4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid

Description

AM-580 (102121-60-8) is a retinoic acid analog acting as a RARα agonist (Kd = 8 nM).1 Induces or blocks differentiation depending on cell type and environment.2,3 In combination with CHIR-99021 it induces differentiation of human induced pluripotent stem cells (iPSCs) into intermediate mesoderm (80% induction rate in 5 days) capable of forming kidney structures.4 AM-580 exhibits anti-angiogenic activity in vivo, and induces differentiation of acute promyelocytic leukemia cells.5,6

Uses

Retinoid derivative used for gene expression studies of leukemia-retinoic acid receptor (PHL-RAR) cell line differentiation. AM 580 inhibits tumor proliferation by reducing the level of RARγ and activates RAR β. This receptor increases the expression of disintegrin and metalloprotease.

Definition

ChEBI: An amidobenzoic acid obtained by formal condensation of the carboxy group of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzoic acid with the anilino group of 4-aminobenzoic acid. A selective RARalpha agonist.

General Description

AM580 is a retinobenzoic derivative and a RAR-α (retinoic acid receptor-α) agonist. It stimulates the maturation of granulocytes in NB4 promyelocytic leukemia cell line and APL (acute promyelocytic leukemia) blasts. AM580 suppresses endometrial cancer cell proliferation.

Biological Activity

An analog of retinoic acid that acts as a selective RAR α agonist (EC 50 values are 0.3, 8.6 and 13 nM for RAR α , RAR β and RAR γ respectively). Significantly induces IL-4, IL-5 and IL-13 and inhibits IL-12 and IFN γ synthesis, and induces cell differentiation with over 7 times the activity of retinoic acid in vitro .

Synthesis

To a 25 mL round-bottomed flask equipped with a reflux condenser tube was added methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoate (0.200 g, 0.547 mmol), methanol (10 mL) and potassium hydroxide (0.122 g, 2.18 mmol). The reaction mixture was stirred under reflux conditions for 16 h and subsequently evaporated to dryness. The residue was partitioned between ethyl acetate and deionized water and adjusted to acidic pH with 6 N hydrochloric acid. the organic layer was separated, washed sequentially with deionized water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to afford 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoic acid as a white solid (0.151 g, 78% yield ). Molecular weight: 351.43; melting point: 265°C; Rf value: 0.3 (ethyl acetate:cyclohexane=50:50).1H NMR (CDCl3, δ): 1.32 (s, 6H, 2×CH3), 1.34 (s, 6H, 2×CH3), 1.73 (s, 4H, 2×CH2), 7.43 (d, 1H, J=8.53 Hz. ArH), 7.57 (d, 1H, J=8.25 Hz, J=1.98 Hz, ArH), 7.78 (d, 2H, J=8.74 Hz, ArH), 7.88 (d, 1H, J=8.74 Hz, ArH), 7.92 (s, 1H, NH), 8.13 (d, 2H, J=8.70 Hz, ArH), and no observed carboxylic acid proton signal.MS-ESI: m/z (relative intensity) 352.1 ([M+H]+, 100).HPLC analysis (Method A, detection wavelength 254 nm): retention time = 6.66 min, peak area = 96.3%.

storage

Store at RT

Background

The synthetic retinoic acid analog AM-580 displays high selectivity for nuclear retinoic acid receptors, binding RARα more potently than either RARβ or RARγ. Signaling pathways controlled by retinoic acid coordinate cell proliferation, differentiation, apoptosis, and development of many organs and tissues. Treatment of a mouse model of Alzheimer's Disease with the retinoid receptor agonist AM-580 produced an anti-inflammatory effect and regulated the neurotoxic activation of microglia, shifting microglial activity toward a neuroprotective phenotype. AM-580 also interrupts the life cycle of diverse viruses by inhibiting host lipid biosynthesis through interaction with sterol regulatory element binding protein, which binds sterol response elements in the promoter/enhancer regions of multiple lipogenic genes. In a screen of multiple antiviral agents, AM-580 exhibited anti-SARS-CoV-2 activity, with AM-580 treatment producing a substantial reduction in viral load.

References

[1] BRUNO A. BERNARD . Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor γ[J]. Biochemical and biophysical research communications, 1992, 186 2: Pages 977-983. DOI:10.1016/0006-291x(92)90842-9
[2] SAFONOVA I. Fatty Acids and Retinoids Act Synergistically on Adipose Cell Differentiation[J]. Biochemical and biophysical research communications, 1994, 204 2: Pages 498-504. DOI:10.1006/bbrc.1994.2487
[3] NATSUKO SHIBUYA. Retinoic acid is a potential negative regulator for differentiation of human periodontal ligament cells[J]. Journal of periodontal research, 2005, 40 6: 432-440. DOI:10.1111/j.1600-0765.2005.00811.x
[4] TOSHIKAZU ARAOKA. Efficient and rapid induction of human iPSCs/ESCs into nephrogenic intermediate mesoderm using small molecule-based differentiation methods.[J]. ACS Applied Bio Materials, 2014: e84881. DOI:10.1371/journal.pone.0084881
[5] TSUTOMU OIKAWA . Three novel synthetic retinoids, Re 80, Am 580 and Am 80, all exhibit anti-angiogenic activity in vivo[J]. European journal of pharmacology, 1993, 249 1: Pages 113-116. DOI:10.1016/0014-2999(93)90669-9
[6] M GIANNÍ. AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells.[J]. Blood, 1996, 87 4: 1520-1531.