1996
DOI: 10.1021/jm9603126
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Conformationally Defined 6-s-trans-Retinoic Acid Analogs. 3. Structure−Activity Relationships for Nuclear Receptor Binding, Transcriptional Activity, and Cancer Chemopreventive Activity

Abstract: We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with di… Show more

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Cited by 22 publications
(35 citation statements)
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“…In comparison with known rexinoids, most of which contain carboxylic acids (3234), the indenoisoquinoline rexinoids constitute a fundamentally different type of RXR ligand. The fact that indenoisoquinolines are structurally unique rexinoids offers the possibility of them having unique pharmacological properties that could be clinically useful.…”
Section: Discussionmentioning
confidence: 99%
“…In comparison with known rexinoids, most of which contain carboxylic acids (3234), the indenoisoquinoline rexinoids constitute a fundamentally different type of RXR ligand. The fact that indenoisoquinolines are structurally unique rexinoids offers the possibility of them having unique pharmacological properties that could be clinically useful.…”
Section: Discussionmentioning
confidence: 99%
“…Each mixture was preparatively separated by HPLC on silica gel (0.5% Et 2 O, 0.1% THF in hexane for the former and 1% Et 2 O, 0.5% THF in hexane for the latter) using methods similar to those we previously described. [8][9][10][11] Individual isomers of ester 5 were then hydrolyzed to the corresponding acids in KOH, without E/Z-isomerization. 12 The isomeric purity for the final acids (>97%) was verified by NMR and reverse-phase HPLC.…”
Section: Chemistrymentioning
confidence: 99%
“…12 The isomeric purity for the final acids (>97%) was verified by NMR and reverse-phase HPLC. [8][9][10][11] Experimental yields and selected data for the intermediates and products in Scheme 1 are summarized in Table 1. The UV/vis spectral data of the purified isomers are given in Table 1, and the complete 1 H NMR assignments are contained in Table 2.…”
Section: Chemistrymentioning
confidence: 99%
“…18,19 In addition, synthetic analogues have been identified which show significant selectivity toward the R, β, and γ receptor subtypes or which preferentially activate the RAR or RXR responsive pathway. [20][21][22][23][24][25][26] The identification of new analogues with specific binding and/or transactivation patterns is critical for the development of retinoids with specific biological activities. Successful analogue design based on lead compounds should include skeletal changes in order to obtain different physicochemical characteristics from those leads.…”
Section: Introductionmentioning
confidence: 99%
“…These retinoid receptors can also inhibit the activity of another transcription factor, AP-1, resulting in growth inhibition . Whereas the naturally occurring RA acts via both these mechanisms, synthetic analogues have been developed which can independently activate these two pathways. , In addition, synthetic analogues have been identified which show significant selectivity toward the α, β, and γ receptor subtypes or which preferentially activate the RAR or RXR responsive pathway. The identification of new analogues with specific binding and/or transactivation patterns is critical for the development of retinoids with specific biological activities.…”
Section: Introductionmentioning
confidence: 99%