Structure-activity relationships of retinoids in developmental toxicology

Howard, W. Brian; Willhite, Calvin C.; Dawson, Marcia I.; Sharma, R.P.

doi:10.1016/s0041-008x(88)80013-9

Cited by 25 publications

(3 citation statements)

References 109 publications

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“…Therapeutic retinoids that interact with the RAR subtypes, such as those listed above, are not without significant adverse effects that limit their use [37,[50][51][52][53][54][55][56][57][58][59][60][61]. Because disease relapse can occur when retinoids are discontinued, patients must be on long-term therapy [23,28,38].…”

Section: Role and Development Of Selective Retinoidsmentioning

confidence: 99%

Synthetic Retinoids and Their Nuclear Receptors

Dawson¹

2004

CMCACA

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In addition to all-trans-retinoic acid and its 9 and 13-cis isomers, four synthetic retinoids are currently available to treat diseases of hyperproliferation, such as acne, psoriasis, and actinic keratosis, or cancers such as acute promelocytic leukemia, cutaneous T-cell lymphoma, and squamous or basal cell carcinoma. The retinoids extert their antiproliferative effects by interacting with their retinoic acid and retinoid X receptors that act as ligand-inducible transcription factors. These homologous receptors function either directly on retinoid response elements or indirectly by modifying the responses of other transcription factors. Their major domains for binding DNA and their ligands have been characterized by either nuclear magnetic resonance spectroscopy or X-ray crystallography. The identification and design of synthetic retinoids are overviewed, as are their selective interactions with specific retinoid receptor subtypes and their clinical effects against cancer. Emphasis is placed on the retinoid X receptors and their ligands.

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Section: Role and Development Of Selective Retinoidsmentioning

confidence: 99%

Synthetic Retinoids and Their Nuclear Receptors

Dawson¹

2004

CMCACA

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“…The litters were examined for resorp- Table I. tions, deaths, and live fetuses. A litter was considered affected if it contained one or more malformed or dead fetuses or three or more resorptions [11]. The retinoid doses were measured in molar equivalents to all-trans retinoic acid (cpd 31, see Fig.…”

Section: Experimental Datamentioning

confidence: 99%

“…Willhite et al have published a series of papers specifically dealing with the effects of retinoid structure on teratogenic activity [9][10][11]. We have used in the past the Computer Automated Structure Evaluation (CASE) methodology to study successfully several databases for structure-activity relationships such as the mutagenicity of non-fused-ring nitroarenes [12], antileukemic activity of 9-anilinoacridines [13], antibacterial activity of quinolones [14], and glyoxalase I inhibition of flavonoids [15], just to mention a few.…”

Section: Introductionmentioning

confidence: 99%

Computer Automated Structure Evaluation (CASE) of the teratogenicity of retinoids with the aid of a novel geometry index

Klopman

1990

J Computer-Aided Mol Des

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The CASE (Computer Automated Structure Evaluation) program, with the aid of a geometry index for discriminating cis and trans isomers, has been used to study a set of retinoids tested for teratogenicity in hamsters. CASE identified 8 fragments, the most important representing the non-polar terminus of a retinoid with an additional ring system which introduces some rigidity in the side chain. The geometry index helped to identify relevant fragments with an all-trans configuration and to distinguish them from irrelevant fragments with other configurations.

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Characterization of heterologously expressed recombinant retinoic acid receptors with natural or synthetic retinoids

Kim

Sharma

1994

J. Biochem. Toxicol.

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The first step in retinoid action is binding to their nuclear receptors. Therefore, characterization of binding characteristics of retinoids is of major importance. Human retinoic acid receptors alpha (hRAR alpha), hRAR beta, and mouse RAR gamma (mRAR gamma) were expressed heterologously in Escherichia coli as a recombinant glutathione S-transferase (GST) fusion protein. The expressed fusion proteins were functional and bound specifically to the all-trans-retinoic acid (RA). The dissociation constants (Kd) for RA were 1.4 nM for GST-hRAR alpha, 1.4 nM for GST-hRAR beta, and 3.3 nM for GST-mRAR gamma, respectively. The fusion proteins were further used for competitive displacement assays to determine the displacement constant (DC50) for other selected retinoids. All-trans-RA and 4-oxo-all-trans-RA have high affinity with all three receptors (DC50 = 0.8-55 nM). The 13-cis RA binds to hRAR alpha with low affinity, but not to other RARs evaluated here. All-trans-N-ethylretinamide, all-trans-retinylacetate, and an ethyl ester of tetrahydronaphthalene derivative had no affinity to any RARs. The hRAR alpha and mRAR gamma receptors did not bind a naphthalene carboxylic acid derivative of RA, but hRAR beta binds this chemical with high affinity. Results indicated that the three recombinant proteins were functional in binding various RA congeners. The affinity and binding data of these retinoids were compared to their observed teratogenic activity.

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Structure-activity relationships of retinoids in developmental toxicology

Cited by 25 publications

References 109 publications

Synthetic Retinoids and Their Nuclear Receptors

Synthetic Retinoids and Their Nuclear Receptors

Computer Automated Structure Evaluation (CASE) of the teratogenicity of retinoids with the aid of a novel geometry index

Characterization of heterologously expressed recombinant retinoic acid receptors with natural or synthetic retinoids

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