A method for the stereoselective synthesis of (E)-methylstilbene retinoids

Dawson, Marcia I.; Derdzinski, K.; Hobbs, Peter D.; Chan, Rebecca L. C.; Rhee, Sung W.; Yasuda, Dennis

doi:10.1021/jo00200a055

Cited by 8 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To a suspension of phosphonium salt 17 (1.24 g, 2.17 mmol) in THE (50 mL) was added n-BuLi (1.6 M in hexanes, 1.5 mL, 2.4 mmol). The resulting red solution was stirred for 30 min, and then aldehyde 19 (330 mg, 1.81 mmol) in 1.5 mL of THE was added. The solution was stirred at room temperature for 18 h to yield a peach-colored suspension.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Structure-Activity Relationships of Stilbene Retinoid Analogs Substituted with Heteroaromatic Carboxylic Acids

Beard¹,

Colon²,

Gillett³

et al. 1995

J. Med. Chem.

View full text Add to dashboard Cite

Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.

show abstract

Section: Methodsmentioning

confidence: 99%

Synthesis and Structure-Activity Relationships of Stilbene Retinoid Analogs Substituted with Heteroaromatic Carboxylic Acids

Beard¹,

Colon²,

Gillett³

et al. 1995

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Consequently, a major conformation in solution (DCC13) for the cis isomers may have ring B out of plane with the central double bond and twisted in such a manner that H(4) is closer to ring C (and its shielding cone) than is H(6) [such as is implied for the isomeric system (Z)-3d herein]. In this arrangement, H(7) would seemingly be more distant from ring C (and its shielding cone) than perhaps H (15,17) are from ring B. This appears to be supported by the smaller chemical shift differences observed for meta proton H(7) [A5 = 0.07-0.11] in ring B compared to those of meta protons H (15,17) [A6 = 0.23-0.28] in ring C. In the major conformation in solution, it is likely that ring C of the cis isomers is also turned out of plane with the middle double bond, which could explain the large shielding of H(4,6) in the cis isomers relative to that found in the trans isomers.…”

Section: Resultsmentioning

confidence: 93%

“…In this arrangement, H(7) would seemingly be more distant from ring C (and its shielding cone) than perhaps H (15,17) are from ring B. This appears to be supported by the smaller chemical shift differences observed for meta proton H(7) [A5 = 0.07-0.11] in ring B compared to those of meta protons H (15,17) [A6 = 0.23-0.28] in ring C. In the major conformation in solution, it is likely that ring C of the cis isomers is also turned out of plane with the middle double bond, which could explain the large shielding of H(4,6) in the cis isomers relative to that found in the trans isomers. The same situation exists for 3h-m.…”

Section: Resultsmentioning

confidence: 97%

“…In general, the 13C NMR spectra were less informative concerning the configuration around the central double bond. Nevertheless, trans isomers displayed a signal in 3a-m for the methyl carbon [C(ll), Z = H] at [17][18] ppm [this is C( 12) in 3h-m; (E)-lh and (E)-lk had the signal reported at 16.5 ppm10] while the cis isomers had the signal at ~27 ppm. A single explanation for the deshielding of C(ll) in 3a-g [or C (12) in 3h-m] in the cis isomers, relative to the trans isomers, is not intuitively obvious.…”

Section: Resultsmentioning

confidence: 99%

“…Recrystallization from boiling 95% ethanol (50 mL) gave the heteroarotinoid ester (£)-3d as white crystalline flakes (1.87 g, 59.0%) which was essentially pure (mother liquors set aside, see isolation of (Z)-3d below). A second recrystallization (95% EtOH, 50 mL) gave pure (E)-3d (1.62 g, 51.1%) as assessed by TLC (silica gel, 9:1 hexane-ether): mp 120.9-122.0 °C; IR (KBr) 1716 (C=0 cnT1); !H NMR (DCC13) 8 1.42 [s, 6 H, H(8,9)], 2.28 [d, J = 1.4 Hz, 1 H, H(ll)], 3.21 [s, 1 H, H(2)], 3.93 [s, 3 H, H(20)], 6.81 [br s, 1 H, H( 12)], 7.20 [d, J= 2 Hz, 1 H, H(4)], 7.19 [d, J = 8 Hz, 1 H, H(7)], 7.30 [dd, J = 8 Hz, J = 2 Hz, 1 H, H( 6)], 7.42 [d, J = 8.3 Hz, 2 H, H(14,18)], 8.04 [d,J = 8.3 Hz,2 H,H(15,17)]; 13C NMR (DCC13) ppm 17.8 [C(ll)], 27.4 [C(8,9)], 47.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Heteroarotinoids: analytical criteria for the rapid identification of E and Z isomers of these novel retinoids via NMR, UV, and x-ray analyses of selected examples

Gale¹,

Rajadhyaksha²,

Spruce³

et al. 1990

J. Org. Chem.

View full text Add to dashboard Cite

Retinoids

Dawson¹

2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

Retinoid drugs find major applications in the topical treatment of cutaneous proliferative disorders such as acne, psoriasis, and photoaging and cutaneous cancers such as cutaneous T‐cell lymphoma (CTCL) and Kaposi's sarcoma. Oral retinoids are successfully used to treat nodular/cystic acne, systemic CTCL, and acute promyelocytic leukemia. This overview of available retinoid drugs and those in the preclinical or clinical pipeline covers their development, indications, clinical trial results, adverse effects, and pharmacology/metabolism. Retinoids have been described historically and functionally in the context of interaction with their nuclear receptors—retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—in inducing gene transcription. RAR‐selective retinoids or their prodrugs include first‐generation all‐ trans ‐retinoic acid (tretinoin) and its 13‐ cis isomer (isotretinoin), and second‐generation acitretin and its ethyl ester (etretinate), both having an aromatic 2,3,6‐trimethyl‐4‐methoxyphenyl terminus. Third‐generation more aromatic analogs include ethyl ester tazarotene (Tazorac®) and adapalene (Differin®), both selective for RAR subtypes β and γ, and RARα‐selective pipeline candidates Am80 and NRX 195183, which are in clinical trials. RAR and RXR transcriptional panagonist 9‐ cis ‐retinoic acid is next and is followed by RXR‐selective bexarotene (Targretin™) and two RXR‐selective clinical trial candidates, 9cUAB and NRX 194204. The fourth generation includes three compounds that may have applications in the treatment or prevention of cancer. While originally considered as retinoids, such as N ‐(4‐hydroxyphenyl) retinamide, or as retinoid‐related or derived, such as ST1926 (AHPC) and SHetA2, they subsequently were found to function independently of the RARs and RXRs in inhibiting cancer cell proliferation and inducing apoptosis.

show abstract

A method for the stereoselective synthesis of (E)-methylstilbene retinoids

Cited by 8 publications

References 0 publications

Synthesis and Structure-Activity Relationships of Stilbene Retinoid Analogs Substituted with Heteroaromatic Carboxylic Acids

Synthesis and Structure-Activity Relationships of Stilbene Retinoid Analogs Substituted with Heteroaromatic Carboxylic Acids

Heteroarotinoids: analytical criteria for the rapid identification of E and Z isomers of these novel retinoids via NMR, UV, and x-ray analyses of selected examples

Retinoids

Contact Info

Product

Resources

About