- Synthesis, structural characterization, and catalytic evaluation of phosphinoferrocene ligands bearing extended urea-amide substituents
-
New phosphinoferrocene ligands bearing extended polar amidourea pendants with the general formula Ph2PfcCONHCH2CH 2NHCONR2 (1; R2 = H2 (b), H/Et (c), Me2 (d), H/Ph (e)) and their model bis-amide Ph 2PfcCONHCH2CH2NHCOCH3 (1a) were prepared in good yields by amidation of 1′-(diphenylphosphino)ferrocene-1- carboxylic acid (Hdpf) with the appropriate amines in the presence of peptide coupling reagents. These ferrocene-based phosphinoureas were further employed as ligands in palladium(II) complexes with η3-allyl and NC-chelating supporting ligands: viz., [PdCl(η3-C 3H5)(1-κP)] (5a-e) and [PdCl(LNC)(1- κP)] (6a-e; LNC = [2-(dimethylamino-κN)methyl]phenyl- κC1). Both the free ligands and their Pd(II) complexes were characterized by spectroscopic methods (multinuclear NMR, IR, and MS) and by elemental analysis. The molecular structures of 1b·CH3OH, 1c, 5b,c, 6a, and two additional model complexes, [PdCl(η3-C 3H5)(Hdpf-κP)] (5f) and [PdCl(η3- C3H5)(Ph2PfcCONH2-κP)] (5g), were determined by single-crystal X-ray diffraction analysis. All Pd(II) complexes were evaluated as catalysts in the cross-coupling of boronic acids and acyl halides to give ketones in a toluene/water biphasic mixture. Extensive reaction studies with compound 5e, which not only exerts good catalytic activity but is also readily accessible in a defined crystalline form, demonstrated efficient coupling reactivity for unsaturated substrates such as (substituted) benzeneboronic acids and benzoyl chlorides. The results also revealed that reaction difficulties encountered with less reactive substrates (e.g., insoluble aromatic boronic acids and all saturated aliphatic boronic acids) can be avoided by properly selecting the reaction partners, for example through transposition of substituents between reaction partners. Three representative benzophenones (4-fluoro-, 4-nitro-, and 4,4′-dinitrobenzophenone) were structurally characterized by single-crystal X-ray crystallography.
- Solarova, Hana,Cisarova, Ivana,Stepnicka, Petr
-
p. 4131 - 4147
(2014/10/15)
-
- Sulfur incorporation generally improves Ricin inhibition in pterin-appended glycine-phenylalanine dipeptide mimics
-
Several 7-aminoamido-pterins were synthesized to evaluate the electronic and biochemical subtleties observed in the 'linker space' when N-{N-(pterin-7-yl)carbonylglycyl}-l-phenylalanine 1 was bound to the active site of RTA. The gylcine-phenylalanine dipeptide analogs included both amides and thioamides. Decarboxy gly-phe analog 2 showed a 6.4-fold decrease in potency (IC50 = 128 μM), yet the analogous thioamide 7 recovered the lost activity and performed similarly to the parent inhibitor (IC50 = 29 μM). Thiourea 12 exhibited an IC50 nearly six times lower than the oxo analog 13. All inhibitors showed the pterin head-group firmly bound in their X-ray structures yet the pendants were not fully resolved suggesting that all pendants are not firmly bound in the RTA linker space. Calculated log P values do not correlate to the increase in bioactivity suggesting other factors dominate.
- Wiget, Paul A.,Manzano, Lawrence A.,Pruet, Jeff M.,Gao, Grace,Saito, Ryota,Monzingo, Arthur F.,Jasheway, Karl R.,Robertus, Jon D.,Anslyn, Eric V.
-
p. 6799 - 6804
(2014/01/06)
-
- Synthesis and in vitro and in vivo characterization of highly β1-selective β-adrenoceptor partial agonists
-
β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),(1) a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1's aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of -7.75 and -5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β1-selectivity.
- Mistry, Shailesh N.,Baker, Jillian G.,Fischer, Peter M.,Hill, Stephen J.,Gardiner, Sheila M.,Kellam, Barrie
-
supporting information
p. 3852 - 3865
(2013/07/05)
-
- PHENOXYPROPANOL DERIVATIVES AND THEIR USE IN TREATING CARDIAC AND CARDIOVASCULAR DISEASES
-
A compound of formula I-0, and its pharmaceutically acceptable salt or salts and physiologically hydrolysable derivatives in free form or salt form: wherein Z1 is C1-C4 linear or branched alkyl or alkenyl; R4 is selected from unsubstituted and substituted C3-C8 cycloalkyl, C1-C8 linear or branched alkyl, C2-5 alkenyl, C6-C10 heteroaryl or aryl, or C3-C8 heterocyclyl which may be part unsaturated, and combinations thereof; is linear C2-3 alkylene,; X1 is selected from NH and O; X2 is selected from unsaturated C and unsaturated S; and X3 is selected from NH and CH2; or one of X1 and X3 is a single bond; or X1 is O and X2 and X3 together are a single bond; and R7 is selected from oxo, F, Cl, Br, CN, NH2, NR92, NO2, CF3, OR9, COR9, OCOR9, COOR9, NR9COR9, CONR92 SO2NR92, NR9SO2R9; and R8 is selected from C1-5 alkyl, C1-5 alkoxyl, C2-5 alkenyl or alkynyl, C6-10) aryl and C3-8 cycloalkyl and combinations thereof, which may be unsubstituted or f urther substituted by one or more F, Cl, Br, CN, NH2, NR32, NO2, CF3; and R9 is selected from H and a group R8 as hereinbefore defined; n7 and n8 and the sum thereof are independently selected from zero and the whole number integer 1 to 4; processes for the preparation thereof, compositions and uses.
- -
-
Page/Page column 25
(2012/02/01)
-
- Design of new beta1-selective adrenoceptor ligands as potential radioligands for in vivo imaging.
-
In general, the failing human heart is characterized by a selective reduction in beta(1)-adrenoceptors (beta(1)-ARs) without change in beta(2)-AR density. Medical imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET) with appropriate radioligands, offer the possibility of assessing beta-adrenoceptor density non-invasively in humans. To date, neither a SPECT nor a PET radioligand is available for the selective imaging of cardiac beta(1)-ARs. The aim of this study was to develop potential high affinity beta(1)-selective AR radioligands for the non-invasive in vivo imaging of the beta(1)-AR density in the human heart using SPECT or PET. A variety of racemic N-aryl-N'-[2-[3-aryloxy-2-hydroxy-propylamino]-ethyl]-urea derivatives and chain-elongated analogues, related to the established beta(1)-AR antagonist, ICI 89,406 8i, were synthesized. Competition studies using the non-selective AR ligand, [(125)I]iodocyanopindolol ([(125)I]ICYP), and ventricular membrane preparations of wild-type mice revealed nine ligands with higher beta(1)-AR affinities (up to 76-fold) and beta(1)-AR selectivities (up to 139-fold) than 8i. Mostly, these ligands possess a 2-substituted phenoxy group and a 4-substituted phenyl residue in contrast to the lead compound 8i. The non-radioactive counterparts of the desired SPECT- and PET-radiotracers were synthesized as reference compounds [e.g., 8f, 8g, 8h and 8l as the non-radioactive analogues of the radioiodinated SPECT radioligands, 8e and 8h as the non-radioactive compounds of C-11 labelled PET-tracers (C-11 in the methoxy group)]. The established library of high affinity beta(1)-selective AR antagonists was screened for chemical precursors for the radiosynthesis of the mentioned radioligands. Furthermore, the library consists of some comparison compounds that are unsubstituted, allyl- and alkyl-substituted or chain-elongated (e.g., 8a, 8j, 8o and 8r-t). Future steps will include radiolabelling and pharmacokinetic evaluation of the beta(1)-selective target compounds, which could be applied as sympathetic innervation agents for in vivo investigations and diagnostics in patients suffering from cardiac diseases like heart failure and ventricular arrhythmias.
- Kopka, Klaus,Wagner, Stefan,Riemann, Burkhard,Law, Marilyn P,Puke, Carsten,Luthra, Sajinder K,Pike, Victor W,Wichter, Thomas,Schmitz, Wilhelm,Schober, Otmar,Schaefers, Michael
-
p. 3513 - 3527
(2007/10/03)
-
- Ultra-Short-Acting β-Adrenergic Receptor Blocking Agents. 3. Ethylenediamine Derivatives of (Aryloxy)propanolamines Having Esters on the Aryl Function
-
Various ethylenediamine derivatives have been incorporated into the nitrogen substituent of certain short-acting (aryloxy)propanolamine systems that contain esters on their aryl functions.Although several of these compounds showed durations of action comparable to their prototypes, most of the nitrogen substituents significantly prolonged the duration of β-adrenergic blockade.Similarly, while one of the compounds showed appreciable cardioselectivity in vitro, generally, little enhancement of cardioselectivity was obtained.A brief discussion of structure-activity relationships observed for the ethylenediamine derivatives is presented.
- Erhardt, Paul W.,Woo, Chi M.,Matier, William L.,Gorczynski, Richard J.,Anderson, William G.
-
p. 1109 - 1112
(2007/10/02)
-