Synthesis and pharmacological activity of 6-[(E)-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethen-1-yl)]- and 6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylic acids

Dawson, Marcia I.; Chan, Rebecca Wing-Yan; Derdzinski, K.; Hobbs, Peter D.; Chao, Wan Ru; Schiff, Leonard J.

doi:10.1021/jm00365a021

Cited by 39 publications

(11 citation statements)

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“…Synthetic retinoids that contain one or more aromatic rings are termed arotinoids. By means of these modifications, the trimethylcyclohexenyl ring and the conjugated tetraene of the natural retinoids may be replaced by robust structural units such as stilbene, tolan or biaryl to give retinoids which exhibit high activity and stability such as TTNPB, [35] EC23, [12] and TTNN, [36] respectively. Scheme 3.…”

Section: =Cmentioning

confidence: 99%

“…TTNPB is one of the most active synthetic retinoids yet discovered, possessing an activity in the hamster TOC assay five times greater than that of ATRA. [38] Retinoids TTNN [36] and TTAB (SRI 6751-84) [45] can be considered as isomeric, benzo-fused analogues of TTNPB and display high biological activities, with that of TTNN comparable to TTNPB, and TTAB being approximately 7.5 times more potent than ATRA or TTNPB for the induction of differentiation in F9 embryonal carcinoma cells. [46] Other hydrocarbon linker units include the biaryl groups of (E)-, and (Z)-cinnamate retinoids SRI 7101-27 and SRI 7101-53, respectively, which show limited biological activities in the TOC assay, and the triple bond of the photostable retinoid EC23, which is highly effective in the induction of neural differentiation in human TERA2.cl.SP12 embryonal carcinoma cells, with activity greater than that of the natural ligand ATRA.…”

Section: Modification Of the Linker Unitmentioning

confidence: 99%

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Synthetic Retinoids: Structure–Activity Relationships

Barnard

Collings

Whiting

et al. 2009

Chemistry A European J

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Retinoid signalling pathways are involved in numerous processes in cells, particularly those mediating differentiation and apoptosis. The endogenous ligands that bind to the retinoid receptors, namely all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, are prone to double-bond isomerisation and to oxidation by metabolic enzymes, which can have significant and deleterious effects on their activities and selectivities. Many of these problems can be overcome through the use of synthetic retinoids, which are often much more stable, as well as being more active. Modification of their molecular structures can result in retinoids that act as antagonists, rather than agonists, or exhibit a large degree of selectivity for particular retinoid-receptor isotypes. Several such selective retinoids are likely to be of value as pharmaceutical agents with reduced toxicities, particularly in cancer therapy, as reagents for controlling cell differentiation, and as tools for elucidating the precise roles that specific retinoid signalling pathways play within cells.

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Section: =Cmentioning

confidence: 99%

Section: Modification Of the Linker Unitmentioning

confidence: 99%

Synthetic Retinoids: Structure–Activity Relationships

Barnard

Collings

Whiting

et al. 2009

Chemistry A European J

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“…NMR (90 MHz, CDC13) ó 0.3 (s, 6H), 1.1 (s, 9H), 1.35 (s, 9H), 6.65 Methyl 6-[3-íerí-ButyI-4-[(íerí-butyldimethylsilyl)oxy]phenyl]-2-naphthoate (25). Compound 24 (11.3 g, 33 mmol) was transformed into zincate derivative and condensed with methyl 6-bromo-2-naphthoate (5.1 g, 19.3 mmol) using exactly the same procedure as for preparation of 22.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis, Structure-Affinity Relationships, and Biological Activities of Ligands Binding to Retinoic Acid Receptor Subtypes

Charpentier

Bernardon²,

Eustache³

et al. 1995

J. Med. Chem.

114

109

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The retinoic acid receptors (RARs) transduce retinoid dependant gene regulation, and many biological effects of retinoids are mediated through binding and activation of three closely related receptor subtypes (RAR alpha, RAR beta, and RAR gamma). In order to investigate the role of receptor subtypes, we have carried out a chemical synthesis program to seek selective retinoids for these receptors. We measured receptor binding affinity using recombinant RAR alpha, -beta, and -gamma proteins and assessed cellular differentiating activity in F9 murine teratocarcinoma cells (F9 cells). This research has identified the 4-substituted-3-(1-adamantyl)phenyl moiety as a new pharmacophore which can replace the beta-cyclogeranylidene ring of the naturally occurring all-trans-retinoic acid. Two chemical series derived from the general structures 6-(3-tertioalkylphenyl)-2-naphthoic acid (series I) and 4-[(E)-2-(3-tertioalkylphenyl)propenyl]benzoic acid (series II) were developed. In particular, we have obtained the RAR gamma selective derivatives 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid (7) [Ki(RAR alpha) = 6500 nM, Ki(RAR beta) = 2480 nM, Ki(RAR gamma) = 77 nM] and 4-[(E)-2-[3-(1-adamantyl)-4-hydroxyphenyl]propenyl]benzoic acid (19) [Ki(RAR alpha) = 1,144 nM, Ki(RAR beta) = 1245 nM, Ki(RAR gamma) = 53 nM]. In series I, the presence of a phenol group, irrespective of the nature of tertioalkyl group, imparted at least partial RAR gamma selectivity, whereas in series II, the presence of both adamantyl and phenol groups is needed to confer RAR gamma selectivity. The RAR gamma selective ligands induce differentiation in F9 cells (7, AC50 = 33 nM; 19, AC50 = 66 nM). From series I, a mixed RAR beta-gamma agonist with potent cellular differentiating activity was selected for development as a topical antiacne agent, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (5, CD 271) [Ki(RAR alpha) = 1100 nM, Ki-(RAR beta) = 34 nM, Ki(RAR gamma) = 130 nM, AC50(F9) = 37 nM]. Finally, from series II, we have obtained a weak antagonist in the F9 cellular differentiation assay, 4-[(E)-2-(3-tert-butyl-4-hydroxyphenyl)propenyl]benzoic acid (15, IC50 = 700 nM).

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“…New retinoid analogs were synthesized [46][47][48][49][50][51][52][53][54] in an attempt to obtain compounds more stable and/or more active than RA. The new retinoids were screened for bio logical activity on F9 embryonal carcinoma differentiation in comparison to RA and re tinol.…”

Section: Biological Activity O F Ra Analogsmentioning

confidence: 99%

Biological Activity of Retinoids Correlates with Affinity for Nuclear Receptors but Not for Cytosolic Binding Protein

Darmon¹,

Rocher²,

Cavey³

et al. 1988

Skin Pharmacol Physiol

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In order to better understand the respective roles of the nuclear retinoic acid receptors (RARs) and the cytosolic retinoic acid binding protein (CRABP) in the mode of action of retinoic acid (RA), several types of RA analogs have been synthesized. Representative compounds have been radiolabeled to a high specific activity and their binding (direct and competition) to RARs and CRABP was determined. Their biological activity on F9 embryonal carcinoma cell differentiation has been determined by a quantitative assay of plasminogen activator (PA). All biologically active analogs studied in this work bound to RARs. A good correlation was found between PA induction and affinity for the RARs, with the exception of RA itself which was a good ligand but a moderate inducer of F9 differentiation. Two biologically active analogs (compounds II and III) did not bind to the CRABP. One biologically inactive analog (compound VIII) bound to CRABP. These results strongly suggest that retinoids must bind to RARs but not necessarily to CRABP in order to induce cell differentiation in F9 cells.

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Synthesis and pharmacological activity of 6-[(E)-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethen-1-yl)]- and 6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylic acids

Cited by 39 publications

References 4 publications

Synthetic Retinoids: Structure–Activity Relationships

Synthetic Retinoids: Structure–Activity Relationships

Synthesis, Structure-Affinity Relationships, and Biological Activities of Ligands Binding to Retinoic Acid Receptor Subtypes

Biological Activity of Retinoids Correlates with Affinity for Nuclear Receptors but Not for Cytosolic Binding Protein

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