2-Propenamide, N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-, (2E)-

Preparation

mixture of (2E)-3-[4-[[[[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propionate (20.00 g, 59.81 mmol), β-bromoethanol (21.5 mL, 37.9 g, 303 mmol) and K2CO3 in MeCN was heated at 60°C for 18 h, cooled, filtered, and the filtrate was evaporated. The residue was purified by rapid chromatography to give (2E)-3-[4-([((2-hydroxyethyl)-[2-(1-Hindol-3-yl)ethyl]amino]methyl)phenyl]-2-propanoic acid methyl ester (13.97 g, 62%): m/z 379 (MH+). Following method C, the ester (13.90 g, 36.73 mmol) was converted to hydroxamic acid ester and treated with 1 equivalent of lactic acid to give Dacinostat lactate (7.44 g, 53%). Method C: At 0 °C, HONH2 (50% aqueous solution, 10-15 equivalents) was added to a solution of the methyl ester in MeOH or EtOH, followed by the addition of 1 M NaOH (7-10 equivalents). The mixture was stirred at 0 °C for 2-4 hours, warmed to room temperature, and stirred until the reaction was complete (TLC). The solution was acidified to pH 1 with 1 M HCl. pH 7-8 (pH test paper) caused product precipitation. The precipitate was filtered, analyzed by RPHPLC, and purified by preparative RPHPLC if necessary.

Uses

Dacinostat is an inhibitors of aberrant chromatin accessibility. It is also used in the synthesis of triazole-linked indole and oxindole glycoconjugates as potential anticancer agents that inhibits the proliferation of the growth of cancer cell lines.

Definition

ChEBI: N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide is a member of tryptamines.

Biological Activity

laq824 (also known as nvp-laq824 or dacinostat), a derivative of 4-aminomethylcinnamic hydroxamic acid, is a novel and potent inhibitor of histone deacetylase (hdac) that inhibits the activity of hdac with 50% inhibition concentration ic50 value of 0.03 μm. laq824 has been found to inhibit the growth of a variety of cancer cell lines, including colon cancer h1299 and hct116 cells, breast cancer mda435 cells, prostate cancer du145 and pc3 cells and non-small cell lung cancer a549 cells, with ic50 value < 1 μm and induce apoptosis in human breast cancer skbr-3, bt-474 and mb-468 cells. laq824 also dose- and time-dependently inhibits the growth of multiple myeloma cells.catley l, weisberg e, tai yt, atadja p, remiszewski s, hideshima t, mitsiades n, shringarpure r, leblanc r, chauhan d, munshi nc, schlossman r, richardson p, griffin j, anderson kc. nvp-laq824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. blood. 2003 oct 1;102(7):2615-22. epub 2003 jun 19.

in vivo

target

HDAC

IC 50

HDAC1: 9 nM (IC₅₀); HDAC: 32 nM (IC₅₀)