123239-70-3Relevant academic research and scientific papers
Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach
Lucas, Simon,Heim, Ralf,Negri, Matthias,Antes, Iris,Ries, Christina,Schewe, Katarzyna E.,Bisi, Alessandra,Gobbi, Silvia,Hartmann, Rolf W.
supporting information; experimental part, p. 6138 - 6149 (2009/10/01)
Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC 50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.
2-Substituted-1-naphthols as potent 5-lipoxygenase inhibitors with topical antiinflammatory activity
Batt,Maynard,Petraitis,Shaw,Galbraith,Harris
, p. 360 - 370 (2007/10/02)
The synthesis, biological evaluation, and structure-activity relationships of a series of 1-naphthols bearing carbon substituents at the 2-position are described. These compounds are potent inhibitors of the 5-lipoxygenase from RBL-1 cells and also inhibi
The Complexation of the Diquat Dication by Dibenzo-3n-crown-n Ethers
Colquhoun, Howard M.,Goodings, Eric P.,Maud, John M.,Stoddart, J. Fraser,Wolstenholme, John B.,Williams, David J.
, p. 607 - 624 (2007/10/02)
Spectrophotometric investigations of equimolar mixtures of diquat bis(hexafluorophosphate) (2) and a range of dibenzo-3n-crown-n ethers in acetonitrile reveal the existence of charge-transfer absorption bands at ca. λmax 400 nm.These absorptions are attributable to intermolecular ?-? charge transfer between the electron-rich catechol units of the dibenzo-crown ethers and the electron-deficient bipyridinium ring system of the diquat dication.The qualitative conclusion from these experiments, that the most stable 1:1 complex is formed between dibenzo-30-crown-10 (14) and diquat bis(hexafluorophosphate) (2), led to the isolation from dichloromethane methanol-n-heptane of red crystals of 2 suitable for X-ray crystallography.Although the crystal structure analysis revealed that there are two independent sets of 1:1 complexes (I and II) in the unit cell, the gross structural features of the two complexes are very similar.In addition to the paralell alignment of their three aromatic rings to accommodate the stabilising intermolecular ?-? charge-transfer interaction, there is probably some further host-guest stabilisation to be gained on account of favourable electrostatic interactions between the phenolic oxygen atoms in the host and the nitrogen atoms in the pyridinium rings of the guest.Moreover, there is some evidence for weak C-H...O hydrogen bonding involving principally H-6 and H-6' on the bipyridinium ring system of the guest and certain -CH2OCH2- oxygen atoms in the host.As evidenced by 1H n.m.r. spectroscopy in CD3COCD3, these non-covalent bonding interactions are probably responsible for the formation of stable and ordered 1:1 complexes with similar gross structural features in solution, at least in the cases where dibenzo-30-crown-10 (14), dibenzo-33-crown-11 (15), and dibenzo-36-crown-12 (16) are the hosts.Further evidence for the 1:1 stoicheiometry of these solution complexes, as well as for the complex involving dibenzo-27-crown-9 (13), has come from equilibrium constant measurements for the association between the dibenzo-3n-crown-n (n = 9-12) hosts (13)-(16) and diquat bis(hexafluorophosphate) (2) in acetone.A quantitative treatment of the charge-transfer absorption bands at 400 nm, which affords Ka values of 410, 17500, 10800, and 2000 M-1 for n = 9, 10, 11, and 12, respectively, provides convincing quantitative evidence for (a) 1:1 stoicheiometry and (b) the relative stabilities of the 1:1 complexes in solution.In the case of dibenzo-24-crown-8 (11), a complex of 2:1 (guest-host) stoicheiometry is believed to be formed in acetone with a Ka value of 385000 M-2, as shown by a successfull quantitative treatment of the charge-transfer absorption data by an independent method.
