2,4-Diamino-6-hydroxypyrimidine specifically inhibits GTP cyclohydrolase I, which is crucial in the initial step of pterin synthesis. It impedes the formation of Tetrahydrobiopterin (BH4) and consequently reduces the production of nitric oxide (NO)[1][2]. 2,4-Diamino-6-hydroxypyrimidine, also known as DAHP, demonstrates a dose-related decrease in nitric oxide (NO) levels in chicken peritoneal macrophages (PECs) and the avian MC29 virus-transformed macrophage cell line, HD11[1]. Treatment with 2,4-Diamino-6-hydroxypyrimidine (DAHP; at a concentration of 5 mM for 24 hours) notably decreases levels of both BH4 and VCAM-1 over time in HUVEC cells. The synthesis of VCAM-1 and GTPCH proteins is reduced by 2,4-Diamino-6-hydroxypyrimidine, which is partially due to the suppression of NF-κB within the nucleus of HUVEC[2].
To investigate the effect of DAHP on IDO1 expression, results showed that DAHP downregulated IDO1 expression at concentrations as low as 0.5 mM after 3 h of supplementation.
J Immunother Cancer. 2021 Jul;9(7):e002383.
BT549 cells
0.25–4 mM
24 h
To investigate the effect of DAHP on IDO1 expression, results showed that DAHP downregulated IDO1 expression at concentrations as low as 0.5 mM after 3 h of supplementation.
J Immunother Cancer. 2021 Jul;9(7):e002383.
Human foreskin fibroblasts
3–5 mM
7 days
To evaluate the inhibitory effect of DAHP on Toxoplasma growth, results showed that high doses of DAHP slowed parasite growth, and this effect could be rescued by BH4 supplementation.
Nat Microbiol. 2024 Sep;9(9):2323-2343.
human umbilical vein endothelial cells (HUVECs)
10 nM
6 h
FAM3D caused eNOS uncoupling and reduced NO production
Cell Rep Med. 2023 Jun 20;4(6):101072.
IGROV1 cells
0.55 nM
96 h
Evaluate the antiproliferative activity of compound 3 toward IGROV1 cells, showing an IC50 of 0.55 nM
J Med Chem. 2011 Oct 27;54(20):7150-64.
KB cells
0.26 nM
96 h
Evaluate the antiproliferative activity of compound 3 toward KB cells, showing an IC50 of 0.26 nM
J Med Chem. 2011 Oct 27;54(20):7150-64.
CHO cells
0.31 nM
96 h
Evaluate the antiproliferative activity of compound 3 toward FR α-expressing cells, showing an IC50 of 0.31 nM
J Med Chem. 2011 Oct 27;54(20):7150-64.
bovine aortic endothelial cells
10 mM
24 h
reduced both total biopterins and BH4 levels, increased superoxide levels, decreased NO release
To investigate the effect of DAHP on tumor growth and the immune microenvironment, results showed that DAHP significantly inhibited tumor growth and enhanced the antitumor effect of PD-1 blockade immunotherapy.
J Immunother Cancer. 2021 Jul;9(7):e002383.
Mice
AngII-induced hypertensive model
Administered in drinking water
10 mM
For 14 days
DAHP caused eNOS uncoupling by reducing intracellular BH4 and abolished the protective effect of FAM3D deficiency against AngII-induced hypertension
Cell Rep Med. 2023 Jun 20;4(6):101072.
ICR SCID mice
IGROV1 ovarian carcinoma model
Intravenous administration
40 mg/kg
Q4dx5 schedule, administered on days 3, 7, 11, 15, and 19
Evaluate the in vivo antitumor activity of compound 3 toward IGROV1 tumor model, showing T/C values of 14% and gross log kill values of 2.7
J Med Chem. 2011 Oct 27;54(20):7150-64.
Mice
DAHP-induced pulmonary hypertension model
Drinking water
10 mM
3, 6, and 9 weeks
DAHP induces eNOS uncoupling by inhibiting GTP cyclohydrolase 1, leading to pulmonary hypertension phenotypes including increased mean pulmonary arterial pressure (mPAP) and right ventricular systolic blood pressure (RVSP), and pulmonary vascular remodeling.
Circ Res. 2024 Feb 16;134(4):351-370
Wistar rats
Myocardial ischemia and reperfusion injury model
Intraperitoneal
200 mg/kg
Single dose
Inhibition of GTPCH-1, abolishing the cardioprotective effects of isoflurane preconditioning
Anesthesiology. 2015 Sep;123(3):582-9
Nude mice
Carotid artery injury model
Injection after pretreatment of EPCs
3 µmol/L
24 hours pretreatment before injection
Enhanced the ability of EPCs to repair injured endothelium
Upon administering 2,4-Diamino-6-hydroxypyrimidine at a dosage of 3 g/kg/day for four days in mice, there was a reduction in serotonin levels in the duodenum and colon to about 46% and 40% of control values, respectively. 2,4-Diamino-6-hydroxypyrimidine led to a swift decline (with a half-life of under 12 hours) in BH4 concentrations across all tested tissues except the brain. The BH4 levels normalized within less than 24 hours after stopping the administration of 2,4-Diamino-6-hydroxypyrimidine[3].
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