153559-49-0 Usage
Description
Different sources of media describe the Description of 153559-49-0 differently. You can refer to the following data:
1. Bexarotene was launched in the US for the treatment of manifestations of cutaneous T-cell
lymphoma in patients who are refractory to at least one prior systemic therapy. The
four step synthesis of bexarotene involves a double Friedel-Craft alkylation of toluene with
2,5-dichloro-2,5-dimethylhexane followed by acylation with monomethylterephthalic acid
chloride, then Wittig methylidenation. Bexarotene is the first retinoid X receptor (RXR)
agonist to be selective versus retinoid A receptors (RAR). Its activation of the three
RXRα, β, γ isoforms induces cell differentiation and apoptosis and inhibits cell proliferation
in several models of cancer. In phase ll/lll clinical trials, 48% of patients with refractory or
persistent early-stage cutaneous T-cell lymphoma achieved a complete or partial response
when treated with 300 mg/m2/day of bexarotene. It was shown in phase I trials that this
second-generation retinoid was substantially less toxic than the broad-spectrum or RARselective
retinoids.
2. Bexarotene is an agonist of retinoid X receptors (RXRs; EC50s = 28, 25, and 20 nM for RXRα, RXRβ, and RXRγ, respectively, in reporter assays). It is selective for RXRs over retinoic acid receptors (RARs; EC50s = >10 μM for RARα, RARβ, and RARγ). Bexarotene (10 μM) induces apoptosis in MJ, HuT 78, and HH cutaneous T cell lymphoma (CTCL) cells, as well as inhibits lung metastasis and angiogenesis in A549 and MDA-MB-231 mouse xenograft models when administered at a dose of 100 mg/kg per day. It reduces increased brain interstitial fluid levels of amyloid-β (1-40) (Aβ40) and Aβ42 in the APP/PS1 transgenic mouse model of Alzheimer’s disease. It also reduces viral load in the culture supernatant of Vero E6 cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; EC90 = 9.4 μM) and inhibits SARS-CoV-2 replication in a plaque reduction assay (EC50 = 2.01 μM). Formulations containing bexarotene have been used in the treatment of CTCL.
Chemical Properties
White Solid
Originator
Ligand (US)
Uses
Different sources of media describe the Uses of 153559-49-0 differently. You can refer to the following data:
1. Used as an antineoplastic. A selective retinoid X receptor (RXR) agonist
2. Bexarotene is used as a Synthetic retinoid analog with specific affinity for the retinoid X receptor, an antineoplastic agent, already approved as an oral antineoplastic agent for cutaneous T cell lymphoma and being investigated against other cancers. A study has found that bexarotene in a mouse Alzheimer?s model lowered the most toxic form of β-amyloid peptide and increased cognitive ability.
Indications
Bexarotene (Targretin) belongs to a subclass of
retinoids that selectively bind to and activates retinoid
X receptors (RXRs), which have biological properties
distinct from those of RARs. In vitro, bexarotene exerts
antiproliferative effects on some tumor lines of
hematopoietic and squamous cell origin.
Manufacturing Process
(a) Methyl [4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)
carbonyl]benzoate (1):
To a suspension of aluminum chloride (1.10 g, 8.25 mmol) in 30 mL of 1,2-
dichloroethane under argon at room temperature was added a solution of
1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene (1.52 g, 7.5 mmol)
(Kagechika, H. et al., J. Med. Chem, 31:2182 (1988)) and 4-
carbomethoxybenzoyl chloride (1.57 g, 7.87 mmol) in 15 mL of 1,2-dichloroethane. The reaction mixture was stirred overnight and poured onto
ice water and extracted with 40% ethyl acetate/hexane. The combined
organic layers were washed with saturated aqueous NaHCO3and brine. The
solution was dried over anhydrous MgSO4, filtered and concentrated to afford
a brown solid (2.56 g). Flash chromatography (60% dichloromethane/hexane)
yielded the desired product (1) as a white, crystalline solid (1.733 g, 64 %):
m.p. 146°-149°C; Rf 0.11 (50% CH2Cl2/hexane). The structure of the product
was also confirmed using IR, 1H NMR and mass spectroscopy.
(b) [4-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)
carbonyl]benzoic acid (2):
To a suspension of the ester (1) (0.120 g, 0.329 mmol) in 75% aqueous
methanol (2 mL) was added potassium hydroxide (0.055 g). The reaction
mixture was stirred at 60°C for 1 h during which time the material dissolved.
The solution was cooled to room temperature, acidified with 1 N aqueous
hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The
combined organic layers were dried over anhydrous MgSO4, filtered and
concentrated to afford a white solid (0.109 g). Recrystallization from
benzene/hexane afforded (2) as a white, crystalline solid (0.102 g, 89%):
m.p. 209°-212°C. The structure of the product was also confirmed using IR,
1H NMR and mass spectroscopy.
(c) Methyl 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-
ethenyl]benzoate (3):
To a suspension of methyltriphenylphosphonium bromide (0.196 g, 0.55
mmol) in 1 mL of benzene under argon at room temperature was added a 0.5
M solution of potassium hexamethyldisilazide in toluene (1.2 mL, 0.6 mmol),
and the yellow solution was stirred for 5 min. A solution of keto-ester (1) (0.1
g, 0.274 mmol) in 1.5 mL of benzene was added and the orange solution was
stirred for 3 h at room temperature. The reaction mixture was filtered through
a plug of silica gel with 40% ethyl acetate/hexane. The filtrate was
concentrated to afford a solid. Flash chromatography (30%; 40%
dichloromethane/hexane) yielded the desired product (3) as a white solid
(0.077 g, 78%): m.p. 167°-168°C; Rf 0.4 (50% dichloromethane/hexane).
The structure of the product was also confirmed using IR, 1H NMR and mass
spectroscopy.
(d) [4-[1-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-
ethenyl]benzoic acid (4):
To a suspension of the ester (3) (0.058 g, 0.16 mmol) in 75% aqueous
methanol (2 mL) was added one pellet of potassium hydroxide (0.1 g). The
mixture was stirred at 70°C for 1 h during which time the material dissolved.
The solution was cooled to room temperature, acidified with 1 N aqueous
hydrochloric acid and then extracted with 80% ethyl acetate/hexane. The
combined organic layers were dried over anhydrous MgSO4, filtered and
concentrated to afford a white solid. Recrystallization from
dichloromethane/hexane afforded the desired acid (4) as a white, crystalline
solid (42 mg, 91%): melting point 230°-231°C. The structure of the product
was also confirmed using IR, 1H NMR and mass spectroscopy.
Brand name
Targretin (Ligand).
Therapeutic Function
Antineoplastic
General Description
Bexarotene is available in 75-mg capsules for oral administrationin the treatment of refractory cutaneous T-cell lymphoma.The agent is also available as a gel that may be usedtopically. The mechanism of action has not been fully establishedbut is thought to involve binding to retinoid receptorsresulting ultimately in the formation of transcription factorsthat promote cell differentiation and regulate cellular proliferation.168 Bexarotene has been demonstrated to activateapoptosis as a result of stimulation of caspase 3 and inhibitionof survivin, an antiapoptotic protein that would normallyinhibit caspase activity.Apoptosis is also stimulatedbecause of cleavage of poly(ADP-Ribose) polymerase,which is antiapoptotic. Reduced expression of the retinoidreceptor subtypes RXR and RAR has also been demonstratedfor the agent. Absorption is nearly complete afteroral administration and plasma protein binding is high(＜99%).There is extensive metabolism in the liver togive 6- and 7-hydroxy-bexarotene and 6- and 7-oxobexaroteneas well as glucuronides of these metabolites andthe parent. Elimination occurs via the feces with an eliminationhalf-life of 7 hours. Adverse effects include hypercholesterolemia,hypertriglyceridemia, hypothyroidism, myelosuppression,nausea, and skin rash.
Biochem/physiol Actions
Bexarotene is a highly selective retinoid X receptor (RXR) agonist. It is an antineoplastic agent, already approved as an oral antineoplastic agent for cutaneous T cell lymphoma and being investigated against other cancers. A study has found that bexarotene in a mouse Alzheimer′s model lowered the most toxic form of β-amyloid peptide and increased cognitive ability. The activity in the mouse Alzheimer′s models are believed to be by activating PPARγ:RXR and LXR:RXR dimers which induces the expression of apoE and facilitates Aβ clearance and promotes microglial phagocytosis.
Pharmacology
Bexarotene is available in oral and topical formulations.
Peak plasma levels are achieved within 2 hours of
oral administration, although higher levels are obtained
when the drug is ingested with a fatty meal. It is thought
to be metabolized primarily by the hepatobiliary system,
with a terminal half-life of approximately 7 hours.
Topical and oral bexarotene are approved for earlystage
(patch and plaque) cutaneous T-cell lymphoma
that is refractory to at least one other therapy. Oral
bexarotene is also approved for refractory cases of advanced
disease; however, the best response has been
noted in early disease.
Local irritation, such as burning, pruritus, and irritant
contact dermatitis, is common following topical application.
Clinical Use
Antineoplastic agent:
Treatment of skin manifestations of cutaneous T-cell
lymphoma
Side effects
Major side effects seen after systemic administration
include dyslipidemia, leukopenia, liver function test
abnormalities, and possibly development of cataracts.
Unlike other systemic retinoids, oral bexarotene causes
thyroid abnormalities in approximately half of patients,
which may necessitate treatment for hypothyroidism.
Bexarotene is teratogenic and should not be prescribed
in topical or oral form to women of childbearing potential
unless a negative serum pregnancy test has been obtained
and the patient agrees in writing to use two effective
forms of contraception from 1 month before to 1
month after treatment.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis)
Lipid-regulating drugs: concentration increased by
gemfibrozil - avoid.
Metabolism
Hepatic metabolism. Studies suggest glucuronidation
as a metabolic pathway, and that cytochrome P450 3A4
is the major cytochrome P450 isozyme responsible
for formation of the oxidative metabolites. Bexarotene
metabolites have little pharmacological activity.
No studies have been done in renal failure although the
pharmacokinetic data indicates that renal elimination is a
minor excretory pathway
References
1) Boehm et al. (1995), Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells; J. Med. Chem., 38 3146
2) Gniadecki et al. (2007), The optimal use of bexarotene in cutaneous T-cell lymphoma; Br. J. Dermatol., 157 433
3) Bischoff et al. (1998), Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma; Cancer Res., 58 479
4) Cramer et al. (2012), ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models; Science, 335 1503
5) Boehm-Cagan and Michaelson (2014), Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene; J. Neurosci., 34 7293
Check Digit Verification of cas no
The CAS Registry Mumber 153559-49-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,3,5,5 and 9 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 153559-49:
(8*1)+(7*5)+(6*3)+(5*5)+(4*5)+(3*9)+(2*4)+(1*9)=150
150 % 10 = 0
So 153559-49-0 is a valid CAS Registry Number.
InChI:InChI=1/C24H28O2/c1-15-13-20-21(24(5,6)12-11-23(20,3)4)14-19(15)16(2)17-7-9-18(10-8-17)22(25)26/h7-10,13-14H,2,11-12H2,1,3-6H3,(H,25,26)
153559-49-0Relevant articles and documents
Indolizines Enabling Rapid Uncaging of Alcohols and Carboxylic Acids by Red Light-Induced Photooxidation
Watanabe, Kenji,Terao, Nodoka,Kii, Isao,Nakagawa, Reiko,Niwa, Takashi,Hosoya, Takamitsu
supporting information, p. 5434 - 5438 (2020/07/24)
The irradiation of red light-emitting-diode light (λ = 660 nm) to 3-acyl-2-methoxyindolizines in the presence of a catalytic amount of methylene blue triggered the photooxidation of the indolizine ring, resulting in a nearly quantitative release of alcohols or carboxylic acids within a few minutes. The method was applicable for photouncaging various functional molecules such as a carboxylic anticancer drug and a phenolic fluorescent dye from the corresponding indolizine conjugates, including an insulin-indolizine-dye conjugate.
Carboxylation of Aryl Triflates with CO2 Merging Palladium and Visible-Light-Photoredox Catalysts
Bhunia, Samir Kumar,Das, Pritha,Nandi, Shantanu,Jana, Ranjan
supporting information, p. 4632 - 4637 (2019/06/27)
We report herein a visible-light-promoted, highly practical carboxylation of readily accessible aryl triflates at ambient temperature and a balloon pressure of CO2 by the combined use of palladium and photoredox Ir(III) catalysts. Strikingly, the stoichiometric metallic reductant is replaced by a nonmetallic amine reductant providing an environmentally benign carboxylation process. In addition, one-pot synthesis of a carboxylic acid directly from phenol and modification of estrone and concise synthesis of pharmaceutical drugs adapalene and bexarotene have been accomplished via late-stage carboxylation reaction. Furthermore, a parallel decarboxylation-carboxylation reaction has been demonstrated in an H-type closed vessel that is an interesting concept for the strategic sector. Spectroscopic and spectroelectrochemical studies indicated electron transfer from the Ir(III)/DIPEA combination to generate aryl carboxylate and Pd(0) for catalytic turnover.
Selective arylation and vinylation at the α position of vinylarenes
Zou, Yinjun,Qin, Liena,Ren, Xinfeng,Lu, Yunpeng,Li, Yongxin,Zhou, Jianrong
, p. 3504 - 3511 (2013/07/05)
In intermolecular Heck reactions of styrene and vinylarenes, the aryl and vinyl groups routinely insert at the β position. However, selective insertion at the α position has been very rare. Herein, we provide a missing piece in the palette of Heck reaction, which gave >20:1 α selectivity. The key to our success is a new ferrocene 1,1′-bisphosphane (dnpf) that carries 1-naphthyl groups. Our mechanistic studies revealed that the high α selectivity is partly attributable to the steric effect of dnpf. The rigid and bulky 1-naphthyl groups of dnpf sterically disfavor β insertion. What the Heck! In intermolecular Heck reactions, insertion at the β position of aromatic olefins is very common, but reversal of the selectivity for selective α insertion has been a longstanding problem. A general method to couple aryl and vinyl triflates with aromatic olefins in >20:1 α selectivity is presented. The key to this successful approach is a new ferrocene bisphosphane with naphthyl groups on the phosphorus atom (see scheme; OTf=triflate). Copyright
