Preparation of high specific activity all <i>trans</i>‐α‐retinyl‐11‐<sup>3</sup>H acetate

Hale, R.; Burger, Walter; Perry, Clark W.; Liebman, Arnold A.

doi:10.1002/jlcr.2580130113

Cited by 9 publications

(6 citation statements)

References 6 publications

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“…After preparative HPLC separation of the 9Zand 9Z,13Z-isomers of 12 on silica gel, the corresponding acids 1 were generated, without isomerization, by hydrolysis in KOH. 30 We have also reported similar success in hydrolyzing other retinoid esters without isomerization under these conditions. 29 In order to produce the all-Eand 13Z-isomers of 1, aldehyde (2Z)-11 was thermally isomerized at room temperature, using I2 as a catalyst, to give a 2:1 mixture of (2Z)-11 and (a//-E)-ll (Scheme 1).…”

supporting

confidence: 56%

A Conformationally Defined 6-s-trans-Retinoic Acid Isomer: Synthesis, Chemopreventive Activity, and Toxicity

Vaezi

Alam²,

Sani³

et al. 1994

J. Med. Chem.

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A conformationally defined retinoic acid analog (1) which contains a dimethylene bridge to maintain the 6-s-trans orientation for two terminal double bonds in the polyene chain was synthesized. A Reformatsky reaction was utilized to extend the polyene chain of the starting enone, which provided exclusively the 9Z-configuration for the intermediate aldehyde. A Horners-Emmons condensation with this aldehyde then produced retinoic acid analogs with both 9Z- and 9Z,13Z-configurations. An I2-catalyzed isomerization of the intermediate 9Z-aldehyde yielded the all-E-aldehyde, which was olefinated as above to yield the (all-E)- and (13Z)-retinoic acid analogs of 1. Each configurational isomer of 1 was evaluated for its ability to inhibit the binding of retinoic acid to CRABP (chick skin) and to inhibit the chemical induction of ornithine decarboxylase in mouse skin. In each assay (all-E)-1 was the most active isomer, and this activity was comparable to or better than that for (all-E)-retinoic acid. (all-E)-1 and (13Z)-1 were both shown to be equally effective as (13Z)-retinoic acid in suppressing the proliferation of human sebaceous cells in vitro. (all-E)-1 was further evaluated for its ability to prevent the induction of mouse skin papillomas and to induce signs of vitamin A toxicity in mice. The cancer chemopreventive activity of (all-E)-1 was comparable to that of (all-E)-retinoic acid, and the toxicity was comparable to or slightly better than that of the natural vitamin.

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supporting

confidence: 56%

A Conformationally Defined 6-s-trans-Retinoic Acid Isomer: Synthesis, Chemopreventive Activity, and Toxicity

Vaezi

Alam²,

Sani³

et al. 1994

J. Med. Chem.

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“…19,20,22 Individual isomers of ester 5 were hydrolyzed to the corresponding acids in KOH, without E/Z-isomerization. 23 In order to produce (all-E)-UAB4, intermediate aldehyde (9Z)-4 was isomerized using I 2 to yield a 1:2 ratio of all-E-and 9Z-isomers. As for (9Z)-4, a Horner-Emmons condensation using (all-E)-4 produced a 2:1 mixture of all-E-and 13Z-ester 5.…”

Section: Chemistrymentioning

confidence: 99%

“…Unlike previous reports, , a δ-lactone intermediate was not detected but was assumed to be an intermediate in the production of (9 Z )- 2 . (9 Z )- 5 and (9 Z ,13 Z )- 5 were preparatively separated by HPLC on silica gel (0.5% Et 2 O, 0.1% THF in hexane) using methods similar to those we previously described. ,, Individual isomers of ester 5 were hydrolyzed to the corresponding acids in KOH, without E / Z -isomerization . In order to produce ( all-E )-UAB4, intermediate aldehyde (9 Z )- 4 was isomerized using I 2 to yield a 1:2 ratio of all-E - and 9 Z -isomers.…”

Section: Chemistrymentioning

confidence: 99%

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

et al. 1996

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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.

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“…[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. [8][9][10][11] Experimental yields and selected data for the intermediates and products in Scheme 1 are summarized in Table 1.…”

Section: Chemistrymentioning

confidence: 99%

“…Each pure isomer of 4 was olefinated as shown to provide a mixture of either (9 Z )- and (9 Z ,13 Z )- 5 or ( all-E )- and (13 Z )- 5 . 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. − Individual isomers of ester 5 were then hydrolyzed to the corresponding acids in KOH, without E / Z -isomerization − Experimental yields and selected data for the intermediates and products in Scheme are summarized in Table .…”

Section: Chemistrymentioning

confidence: 99%

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

et al. 1998

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We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R1 = Et; R2 = iPr), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells (an APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3', 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4, 6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RARalpha but did not activate transcription-mediated RARalpha homodimers, even though it was effective in RARbeta- and RARgamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays.

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Preparation of high specific activity all trans‐α‐retinyl‐11‐³H acetate

Cited by 9 publications

References 6 publications

A Conformationally Defined 6-s-trans-Retinoic Acid Isomer: Synthesis, Chemopreventive Activity, and Toxicity

A Conformationally Defined 6-s-trans-Retinoic Acid Isomer: Synthesis, Chemopreventive Activity, and Toxicity

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

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

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Preparation of high specific activity all trans‐α‐retinyl‐11‐3H acetate

Cited by 9 publications

References 6 publications

A Conformationally Defined 6-s-trans-Retinoic Acid Isomer: Synthesis, Chemopreventive Activity, and Toxicity

A Conformationally Defined 6-s-trans-Retinoic Acid Isomer: Synthesis, Chemopreventive Activity, and Toxicity

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

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

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Preparation of high specific activity all trans‐α‐retinyl‐11‐³H acetate