Tricirbine

Category	Human immunodeficiency Virus (HIV)
CAS	35943-35-2
Description	Triciribine is a potent AKT inhibitor and a cell-permeable tricyclic nucleoside molecule with potential antineoplastic activity. Akt-1, -2, and -3 are serine/threonine protein kinases in the phosphatidylinositol (PI3)-kinase signalling pathway that play a critical role in the regulation of cell proliferation and survival. Following recruitment of Akt to the plasma membrane, phosphorylation at threonine 308 and serine 473 (Akt-1 numbering) by phosphoinositide-dependent kinases (PDK) 1 and 2 results in full activation of the enzyme. Triciribine is a cell-permeable tricyclic nucleoside that inhibits the phosphorylation, activation, and signalling of Akt-1, -2, and -3. It does not inhibit phosphatidylinositol 3 (PI3)-Kinase or PDK1, the direct upstream activators of Akt, nor does it inhibit PKC, PKA, ERK1/2, serum- and glucocorticoid-inducible kinase, p38, STAT3, or JNK signalling pathways. Triciribine effectively inhibits growth of Akt-overexpressing human cancer cell lines in vitro with 50% inhibition at ~5-10 µM. It also inhibit growth of tumor xenografts in mice by greater than 80% at a dose of 1 mg/kg/day.

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Product Information

Synonyms	VQD-002; VQD 002; VQD002; API-2; Akt Inhibitor V; Pentaazacentopthylene; Tricyclic nucleoside; 1,5-Dihydro-5-methyl-1-beta-D-ribofuranosyl-1,4,5,6,8-pentaazaacenaphthylen-3-amine
IUPAC Name	(2R,3R,4S,5R)-2-(5-amino-7-methyl-2,6,7,9,11-pentazatricyclo[6.3.1.04,12]dodeca-1(12),3,5,8,10-pentaen-2-yl)-5-(hydroxymethyl)oxolane-3,4-diol
Molecular Weight	320.30
Molecular Formula	C13H16N6O4
Canonical SMILES	CN1C2=NC=NC3=C2C(=CN3C4C(C(C(O4)CO)O)O)C(=N1)N
InChI	InChI=1S/C13H16N6O4/c1-18-11-7-5(10(14)17-18)2-19(12(7)16-4-15-11)13-9(22)8(21)6(3-20)23-13/h2,4,6,8-9,13,20-22H,3H2,1H3,(H2,14,17)/t6-,8-,9-,13-/m1/s1
InChIKey	HOGVTUZUJGHKPL-HTVVRFAVSA-N
Boiling Point	718.5±70.0 °C at 760 mmHg
Melting Point	211-214°C (dec.)
Flash Point	388.3±35.7 °C
Purity	98%
Density	2.0±0.1 g/cm3
Solubility	In Vitro: DMSO : ≥ 44 mg/mL (137.37 mM)
Appearance	Tan solid powder
Storage	Powder: -20°C: 3 years 4°C: 2 years In solvent: -80°C: 6 months -20°C: 1 month
Animal Admin	Akt1+/+ and Akt1-/- mice are subjected to normoxia or hypoxia (10% O2) for 7 and 14 days (n=2-6 mice per group). Noteworthy, high mortality is observed in Akt1-/- mice exposed to hypoxia longer than 14-16 days. For pharmacological inhibition studies, Akt1+/+ mice, subjected to normoxia or chronic hypoxia for 14 days, received daily i.p. injection of saline, Triciribine (0.5 mg/kg per day) or Rapamycin (1.5 mg/kg per day) for 7 days, and the total continuous exposure to hypoxia or normoxia is 21 days (n=6-8 mice per group). Pharmacological inhibitors are administered daily while the mice are maintained in the hypoxia chamber to minimize exposure to air and spontaneous reversal of pulmonary remodelling.
Complexity	507
Exact Mass	320.12330301
Index Of Refraction	1.928
In Vitro	The nucleoside analog Triciribine (TCN) is a purine analog which is initially shown to inhibit DNA synthesis. Triciribine selectively inhibits the phosphorylation and activation of all three Akt isoforms. At a concentration of 10 μM Triciribine Akt phosphorylation is inhibited at both Thr308 and Ser473. Triciribine effectively inhibits the phosphorylation and consequently the catalytic activity of Akt in PC-3 cells. The Akt inhibitor Triciribine (TCN) does not effectively inhibit the human cell line U87MG but inhibits other astrocytoma cell lines in a grade-dependent manner. The WHO II K1861-10 line is incompletely inhibited (69% maximum inhibition) with a GI50 value of 1.7 µM for Triciribine. Triciribine exhibits maximum growth inhibition around 1-10 µM and inhibits phosphorylation of Akt, as well as downstream p70S6K, to basal levels at 100 µM (IC50=130 nM) in KR158 cells. Triciribine (TCN) is a novel tricyclic compound with known antitumor activity. Using a syncytial plaque assay, Triciribine is active against HIV-1 at 0.01-0.02 μM. Using a microtiter XTT assay, Triciribine is active against a panel of HIV-1 and HIV-2 strains at IC50 values ranging from 0.02 to 0.46 μM.
In Vivo	Triciribine (TCBN) treatment, administered for 7 days after 14 days of hypoxia until 21 days of hypoxia is reached, reversed the vascular thickening as shown by immunohistochemistry and Western analyses. On the other hand, Rapamycin treatment did not prevent hypoxia-induced pulmonary alveolar haemorrhage and congestion. Triciribine partially inhibited progressive pruning of the vasculature, which supports our previous finding that Triciribine alleviates vessel occlusion in microcapillaries. In contrast, Rapamycin treatment did not significantly reverse the reduced vascular density due to chronic hypoxia and had no significant effect on pruning of small vessels.
PSA	144.47000
Target	DNA synthesis Akt:130 nM (IC50, Cell Assay) HIV-1:0.02-0.46 μM (IC50) HIV-2:0.02-0.46 μM (IC50)
Vapor Pressure	0.0±2.4 mmHg at 25°C
XLogP3-AA	-1.6