Description
MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM) with preference for the first bromodomain over the second. MS436 effectively blocks BRD4 transcriptional activity in lipopolysaccharide-induced production of both nitric oxide and IL-6 in mouse macrophages (IC50 values are 3.8 and 4.9 M, respectively). MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.
Uses
MS 436 is a potent bromodomain inhibitor, binding to BRD4 and more tightly to subdomain BD1 than BD2. These domains play a key role in inflammatory gene expression, mitosis and viral/host interaction. Applications involving innhibition of bromodomains include decrease in cell proliferation for leukemia and destruction of tumor cells.
Biological Activity
ms436 is a potent and selective small-molecule inhibitor of brd4 with ki values of ＜0.085μm and 0.34μm, respectively for brd1 and brd2 [1].brd4 plays a role in gene transcription and is a drug target for cancer and inflammation. it has two bromodomains. ms436 is a diazobenzene compound, it is designed from the sar studies to have higher selectivity. in vitro fluorescent anisotropy assay shows ms436 has about 10-fold higher affinity of brd1 over brd2. ms436 binds to brd4 through a set of water-mediated interaction and this is the molecular basis for the binding affinity. ms436 also has activity to cbp brd. in raw264.7 cells, ms436 can block nf-κb-directed no production and block the expression of proinflammatory cytokine interleukin (il)-6 induced by lps [1].
Synthesis
B. Synthesis of (E)-4-((2-amino-4-hydroxy-5-methylphenyl)diazenyl)-N-(pyridin-2-yl)benzenesulfonamide: To a stirred solution of 4-amino-N-(pyridin-2-yl)benzenesulfonamide (12 g, 0.048 mol) in a mixture of methanol and acetonitrile (1:1, 240 mL) was slowly added concentrated hydrochloric acid (20.4 mL), keeping the reaction temperature at 0 °C to -2 °C and stirred for 5 min. Subsequently, isoamyl nitrite (6.48 mL, 0.553 mol) was added dropwise under the protection of inert atmosphere, the dropwise addition time was controlled within 10 min, and after the dropwise addition was completed, the reaction mixture was continued to be stirred at 0 °C for 45 min. Meanwhile, a homogeneous solution of 2-methyl-5-aminophenol (5.92 g, 0.0481 mol) and potassium carbonate (33.2 g, 0.24067 mol) in water (500 mL) was prepared and degassed by nitrogen purging for 15 min. Upon completion of degassing, the solution was added to a pre-prepared and maintained at 0-5 °C diazonium salt solution through a cannula and the resulting reaction mixture was stirred for 1 h at 0-5 °C. After completion of the reaction, the pH of the reaction mixture was adjusted to 6 with 1N hydrochloric acid and the reaction mixture was filtered. The filtrate was extracted with ethyl acetate (2 x 300 mL), the organic phases were combined and the solvent was removed by distillation under reduced pressure to give an orange-red crude product. The crude product was purified by column chromatography (two purifications using methanol/dichloromethane as eluent) to give the final target compound (E)-4-((2-amino-4-hydroxy-5-methylphenyl)diazenyl)-N-(pyridin-2-yl)benzenesulphonamide (2.6 g, 14% yield).TLC conditions: 5% methanol/dichloromethane, Rf value: 0.5.HPLC Purity: 98.63%, Batch No.: IP 10041325. melting point: 217.2 °C. Mass spectrum: 383 (M + 1). 1H NMR (500MHz, DMSO-d6) δ: 9.22 (broad peak, 1H), 8.0 (multiple peaks, 3H), 7.9 (double peaks, 2H), 7.72 (triple peaks, 1H), 7.54 (single peak, 2H), 7.2 (double peaks, 1H), 6.8 (triple peaks, 1H), 2.21 (single peaks, 6H).
References
[1] zhang g, plotnikov an, rusinova e, shen t, morohashi k, joshua j, zeng l, mujtaba s, ohlmeyer m, zhou mm. structure-guided design of potent diazobenzene inhibitors for the bet bromodomains. j med chem. 2013 nov 27;56(22):9251-64.
