Sapropterin Hydrochloride Chemical Properties

Melting point:

245-246° (dec)

alpha 

D25 -6.81° (c = 0.665 in 0.1 M HCl)

storage temp. 

-20°C

solubility 

water, oxygen free: soluble19.60 - 20.40mg/mL, clear to slightly hazy, colorless to faintly yellow

form 

White to off-white powder.

color 

White to off-white

Water Solubility 

water, oxygen free: soluble 19.60-20.40mg/mL, clear to slightly hazy, colorless to faintly yellow

Stability:

Hygroscopic

InChI

InChI=1/C9H15N5O3.2ClH/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7;;/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17);2*1H/t3-,4+,6-;;/s3

InChIKey

RKSUYBCOVNCALL-WDROUVJUNA-N

SMILES

C12NC(N)=NC(=O)C=1N[C@]([H])(CN2)[C@@H](O)[C@@H](O)C.Cl.Cl |&1:9,13,15,r|

CAS DataBase Reference

69056-38-8(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xn

Risk Statements 

22

WGK Germany 

3

RTECS 

UO3516500

Storage Class

11 - Combustible Solids

Hazard Classifications

Acute Tox. 4 Oral

Toxicity

LD50 oral in rat: 1gm/kg

Sapropterin Hydrochloride Usage And Synthesis

Description

Sapropterin hydrochloride is a monoamine biosynthesis enhancer introduced for the treatment of hyperphenylalaninemia.Animal studies indicate that sapropterin hydrochloride increases brain levels of serotonin and enhances the release of acetylcholine from nerve terminals. The compound is also being investigated as a potential cognitive enhancer.

Description

(6R)-5,6,7,8-tetrahydro-L-Biopterin (hydrochloride) (BH₄) is a cofactor that, in the presence of enzyme site iron, binds to phenylalanine hydroxylase, tryptophan or tyrosine hydroxylase, and nitric oxide synthase (NOS), to facilitate the production of aromatic amino acids, neurotransmitters, and nitric oxide (NO), respectively. It is formed de novo from GTP with GTP cyclohydrolase-1 (GCH1) catalyzing the rate limiting conversion of GTP to 7,8-dihydroneopterin (NH2TP) followed by subsequent processing by TS and SPR to convert NH2TP to BH₄. BH₄ acts as a radical-trapping antioxidant that inhibits phospholipid oxidation in lipid membranes. It inhibits IKE- or RSL3-induced ferroptosis in HT-1080 cells (EC₅₀s = 21 and 69 μM), as well as ferroptosis induced by knockout of glutathione peroxidase (Gpx4^-/-) in immortalized mouse fibroblasts. BH₄ also reduces RLS3-induced lipid peroxidation in murine fibroblasts and HT-1080 cells when used at a concentration of 50 μM.

Chemical Properties

White Crystalline Solid

Originator

Suntory (Japan)

Uses

Tetrahydrobiopterin is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine , epinephrine, and is a cofactor for the production of nitric oxide by the nitric oxide synthases. Chemically, its structure is that of a reduced pteridine derivative.

Uses

A natural cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, and nitric oxide synthase. An essential cofactor for the production of neurotransmitters such as catecholamines, serotonin, and nitric oxide. Increasing

Definition

ChEBI: The dihydrochloride salt of sapropterin. It is used for the diagnosis and treatment of variant forms of phenylketonuria (hyperphenylalaninaemia) associated with tetrahydrobiopterin deficiency. Natural cofactor for phenylalanine hydroxylase, tyrosine hydrox lase, tryptophan hydroxylase, and nitric oxide synthetase.

brand name

Biopten

General Description

Tetrahydrobiopterin is a natural cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, nitric oxide synthase and alkylglycerol monooxygenase.

Biochem/physiol Actions

Lack of tetrahydrobiopterin may cause hyperphenylalaninemia. Diseases like, Parkinson′s, autism, depression and Alzheimer′s shows low concentration of tetrahydrobiopterin in the cerebrospinal fluid. This coenzyme participates in dopamine (DA) synthesis.

Synthesis

Sapropterin Hydrochloride is prepared in three steps. A. Hydrolysis of diacetylbiopterin: Diacetylbiopterin is hydrolyzed to biopterin by reacting in 1-butanol with diethylamine and water at 40??C for 16 hours. The aqueous phase is extracted to obtain a biopterin solution. B. Hydrogenation of biopterin: The biopterin-containing aqueous phase is adjusted to pH 11.2 with triethylamine. Platinum black catalyst is added, and hydrogenation is carried out in an autoclave under 35 bar hydrogen pressure for 23 hours, reducing biopterin to (6R)-5,6,7,8-tetrahydrobiopterin. After reaction, the mixture is acidified with HCl to pH <1.0 to stabilize the product. C. Isolation and purification of the crude salt: The acidified solution is concentrated under reduced pressure to remove water and acetic acid. Ethanol is added to adjust water content, followed by 1-butanol to promote crystallization. Filtration yields crude (6R)-5,6,7,8-tetrahydrobiopterin dihydrochloride crystals, which can be further purified.

Purification Methods

Recrystallisation of BH4.2HCl from HCl enriches BH4 in the natural 6R isomer. Dissolve the salt (~6g) in conc HCl (15mL) under gentle warming, then add EtOH (30mL) dropwise, chill and collect the colourless needles (67%, up to 99% if the mother liquors are concentrated), and dry it in vacuo immediately over P2O5 and KOH. It is stable indefinitely at -20o in a dry atmosphere. Better store it in sealed ampoules under dry N2. It can be recrystallised from 6N aqueous HCl. It has UV max (in 2N HCl) at 264nm ( 16,770; pH 3.5 phosphate buffer) 265nm ( 13,900); (in pH 7.6) at 297nm ( 9,500) and 260nm sh ( 4,690). It has been separated from the 6S-isomer by HPLC on a Partisil-10SCX column using 30mM ammonium phosphate buffer (pH 3.0) containing 3mM NaHSO3 (2mL/minute flow rate; 275nm detector) with retention times of 5.87minutes (6R) and 8.45minutes (6S). It is stable in acidic solutions and can be stored for extended periods at -20o in 0.04M HCl. Above pH 7 the neutral species are obtained, and these are readily oxidised by the oxygen in the solvent to the quinonoid species, and then further oxidation and degradation occurs at room temperature. These changes are slower at 0o. The sulfate salt can be obtained by recrystallisation from 2M H2SO4 and is less soluble in water than the hydrochloride salt. The 6R-2,5,1',2'-tetraacetylbiopterin derivative has m 292o(dec) after recrystallisation from MeOH (100 parts) and [] 20 -144o (c 0.5, CHCl3), [] 589 +12.8o (c 0.39, Me2SO). [NMR, UV: Matsuura et al. Heterocycles 23 3115 1985, Viscontini et al. Helv Chim Acta 62 2577 1979, Armarego et al. Aust J Chem 37 355 1984, Beilstein 26 III/IV 4032.]

References

[1] T. JOSEPH KAPPOCK  John P C. Pterin-Dependent Amino Acid Hydroxylases[J]. Chemical Reviews, 1996, 96 7: 2659-2756. DOI: 10.1021/cr9402034
[2] B MAYER E R W. In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxide.[J]. Naunyn-Schmiedeberg’s archives of pharmacology, 1995, 351 5: 453-463. DOI: 10.1007/bf00171035
[3] VANESSA A. N. KRAFT. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling[J]. ACS Central Science, 2019, 6 1: 41-53. DOI: 10.1021/acscentsci.9b01063
[4] MARILUZ SOULA. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers[J]. Nature chemical biology, 2020, 16 12: 1351-1360. DOI: 10.1038/s41589-020-0613-y
[5] YAKOV Y. WOLDMAN . Direct chemiluminescence detection of nitric oxide in aqueous solutions using the natural nitric oxide target soluble guanylyl cyclase[J]. Free Radical Biology and Medicine, 2009, 47 10: Pages 1339-1345. DOI: 10.1016/j.freeradbiomed.2009.09.007

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