143621-35-6

Basic information

• Product Name: 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
• Synonyms: 3-Apct;C078157;Pan 811;Pan811;Pan-811;Triapine;2-((3-AMinopyridin-2-yl)Methylene)hydrazinecarbothioaMide;NSC 663249
• CAS NO: 143621-35-6
• Molecular Formula: C7H9N5S
• Molecular Weight: 195.24
• Product Categories: Inhibitors
• Mol File: 143621-35-6.mol

Chemical Properties

• Melting Point: 234 °C
• Boiling Point: 435.961 °C at 760 mmHg
• Flash Point: 217.462 °C
• Appearance: white to light brown/
• Density: 1.467 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.72
• Storage Temp.: 2-8°C
• Solubility: DMSO: soluble10Meq/mL, clear
• PKA: 10.93±0.70(Predicted)
• CAS DataBase Reference: 3-aminopyridine-2-carboxaldehyde thiosemicarbazone(CAS DataBase Reference)
• NIST Chemistry Reference: 3-aminopyridine-2-carboxaldehyde thiosemicarbazone(143621-35-6)
• EPA Substance Registry System: 3-aminopyridine-2-carboxaldehyde thiosemicarbazone(143621-35-6)

Safety Data

• Hazard Codes: Xn
• Statements: 22-36/37/38
• Safety Statements: 26
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 143621-35-6(Hazardous Substances Data)

Usage

Uses

Used in Anticancer Applications:
3-aminopyridine-2-carboxaldehyde thiosemicarbazone is used as an antitumor agent for its ability to inhibit ribonucleotide reductase, a rate-limiting enzyme in de novo DNA synthesis. This inhibition is particularly effective in cancer cells, where the enzyme's activity is increased, contributing to malignant transformation and proliferation. By forming a redox-active complex with iron, 3-AP destroys the tyrosine free radical in the R2/p53R2 subunits of ribonucleotide reductase, thereby producing reactive oxygen species that contribute to its antitumor effects.
Additionally, 3-AP has been shown to enhance the radiosensitivity of tumor cells in vitro, such as DU145, U251, and PSN1, at a concentration of 5 μM. This enhancement suggests that 3-AP could be a valuable component in combination therapies with radiation treatment.
Furthermore, 3-AP activates an endoplasmic reticulum stress pathway, leading to the unfolded protein response and apoptosis. This mechanism of action provides another avenue through which 3-AP can contribute to the suppression of tumor growth and the treatment of cancer.

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,.

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.

InChI:InChI=1/C7H9N5S/c8-5-2-1-3-10-6(5)4-11-12-7(9)13/h1-4H,8H2,(H3,9,12,13)/b11-4+

Upstream product

• 79-19-6 thiosemicarbazide 
• 143621-33-4 3-amino-2-(1,3-dioxolan-2-yl)pyridine 
• 36625-67-9 3-nitropyridine-2-carboxaldehyde thiosemicarbazone 
• 6298-19-7 2-chloro-3-aminopyridine 
• 5470-18-8 2-Chloro-3-nitropyridine 
• 209798-50-5 (E)-2-styrylpyridin-3-amine 
• 209798-44-7 2-styryl-3-pivaloylamidopyridine 
• 143621-31-2 2-(1,3-dioxolan-2-yl)-3-nitropyridine 
• 109902-33-2 N-2-chloropyrid-3-yl-trimethylacetamide 
• 65156-92-5 (E)-N,N-dimethyl-2-(3-nitropyridin-2-yl)ethenamine 
• 10261-94-6 3-nitropyridine-2-carboxaldehyde 
• 18699-87-1 2-methyl-3-nitropyridine 
• 209798-46-9 2-formyl-3-pivaloylamidopyridine 
• 116026-99-4 (2?formyl?pyridin?3?yl)?carbamic acid tert?butyl ester 

Relevant articles and documents

Synthesis of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP)

Palladium-catalyzed cross-coupling of methylboronic acid with 2-chloro- 3-nitropyridine produced 2-methyl-3-nitropyridine 4 in one step in high yield. Oxidation of 4 with selenium dioxide gave aldehyde 5. Alternatively, condensation of 4 with DMFDMA followed by oxidation gave 5 in a two step higher yielding conversion. Subsequent direct coupling of 5 with thiosemicarbazide followed by reduction of the nitro group using stannous chloride or sodium sulfide provided 3-AP (3). Reduction with sodium hydrosulfite gave 3-HAP (8). Finally a route which avoids the reduction of a nitro function was devised. Thus direct coupling of styrene with 2-chloro-3- aminopyridine 9 under Heck reaction conditions gave 16 which was converted to 17, oxidized to the aldehyde 18 and converted to 3-AP (3) with in situ deblocking of the t-Boc functionality.

2-formylpyridine thiosemicarbazone compounds

A method of treatment of tumors is provided based upon a compound of the formula STR1 Some aspects of the invention were supported in part by U.S. Public Health Service Grant CA-02817 from the National Cancer Institute and support from the Northeast NMR Facility at Yale University insofar as the use of high resolution NMR spectra is concerned that was made possible by a grant from the Chemical Division of the National Science Foundation (Grant No. CHE-7916210).

Synthesis and Antitumor Activity of Amino Derivatives of Pyridine-2-carboxaldehyde Thiosemicarbazone

Variuos substituted pyridine-2-carboxaldehyde thiosemicarbazones (12 compounds) have been synthesized and evaluated for antineoplastic activity in mice bearing the L1210 leukemia.Oxidation of 3-nitro-2-picoline, 5-nitro-2-picoline, 3-nitro-2,4-lutidine, and 5-nitro-2,4-lutidine with selenium dioxide was employed to generate the corresponding pyridine-2-carboxaldehydes, which were then converted to cyclic ethylene acetals and subsequently reduced to amino and hydroxyamino derivatives by catalytic hydrogenation.Condensation of nitro aldehydes and acetals with thiosemicarbazide afforded the respective thiosemicarbazones.Acetylation of the amino acetals and alkylsulfonation of the 5-amino acetal, followed by condensation with thiosemicarbazide was employed to yield amide thiosemicarbazones.The most active compounds synthesiszed were 3-aminopyridine-2-carboxaldehyde thiosemicarbazone and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone which produced against the L1210 leukemia, percent T/C values of 246 and 255, and 40percent 60-day long-term survivors at two daily doses of 40 mg/kg and 10 mg/kg, respectively, for six consecutive days.