
[1] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy
[2] Univ Palermo, Policlin, Div Ematol, I-90123 Palermo, Italy
[3] Univ Palermo, Policlin, Serv AIDS, I-90123 Palermo, Italy
[4] Univ Palermo, Policlin, Ist Farmacochim, I-90123 Palermo, Italy
关键词
D O I
10.1021/jm991059n
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 nest 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 traits 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.
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页码:4961 / 4969
页数:9
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