Onalespib

Onalespib (AT13387) is a potent inhibitor of Hsp90, with a Kd of 0.71 nM.

Onalespib is a member of the class of isoindoles that is isoindole in which the amino group has been acylated by a 2,4-dihydroxy-5-isopropylbenzoyl group and in which position 5 of the isoidole moiety has been substituted by a (4-methylpiperazin-1-yl)methyl group. A second-generation Hsp90 inhibitor. It has a role as a Hsp90 inhibitor and an antineoplastic agent. It is a member of resorcinols, a member of benzamides, a tertiary carboxamide, a member of isoindoles and a N-alkylpiperazine.|Onalespib is a synthetic, orally bioavailable, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Onalespib selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins.

The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with NThe product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with NThe product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with NThe product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with NThe product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol ( 6.8L) and water (1.04 L) and after purging with NThe product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol (6.8 L) and water (1.04 L) and after purging with NIn some batches of product, the title compound (X = H in the formula) can contain small amounts of the impurity 2, 4-Dihydroxy-5-(2-hydroxyprop-2-yl)-phenyl)-[5-(4-methyl- piperazin-1-ylmethyl)-1 , 3-dihydro-isoindol-2-yl]-methanone (X = OH in the formula). The impurities can be removed by the following method.X = H and OHAcetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2, 4- dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1 -ylmethyl)-1 , 3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100 Acetic anhydride (1.04 ml, 11.0 mmol) was added to a stirred suspension of impure 2-(2, 4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1, 3-dihydroisoindole (2.05 g, 5.0 mmol) in toluene (20 ml) and the resulting mixture was stirred and held at 100° C. for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford a brown oil which was dissolved in methanol (20 ml). Concentrated hydrochloric acid (1 ml) was added and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature, the organic solvent and volatile material were removed in vacuo and the aqueous residue was diluted with water (25 ml) and basified to pH 8 with vigorous stirring by the careful addition of 10percent aqueous potassium carbonate solution. 50percent Ethyl acetate in heptane (50 ml) was added and the mixture was stirred vigourously at room temperature for 16 hours. The solid material was collected by suction filtration, rinsed with 50percent ethyl acetate in heptane (50 ml), sucked dry under reduced pressure and dried overnight in a vacuum oven at 50° C. to afford 2-(2, 4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1, 3-dihydroisoindole (1.85 g, 90percent) as an off-white solid.

Molecular Weight:409.5
XLogP3:3.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:409.23654186
Monoisotopic Mass:409.23654186
Topological Polar Surface Area:67.2
Heavy Atom Count:30
Complexity:592
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes