663619-89-4

Basic information

• Product Name: 4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE, 7-METHYL-2-(4-MORPHOLINYL)-9-[1-(PHENYLAMINO)ETHYL]-
• Synonyms: 4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE, 7-METHYL-2-(4-MORPHOLINYL)-9-[1-(PHENYLAMINO)ETHYL]-;TGX 221;(+/-)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)pyrido[1,2-a]pyrimidin-4-one;7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;(+/-)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)pyrido[1,2-a]pyrimidin-4-one TGX 221;TGX 221 (+/-)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)pyrido[1,2-a]pyrimidin-4-one;PI 3-Kβ Inhibitor VI, TGX-221
• CAS NO: 663619-89-4
• Molecular Formula: C₂₁H₂₄N₄O₂
• Molecular Weight: 363.4
• Product Categories: Inhibitors;Akt;mTOR;PI3K
• Mol File: 663619-89-4.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 557.293 °C at 760 mmHg
• Flash Point: 290.841 °C
• Appearance: /
• Density: 1.259 g/cm³
• Storage Temp.: Hygroscopic, Refrigerator, under inert atmosphere
• Solubility: DMSO (Slightly), Methanol (Very Slightly)
• PKA: 3.90±0.50(Predicted)
• CAS DataBase Reference: 4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE, 7-METHYL-2-(4-MORPHOLINYL)-9-[1-(PHENYLAMINO)ETHYL]-(CAS DataBase Reference)
• NIST Chemistry Reference: 4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE, 7-METHYL-2-(4-MORPHOLINYL)-9-[1-(PHENYLAMINO)ETHYL]-(663619-89-4)
• EPA Substance Registry System: 4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE, 7-METHYL-2-(4-MORPHOLINYL)-9-[1-(PHENYLAMINO)ETHYL]-(663619-89-4)

Safety Data

• Hazardous Substances Data: 663619-89-4(Hazardous Substances Data)

Usage

Uses

TGX-221 is a potent, selective, and cell permeable inhibitor of Phosphatidylinositol 3-kinase (PI3K) p110β.

General Description

A cell-permeable morpholino-pyrimidinone compound that acts as a reversible, ATP-competitive, selective, and highly potent inhibitor of PI 3-Kβ (IC50 = 0.005, 0.1, 5, and ≥3.5 μM for -β, -δ, -α and -γ isoforms, respectively) with little activity against a panel of 15 commonly studied protein kinases even at concentrations as high as 10.0 μM. An excellent tool for studying p110β-dependent responses both in cells in vitro and in animals in vivo.

Biological Activity

tgx-221 is a potent inhibitor of (phosphatidylinositol 3-kinases) pi3k which specifically inhibits pi3k -p110β isoform with ic50 value of 8.5 nm [1].in j774.2 macrophage cells, tgx-221 has been demonstrated to reduce insulin-induced phosphorylation of ser473 of protein kinase b (pkb). while in in cho-ir and 3t3-l1 cells, tgx-221 has no effect on pkb phosphprylation [1].

Biochem/physiol Actions

Cell permeable: yes

in vivo

tgx-221 significantly improved blood flow in fecl3-induced arterial thrombosis as well as increased tail and renal bleeding times in mice. in addition, tgx-221 has revealed to disrupt cfrs in a folts model of arterial thrombosis in male sprague-dawley rats [2].

references

[1] chaussade c1, rewcastle gw, kendall jd, denny wa, cho k, gr nning lm, chong ml, anagnostou sh,jackson sp, daniele n, shepherd pr. evidence for functional redundancy of class ia pi3k isoforms in insulin signalling. biochem j. 2007 jun 15;404(3):449-58.[2] bird je1, smith pl, bostwick js, shipkova p, schumacher wa. bleeding response induced by anti-thrombotic doses of a phosphoinositide 3-kinase (pi3k)-β inhibitor in mice. thromb res. 2011 jun;127(6):560-4.

Upstream product

• 62-53-3 aniline 
• 1603-41-4 (5-methyl-pyridin-2-yl)amine 
• 1374310-67-4 C₁₆H₂₁N₃O₅S 
• 1173900-35-0 9-(1-hydroxyethyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one 
• 351002-16-9 TGX₀₆₆ 
• 663619-90-7 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 
• 17282-00-7 3-bromo-5-methylpyridin-2-amine 

Downstream Products

• 1308384-65-7 TGX-D₁ 
• 1307864-99-8 C₂₉H₃₉N₅O₄ 
• 1307865-00-4 NH₂-SL-TGX 
• 1307864-98-7 C₂₄H₂₈N₄O₄ 

Relevant articles and documents

Exploring the isoform selectivity of TGX-221 related pyrido[1,2-a]pyrimidinone-based Class IA PI 3-kinase inhibitors: Synthesis, biological evaluation and molecular modelling

A novel series of TGX-221 analogues was prepared and tested for their potency against the p110α, p110β, and p110δ isoforms of the PI3K enzyme, and in two cellular assays. The biological results were interpreted in terms of a p110β comparative model, in order to account for their selectivity towards this isoform. A CH2NH type linker is proposed to allow binding into the specificity pocket proposed to accommodate the high p110β-selectivity of TGX-221, although there was limited steric tolerance for substituents on the pendant ring with the 2-position most favourable for substitution.

Development of a peptide-drug conjugate for prostate cancer therapy

TGX-221 is a highly potent phosphoinositide 3-kinase β (PI3Kβ) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate to specifically deliver TGX-221 to HER2 overexpressing prostate cancer cells. Four TGX-221 derivatives with added hydroxyl groups were synthesized for peptide conjugation. Among them, TGX-D1 exhibited a similar bioactivity to TGX-221, and it was selected for conjugation with a peptide promoiety containing a HER2-targeting ligand and a prostate specific antigen (PSA) substrate linkage. From this selection, the peptide-drug conjugate was proven to be gradually cleaved by PSA to release TGX-D1. Cellular uptake of the peptide-drug conjugate was significantly higher in prostate cancer cells compared to the parent drug. Moreover, both the peptide-drug conjugate and its cleaved products demonstrated comparable activities as the parent drug TGX-D1. Our results suggest that this peptide-drug conjugate may provide a promising chemotherapy for prostate cancer patients.