ChemicalBook Product Catalog Pharmaceutical intermediates Heterocyclic compound Pyridine compound Aminopyridine 3-AP

3-AP

Product Name3-AP
CAS143621-35-6
MFC7H9N5S
MW195.25
EINECS
MOL File143621-35-6.mol

Chemical Properties

Melting point	234 °C
Boiling point	436.0±55.0 °C(Predicted)
Density	1.46±0.1 g/cm3(Predicted)
storage temp.	2-8°C
solubility	DMSO: soluble10Meq/mL, clear
pka	10.93±0.70(Predicted)
form	powder
color	white to light brown
InChI	1S/C7H9N5S/c8-5-2-1-3-10-6(5)4-11-12-7(9)13/h1-4H,8H2,(H3,9,12,13)/b11-4+
InChIKey	XMYKNCNAZKMVQN-NYYWCZLTSA-N
SMILES	S=C(N\N=C\c1ncccc1N)N
CAS DataBase Reference	143621-35-6

Safety Information

Hazard Codes	Xn
Risk Statements	22-36/37/38
Safety Statements	26
RIDADR	UN 2811 6.1 / PGIII
WGK Germany	3
HS Code	2933.39.6190
Storage Class	6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects
Hazard Classifications	Acute Tox. 3 Oral Eye Irrit. 2 Skin Irrit. 2 STOT SE 3
Toxicity	LDLo ivn-rat: 20 mg/kg IJTOFN 19,85,2000

Usage And Synthesis

Uses

Ribonucleotide reductase, the rate-limiting enzyme for de novo DNA synthesis, is an excellent target for chemotherapy. Its increased activity in cancer cells is associated with malignant transformation and proliferation. 3-AP is a ribonucleotide reductase inhibitor and iron chelator with antitumor activity. At 5 μM it can enhance DU145, U251, and PSN1 tumor cell radiosensitivity in vitro, inhibiting DNA synthesis and repair. It destroys the tyrosine free radical in the R2/p53R2 subunits of ribonucleotide reductase by forming a redox active complex with iron, thus producing reactive oxygen species. Furthermore, 3-AP has been shown to activate an endoplasmic reticulum stress pathway, leading to the unfolded protein response and apoptosis.[Cayman Chemical]

Hazard

A poison.

Biological Activity

3-AP (PAN-811) is a M2 subunit inhibitor of ribonucleotide reductase (RR) and a potent radiosensitizer.

Biochem/physiol Actions

3-aminopyridine carboxaldehyde thiosemicarbazone (3-AP) has a IC50 value of 0.3μM. It exhibits anti-proliferative activity in preclinical models of cancer, such as lung cancer. It also has an ability to increase the cytotoxicity, intracellular uptake and DNA incorporation of gemcitabine in vitro.

Safety Profile

A poison by intravenous route. When heated to decomposition it emits toxic vapors of NOx, and SOx,.

Synthesis

79-19-6

143621-33-4

143621-35-6

General procedure for the synthesis of [(3-aminopyridin-2-yl)methylideneamino]thiourea from amino thiourea and 2-(1,3-dioxolan-2-yl)-3-aminopyridine (CAS:143621-33-4): Example VII: To a solution of 2-(1,3-dioxolan-2-yl)-3-aminopyridine (0.80 g, 4.8 mmol) dissolved in 10 mL of ethanol, 8 mL of water, and 2 mL of concentrated hydrochloric acid was added aminothiourea (0.48 g, 5.3 mmol). The reaction mixture was stirred at room temperature overnight followed by refluxing for 1 hour. It was cooled and filtered to give crude yellow hydrochloride. The hydrochloride was dissolved in 50 mL of hot water and filtered. To the hot filtrate was added 10 mL of 5% sodium bicarbonate solution. The mixture was stirred at room temperature for 1 h. The mixture was filtered and washed sequentially with water and ethanol to give 3-amino-2-formylpyridine acetylthiourea. Yield: 0.72 g (77%); melting point: 240-241°C. Mass spectrum (MS) m/e 194 (M+); 1H NMR (90 MHz, DMSO-d6) δ 6.48 (br s, 2H, 3-NH2, exchangeable in D2O), 7.12 (m, 2H, 4-H and 6-H), 7.83 (dd, 1H, 5-H). 8.10 (br s, 2H, CSNH2, exchangeable for D2O), 8.10 (s, 1H, 2-CH), 10.95 (s, 1H, NNH, exchangeable for D2O). Elemental analysis (C7H9N5S) is consistent with the theoretical values of C, H and N.

in vitro

3-AP (Triapine) is a potent derivative of α-heterocyclic carboxaldehyde thiosemicarbazone (HCT) that inhibits hRRM2 and p53R2 isoforms of the M2 subunit. 3-AP (Triapine) is thought to inhibit ribonucleotide reductase through its preformed iron chelate, rather than directly by removing iron from the active site. In cells containing less topoisomerase IIα fewer DNA strand breaks will be produced, and thus topoisomerase II poisons will be less inhibitory in the K/VP.5 cell line. The IC 50 s for Dp44mT growth inhibition are 48±9 nM and 60±12 nM, for K562 and K/VP.5 cells, respectively. The IC 50 s for 3-AP growth inhibition are 476±39 nM and 661±69 nM for K562 and K/VP.5 cells, respectively. PKIH and DpT Fe chelators show high antiproliferative activity against a range of tumor cell lines. Dp44mT shows the greatest antitumor efficacy with an IC 50 that ranged from 0.005 to 0.4 μM. The average IC 50 of Dp44mT over 28 cell types is 0.03±0.01 μM, which is significantly lower than that of 3-AP (Triapine; average IC 50 : 1.41±0.37 μM).

in vivo

3-AP (Triapine) causes a significant increase (1.7-fold) in splenic weight when expressed as a percentage of total body weight (1.02±0.06%; n=25) compared with control mice (0.6±0.03%; n=27). In the long-term group, a significant increase in heart weight is observed after Dp44mT (0.4 mg/kg per day) (0.8±0.06%; n=4) compared with control mice (0.5±0.01%; n=6). A significant decrease in the expression of Ndrg1, TfR1, and VEGF1 in the liver is noted for Dp44mT- and 3-AP (12 mg/kg per day)-treated animals. The decreased expression could be related to the increased liver Fe in both Dp44mT- and 3-AP-treated mice.

storage

Store at +4°C

References

[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 20, p. 3672 - 3677
[2] Patent: US5281715, 1994, A

3-AP

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