GSK1059615; 958852-01-2; GSK-1059615; UNII-07YMO87363;

• GSK 615

(5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione

5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione

CAS 958852-01-2

nmr……..http://file.selleckchem.com/downloads/nmr/S136001-GSK1059615-NMR-Selleck.pdf

GSK1059615 is a potent, ATP-competitive inhibitor of PI 3-kinase alpha (PI3Kα) with IC50 of 2 nM. Phosphatidylinositol-3 kinases (PI3K) are critical for malignant cellular processes including growth, proliferation, and survival. GSK1059615 is also a novel inhibitor of PI3Kβ, PI3Kδ, PI3Kγ and mTOR with IC50 of 0.6 nM, 2 nM, 5 nM and 12 nM, respectively. GSK1059615 (25 mg/kg) effectively inhibits tumor growth in xenograft mice models of BT474 or HCC1954 breast cancer cells and attenuates MAPK signaling.

GSK1059615 is a  phosphoinositide 3-kinase (PI3K) inhibitor with potential antineoplastic activity. PI3K inhibitor GSK1059615 inhibits PI3K in the PI3K/AKT kinase signaling pathway, which may trigger the translocation of cytosolic Bax to the mitochondrial outer membrane and an increase in mitochondrial membrane permeability, followed by apoptosis. Bax is a member of the proapoptotic Bcl-2 family of proteins. PIK3, an enzyme often overexpressed in cancer cells, plays a crucial role in tumor cell regulation and survival.

Patent

http://www.google.com/patents/US20090306074

http://www.google.com/patents/US20090306074

Example 1 (5Z)-5-{[4-(4-pyridinyl)-6-quinolinyl]methylidene}-1,3-thiazolidine-2,4-dione

a) 4-chloro-6-ethenylquinoline

A mixture of 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J. Med. Chem., 21, 268 (1978)), tributyl(vinyl)tin (8.95 g, 28.22 mmol), and tetrakistriphenylphosphine palladium (0) (0.62 g, 0.54 mmol) in 1,4-dioxane (150 mL) was refluxed for 2.0 h, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-4% MeOH:CH₂Cl₂) to give the title compound (5.1 g) as a pale yellow solid. MS (ES)+m/e 190 [M+H]⁺. This material was used directly in the next step.

b) 4-chloro-6-quinolinecarbaldehyde

A mixture of 4-chloro-6-ethenylquinoline (5.1 g, 26.88 mmol), 2,6-lutidine (5.76 g, 53.75 mmol), sodium (meta) periodate (22.99 g, 107.51 mmol), and osmium tetroxide (5.48 g of a 2.5% solution in tert-butanol, 0.538 mmol) in 1,4-dioxane:H₂O (350 mL of 3:1 mixture) was stirred for 3.5 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH₂Cl₂) to give the title compound (4.26 g, 83% for 2 steps) as a pale yellow solid. MS (ES)+ m/e 192 [M+H]⁺.

c) 4-(4-pyridinyl)-6-quinolinecarbaldehyde

A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol), 4-pyridylboronic acid (3.12 g, 25.38 mmol), tetrakistriphenylphosphine palladium (0) (0.978 g, 0.846 mmol), and 2M aqueous K₂CO₃ (7.02 g, 50.76 mmol, 25.4 mls of 2M solution) in DMF (100 mL) was heated at 100° C. for 3.0 h and cooled to room temperature. The mixture was filtered through celite and the celite was washed with EtOAc. The filtrate was transferred to a separatory funnel, washed with water and saturated NaCl, dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% MeOH:CH₂Cl₂) to give the title compound (2.03 g, 51%) as a tan solid. MS (ES)+ m/e 235 [M+H]⁺.

d) (5Z)-5-{[4-(4-pyridinyl)-6-quinolinyl]methylidene}-1,3-thiazolidine-2,4-dione

A mixture of 4-(4-pyridinyl)-6-quinolinecarbaldehyde (0.108 g, 0.463 mmol), 2,4-thiazolidinedione (0.0417 g, 0.356 mmol), piperidine (0.0303 g, 0.356 mmol), and acetic acid (0.0214 g, 0.356 mmol) in EtOH (5 mL) was heated at 150° C. for 30 minutes in a microwave oven. The reaction was cooled to room temperature and the resulting precipitate was filtered and dried in a Buchner funnel to give the title compound (0.0594 g, 50%) as a tan solid. MS (ES)+ m/e 334 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) □ ppm 9.08 (d, J=4.42 Hz, 1H) 8.80-8.88 (m, 2H) 8.25 (d, J=8.72 Hz, 1H) 8.00-8.07 (m, 2H) 7.98 (s, 1H) 7.65-7.68 (m, 2H) 7.63 (d, J=4.42 Hz, 1H).

……………..

http://www.google.com/patents/WO2007136940A2?cl=en

Schemes/Experimentals

Scheme I:

Conditions: a) Tributyl(vinyl)tin, Pd(PPh₃)₄, dioxane, reflux; b) OsO₄, NaIO₄, 2,6- lutidine, f-BuOH, dioxane, H₂O, rt; c) heteroaryl (R) boronic acid, Pd(PPh₃)₄, 2 M K₂CO₃, DMF, 10O ⁰C; d) 2,4-thiazolidinedione, piperidine, AcOH, EtOH, μwave, 150 ⁰C.

Examples:

Example 1 : (5Z)-5-ff4-(4-pyridinyl)-6-quinolinvnmethylidene}-1 ,3-thiazolidine-

2,4-dione

a) 4-chloro-6-ethenylquinoline

A mixture of 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J. Med. Chem., 21_, 268 (1978) ), tributyl(vinyl)tin (8.95 g, 28.22 mmol), and tetrakistriphenylphosphine palladium (0) (0.62 g, 0.54 mmol) in 1 ,4-dioxane (150 ml.) was refluxed for 2.0 h, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-4% MeOH:CH₂CI₂) to give the title compound (5.1 g) as a pale yellow solid. MS(ES)+ m/e 190 [M+H]⁺. This material was used directly in the next step.

b) 4-chloro-6-quinolinecarbaldehyde

A mixture of 4-chloro-6-ethenylquinoline (5.1 g, 26.88 mmol), 2,6-lutidine (5.76 g, 53.75 mmol), sodium (meta) periodate (22.99 g, 107.51 mmol), and osmium tetroxide (5.48 g of a 2.5% solution in tert-butanol, 0.538 mmol) in 1 ,4- dioxane:H₂O (350 ml. of 3:1 mixture) was stirred for 3.5 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH₂CI₂) to give the title compound (4.26 g, 83% for 2 steps) as a pale yellow solid. MS(ES)+ m/e 192 [M+H]⁺.

c) 4-(4-pyridinyl)-6-quinolinecarbaldehyde

A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol), 4- pyridylboronic acid (3.12 g, 25.38 mmol), tetrakistriphenylphosphine palladium (0) (0.978 g, 0.846 mmol), and 2M aqueous K₂CO₃ (7.02 g, 50.76 mmol, 25.4 mis of 2M solution) in DMF (100 ml.) was heated at 100⁰C for 3.0 h and cooled to room temperature. The mixture was filtered through celite and the celite was washed with EtOAc. The filtrate was transferred to a separatory funnel , washed with water and saturated NaCI, dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% MeOHiCH₂CI₂) to give the title compound (2.03 g, 51%) as a tan solid. MS(ES)+ m/e 235 [M+H]⁺.

d) (5Z)-5-{[4-(4-pyridinyl)-6-quinolinyl]methylidene}-1 ,3-thiazolidine-2,4-dione

A mixture of 4-(4-pyridinyl)-6-quinolinecarbaldehyde (0.108 g, 0.463 mmol), 2,4-thiazolidinedione (0.0417 g, 0.356 mmol), piperidine (0.0303 g, 0.356 mmol), and acetic acid (0.0214 g, 0.356 mmol) in EtOH (5 ml.) was heated at 15O⁰C for 30 minutes in a microwave oven. The reaction was cooled to room temperature and the resulting precipitate was filtered and dried in a Buchner funnel to give the title compound (0.0594 g, 50%) as a tan solid. MS(ES)+ m/e 334 [M+H]⁺. 1 H NMR (400 MHz, DMSO-d₆) D ppm 9.08 (d, J=4.42 Hz, 1 H) 8.80 – 8.88 (m, 2 H) 8.25 (d, J=8.72 Hz, 1 H) 8.00 – 8.07 (m, 2 H) 7.98 (s, 1 H) 7.65 – 7.68 (m, 2 H) 7.63 (d, J=4.42 Hz, 1 H).

Identification of druggable targets for radiation mitigation using a small interfering RNA screening assay.
Zellefrow CD,et al. Radiat Res. 2012 Sep;178(3);150-9. PMID: 22747550.

Saadia et al (2009) Phosphatidylinositol-3-kinase as a therapeutic target in melanoma. Clin.Cancer Res. 15 3029. PMID: 19383818.

Knight et al (2010) Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med.Chem.Lett. 1 39.

////////GSK 1059615,  GSK 615