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 different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.

Induction of Retinoid X Receptor Activity and Consequent Upregulation of p21WAF1/CIP1 by Indenoisoquinolines in MCF7 Cells

“…In comparison with known rexinoids, most of which contain carboxylic acids (32–34), 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.…”

Conformationally Defined Retinoic Acid Analogues. 4. Potential New Agents for Acute Promyelocytic and Juvenile Myelomonocytic Leukemias

“…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.…”

“…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.…”

Synthesis and Structure−Activity Relationships of 2-Pyrazinylcarboxamido- benzoates and β-Ionylideneacetamidobenzoates with Retinoidal Activity

“…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.…”

“…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.…”