AST-1306 TsOH

AST-1306 is a selective, irreversible inhibitor of ErbB2 and EGFR with IC50 values of 0.5nM and 3nM, respectively [1].

AST-1306 is designed and synthesized based on the chemical structure of lapatinib. The molecular docking method shows AST-1306 binds to the ATP-binding pocket of the kinases and form covalent bind with certain amino acids. AST-1306 can inhibit EGFR and ErbB2 in a cell-free assay with more than 3000-fold selectivity to other kinases. Besides the wild-type EGFR, AST-1306 also inhibits EGFR mutant T790M/L858R both in a cell-free assay and in HIH3T3 cells. The growth of the cells is suppressed by AST-1306 due to the inhibition of the phosphorylation of EGFR. It also occurs in some human cancer cells. Experiments have proved that AST-1306 notly inhibits the phosphorylation of EGFR and ErbB2 and subsequently decreases the downstream pathways of these kinases in A549 cells, Calu-3 cells and SK-OV-3 cells. Moreover, AST-1306 potently inhibits the tumor growth both in ErbB2-overexpressing xenograft models and FVB-2/Nneu transgenic mouse model [1].

References:
[1] Xie H, Lin L, Tong L, Jiang Y, Zheng M, Chen Z, Jiang X, Zhang X, Ren X, Qu W, Yang Y, Wan H, Chen Y, Zuo J, Jiang H, Geng M, Ding J. AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo. PLoS One. 2011;6(7):e21487.

Synergistic Effect of the TiCl4/p-TsOH Promoter System on the Aza-Prins Cyclization.[Pubmed:26736061]

J Org Chem. 2016 Feb 5;81(3):849-59.

A novel aza-Prins cyclization promoted by a synergistic combination between a Lewis acid and a Bronsted acid to efficiently afford piperidines is described. Contrary to what has been previously reported in the literature, the generality of the reaction employing N-alkyl, N-aryl, and nonprotected homoallylamines has been demonstrated. The reaction is highly diastereoselective depending on the homoallylic amine used, N-PMP homoallyl amine leading preferentially to the trans diastereomer, and free homoallylamine affording the deprotected piperidine as single cis diastereomer.

Chemoselective hydroamination of vinyl arenes catalyzed by an NHC-amidate-alkoxide Pd(II) complex and p-TsOH.[Pubmed:24039309]

Tetrahedron Lett. 2013 Jul 31;54(31):4083-4085.

The hydroamination of various substituted vinyl arenes with benzenesulfonamide was explored using an NHC-amidate-alkoxide palladium catalyst in conjunction with p-TsOH. Utilizing halide-substituted and electron-rich vinyl arenes, this methodology selectively furnished the cross-coupled hydroamination products in moderate to excellent yields in a Markovnikov fashion while greatly reducing undesired acid-catalyzed homocoupling of the vinyl arenes. Electron-rich vinyl arenes typically required milder conditions than electron-poor ones. While most effective for para-substituted substrates, the catalyst system also furnished the desired products from ortho- and meta-substituted vinyl arenes with high chemoselectivities.

p-TsOH Promoted Au(I)-Catalyzed Consecutive Endo Cyclization of Yne-Tethered Ynamide: Access to Benzofused Dihydroisoquinolones.[Pubmed:26524487]

Org Lett. 2015 Nov 20;17(22):5662-5.

A novel synthetic route to benzo[f]dihydroisoquinolone through a p-TsOH promoted cascade cyclization of easily accessible diyne-tethered ynamides in the presence of a Au(I)-catalyst is described. This reaction unveils a broad substrate scope, constructing a wide range of benzo[f]dihydroisoquinolones in good yields. The diyne-tethered ynamides are synthesized from inexpensive o-iodoaniline through Sonogashira couplings and the Cu-mediated C-N bond formation. The role of p-TsOH is examined, and the reaction pathway is also deduced. The benzo[f]isoquinoline scaffold is constructed from benzo[f]dihydroisoquinolones.

Generation of ortho-quinone methides by p-TsOH on silica and their hetero-Diels-Alder reactions with styrenes.[Pubmed:19385608]

J Org Chem. 2009 May 15;74(10):4009-12.

2-Arylchromans were readily prepared from the hetero-Diels-Alder reactions of styrenes with the ortho-quinone methides (o-QMs) which, in turn, were generated by treating the MOM-protected benzylacetate derivatives with p-TsOH immobilized on silica (PTS-Si) in toluene under mild conditions (0 degrees C to rt). The corresponding chromans were obtained in moderate to excellent yields (42-97%) and in moderate to excellent diastereoselectivity (up to >99:1).

Allitinib tosylate (AST-1306 (TsOH)) is an orally active and irreversible EGFR and ErbB2 inhibitor with IC50s of 0.5 and 3 nM, respectively. Allitinib tosylate also inhibits ErbB4 with an IC50 of 0.8 nM. Allitinib tosylate is an anilino-quinazoline compound and has anti-cancer activity

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