TTNPB (Arotinoid Acid)

TTNPB (Arotinoid Acid) Property

Melting point:

242 °C

Boiling point:

422.83°C (rough estimate)

Density 

1.0932 (rough estimate)

refractive index 

1.4480 (estimate)

storage temp. 

-20°C

solubility 

chloroform/methanol: soluble9.80 - 10.20 mg/mL, clear, colorless to light yellow

form 

White solid

pka

4.28±0.10(Predicted)

color 

White to Almost white

InChI

InChI=1S/C24H28O2/c1-16(14-17-6-8-18(9-7-17)22(25)26)19-10-11-20-21(15-19)24(4,5)13-12-23(20,2)3/h6-11,14-15H,12-13H2,1-5H3,(H,25,26)/b16-14+

InChIKey

FOIVPCKZDPCJJY-JQIJEIRASA-N

SMILES

C(O)(=O)C1=CC=C(/C=C(/C2=CC=C3C(=C2)C(C)(C)CCC3(C)C)\C)C=C1

CAS DataBase Reference

71441-28-6

Safety

Hazard Codes 

T

Risk Statements 

60-61-36/37/38

Safety Statements 

53-26-36/37/39-45

WGK Germany 

3

RTECS 

DH6834900

HS Code 

2916.39.7900

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Danger

Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

H360May damage fertility or the unborn child

Precautionary statements

P202Do not handle until all safety precautions have been read and understood.

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P308+P313IF exposed or concerned: Get medical advice/attention.

TTNPB (Arotinoid Acid) Chemical Properties,Usage,Production

Description

TTNPB (Arotinoid Acid) is a potent RAR agonist, and inhibits binding of [3H]tRA with IC50 of 5.1 nM, 4.5 nM, and 9.3 nM for human RARα, β, and γ, respectively.

Uses

1. TTNPB is an analog of retinoic acid that potently and selectively activates retinoic acid receptors (RAR; EC50 = 21, 4, and 2.4 nM for RARα, RARβ, and RARγ, respectively; Beard et al.; Wong et al.).
2. TTNPB has been used for transcriptional assays in 293T cells. It has also been used as a RAR-agonist in cultured human cord blood CD34+CD38-lin- cells.
3. It does not act on retinoid X receptors and weakly agonizes farnesoid X receptor (EC50 > 1 µM).
4. TTNPB is used to study RAR action in diverse processes, including epidermal cell proliferation, embryogenesis, and stem cell differentiation.

Biochemical Actions

Selective and highly potent retinoic acid analog with affinity for retinoic acid receptors (RAR) α, β, and γ, which are nuclear transcription factors. Produces ligand-activated transcription of genes that possess retinoic acid responsive elements.

In vitro

TTNPB binds to nuclear retinoic acid receptors with high affinity, inhibits binding of [3H]tRA with IC50 of 3.8 nM, 4.0 nM, and 4.5 nM for mRARα, β, and γ, respectively. TTNPB increases transcriptional activation of Mouse RARs in JEG-3 cells after 72 h using conditioned media with EC50 of 2.0 nM, 1.1 nM and 0.8 nM for mRARα, β, and γ, respectively. TTNPB inhibits the growth of normal human mammary epithelial cells (HMECs) and estrogen receptor-positive (ER-positive) breast cancer cells by inducing G1 cell cycle blockade.  TTNPB causes a concentration-dependent decrease in ES-D3 cell differentiation.

In vivo

TTNPB (0.25 mg/kg) causes growth inhibition in both MXT-HS and MXT-HI models by inducing cell apoptosis.

DIFFERENTIATION

1. In combination with CHIR99021 or Activin A, induces intermediate mesoderm formation from human or mouse pluripotent stem cells, respectively (Araoka et al.; Oeda et al.).
2. Promotes neuronal differentiation in cultured chick caudal neural plate explants (Diez del Corral et al.).

REPROGRAMMING

Enables chemical reprogramming (without genetic factors) of mouse embryonic fibroblasts to induced pluripotent stem (iPS) cells, in combination with CHIR99021, Tranylcypromine, Valproic Acid, 3-Deazaneplanocin A, and E-616452 (Hou et al.).

CANCER RESEARCH

Induces the in vitro growth and differentiation to granulocytes of myeloid progenitors isolated from myelodysplastic syndrome (MDS) patients (Fabian et al.).

Uses

TTNPB is an analog of retinoic acid that potently and selectively activates retinoic acid receptors.

Definition

ChEBI: A retinoid that consists of benzoic acid substituted at position 4 by a 2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-en-1-yl group. It is a synthetic retinoid that acts as a selective agonist for the retinoic acid receptors (RAR).

Biological Activity

Extremely potent analog of retinoic acid, selective for the retinoic acid receptor (RAR) subtype.

Biochem/physiol Actions

Selective and highly potent retinoic acid analog with affinity for retinoic acid receptors (RAR) α, β, and γ, which are nuclear transcription factors. Produces ligand-activated transcription of genes that possess retinoic acid responsive elements.

Safety Profile

An experimental teratogen. Otherexperimental reproductive effects. When heated todecomposition it emits acrid smoke and irritating fumes.

Synthesis

In a 10 mL single neck flask, 3 mL of dichloromethane, 558 mg of ethyl (E)-4-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-en-1-yl)benzoate, 267 mg of p-ethoxycarbonylbenzaldehyde, and 16 mg of tetrabutylammonium bromide were added, and mixed by stirring. An aqueous solution of 200 mg sodium hydroxide and 400 mg sodium hydroxide was then added and heated to reflux. After 1 hour of reaction, the reaction progress was monitored by HPLC until the peak area ratio of ethyl (E)-4-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-en-1-yl)benzoate, the intermediate (E)-4-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-en-1-yl)benzoate was less than 5% and the reaction was stopped. The solvent was removed by evaporation under reduced pressure and 2 mL of ethanol, 250 mg of sodium hydroxide and 4 mL of water were added to the residue and heated to reflux with stirring. The reaction was continued for 1 hour and monitored by HPLC until the raw material (E)-ethyl 4-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-en-1-yl)benzoate was completely consumed. After completion of the reaction, the reaction solution was cooled to 40°C with ice water, poured into 5 mL of water and the pH was adjusted to 2-6 with 0.5 N dilute sulfuric acid to precipitate a solid. The organic layer was separated by adding 20 ml of dichloromethane under stirring and washed sequentially with 2 x 10 ml of dichloromethane and 2 x 20 ml of deionized water. The organic layer was dried with 2 g of anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Cooling to -10 °C induced precipitation of a white solid, the filter cake was washed with 0.5 mL of ethanol and dried under reduced pressure at 50 °C to afford the target product (E)-4-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-en-1-yl)benzoic acid (279 mg, 80.1% yield, 99.1% HPLC purity, MS (MH+): 347.2).

storage

Desiccate at -20°C

References

[1] pignatello m a, kauffman f c, levin a a. multiple factors contribute to the toxicity of the aromatic retinoid, ttnpb (ro 13-7410): binding affinities and disposition. toxicology and applied pharmacology, 1997, 142(2): 319-327.