A new strategy for caging proteins regulated by kinases

A strategy has been developed for caging proteins that are endogenously regulated by phosphorylation. A key phosphorylatable serine in cofilin, an F-actin cleaving protein, was replaced with a nonphosphorylatable cysteine. The latter conversion ensures that the protein is no longer regulated by endogenous protein kinases. The cysteine residue was subsequently covalently modified with a negatively charged caging moiety, which electrostatically mimics the natural serine phosphate present in the inactive wild-type protein. Photoremoval of the cage generates an active protein, which cannot be switched off by endogenous protein kinases. Caged cofilin, and its irradiated counterpart, display the anticipated F-actin depolymerization and severing activities.     

Ethylene polymerization catalyzed by substituted pyrazole nickel complexes

(Pyrazole)nickel dibromide complexes, (3,5-Me₂pz)₂NiBr₂ (1), (3-Mepz)₄NiBr₂ (2), (pz)₄NiBr₂ (3) and (3,5-^tBu₂pz)₂NiBr₂ (4), were prepared by the reaction of the appropriate pyrazole with (DME)NiBr₂. Solid-state structures of these complexes show a direct relation between the steric bulk of the pyrazole ligand and structure, with more bulky ligands forming four-coordinate complexes (1 and 4) whereas the less bulky ligands formed six-coordinate complexes (2 and 3). Activation of selected complexes (1 and 3) with methylaluminoxane (MAO) produced species that catalyzed the polymerization of ethylene to form high density polyethylene.     

Transformations of tetrahydrobenzo[b][1,6]naphthyridines and tetrahydropyrido[4,3-b]pyrimidines under the action of dimethyl acetylene dicarboxylate

10-Cyanotetrahydrobenzo[b][1,6]naphthyridines 3, 4 undergo addition of DMAD, followed by a Stevens rearrangement of the intermediate ylide to yield methyl dioates 8 and 9. An alternative transformation sequence starts with migration of the dimethyl butenedioate anion to the carbon of the CN group, followed by the addition of 1 mol of water, to provide succinates 10 and 11. In contrast, tetrahydropyrido[4,3-b]pyrimidines 5-7 undergo a tandem cleavage process, involving one molecule of solvent. The resulting enamines are easily cleaved by strong acids, to give dihydropyrymidinylethylamines, which are scarcely available by other synthetic means.     

Synthesis,structure, and evaluation of the effect of multiple stacking on the electron-donor properties of pi-stacked polyfluorenes

A versatile synthesis of pi-stacked polyfluorenes is described. These polyfluorenes retain their cofacial conformations both in solution and in the solid state as was judged by NMR spectroscopy and X-ray crystallography. The experimental electron-detachment energies of F1-F4 showed linear correlations with the quantity 1/n, where n is the number of fluorene moieties. These correlations allowed the estimation of the vertical ionization potential (IP) of 7.10 eV and the oxidation potential (Eox) of 0.97 V versus SCE for the multiply stacked polyfluorene donor with an infinite number of fluorene moieties. These observations with pi-stacked polyfluorenes may prove to be highly relevant to the electron-transport phenomenon observed in DNA through pi-stacked bases.     

Formation of a paramagnetic Al complex and extrusion of Fe during the reaction of (diiminepyridine)Fe with AlR3 (R = Me, Et)

The reaction of the {2,6-[2,6-(iPr)2PhN=C(CH3)]2(C5H3N)}FeCl2 catalyst precursor with R3Al [R = Me, Et] afforded {2,6-[2,6-(iPr)2PhN=C(CH3)]2(C5H3N)}AlMe2 (1) and [eta4-LAl2Et3(mu-Cl)]Fe-(eta6-C7H8) (2), respectively. These paramagnetic species arises from both transmetalation, during which the strong terdentate ligand loses the Fe center, and reduction. The extent of reduction depends on the nature of the Al alkylating agent. The electrons necessary for the reduction are likely to be provided by cleavage of Fe-C bond of transient low-valent organo-Fe species.     

Structural isomers of aryl-substituted eta(3)-propargyl complexes: eta(2)-1-Metalla(methylene)cyclopropene and eta(3)-benzyl complexes

Hydride abstraction from C(5)Me(5)(CO)(2)Re(eta(2)-PhC triple bond CCH(2)Ph) (1) gave a 3:1 mixture of eta(3)-propargyl complex [C(5)Me(5)(CO)(2)Re(eta(3)-PhCH-C triple bond CPh)][BF(4)] (5) and eta(2)-1-metalla(methylene)cyclopropene complex [C(5)Me(5)(CO)(2)Re(eta(2)-PhC-C=CHPh)][BF(4)] (6). Observation of the eta(2)-isomer requires 1,3-diaryl substitution and is favored by electron-donating substituents on the C(3)-aryl ring. Interconversion of eta(3)-propargyl and eta(2)-1-metalla(methylene)cyclopropene complexes is very rapid and results in coalescence of Cp (1)H NMR resonances at about -50 degrees C. Protonation of the alkynyl carbene complex C(5)Me(5)(CO)(2)Re=C(Ph)C triple bond CPh (22) gave a third isomer, the eta(3)-benzyl complex [C(5)Me(5)(CO)(2)Re[eta(3)(alpha,1,2)-endo,syn-C(6)H(5)CH(C triple bond CC(6)H(5))]][BF(4)] (23) along with small amounts of the isomeric complexes 5 and 6. While 5 and 6 are in rapid equilibrium, there is no equilibration of the eta(3)-benzyl isomer 23 with 5 and 6.     

Zirconium, hafnium, and tantalum amide silyl complexes: their preparation and conversion to metallaheterocyclic complexes via gamma-hydrogen abstraction by silyl ligands

New transition metal silyl amide complexes (Me(2)N)(3)Ta[N(SiMe(3))(2)](SiPh(2)Bu(t)) (1) and (Me(2)N)M[N(SiMe(3))(2)](2)(SiPh(2)Bu(t)) (M = Zr, 2a, and Hf, 2b) were found to undergo gamma-H abstraction by the silyl ligands to give metallaheterocyclic complexes (3) and (M = Zr, 4a, and Hf, 4b), respectively. The conversion of 1 to 3 follows first-order kinetics with DeltaH() = 23.6(1.6) kcal/mol and DeltaS() = 3(5) eu between 288 and 313 K. The formation of 4a from (Me(2)N)Zr[N(SiMe(3))(2)](2)Cl (5a) and Li(THF)(2)SiPh(2)Bu(t) (6) involves the formation of the intermediate 2a, followed by gamma-H abstraction. Kinetic studies of these consecutive reactions, a second-order reaction to give 2a and then a first-order gamma-H abstraction to give 4a, were conducted by an analytical method and a numerical method. At 278 K, the rate constants k(1) and k(2) for the two consecutive reactions are 2.17(0.03) x 10(-)(3) M(-)(1) s(-)(1) and 5.80(0.15) x 10(-)(5) s(-)(1) by the analytical method. The current work is a rare kinetic study of the A + B --> C --> D (+ E) consecutive reactions. Kinetic studies of the formation of a metallaheterocyclic moiety have, to our knowledge, not been reported. In addition, gamma-H abstraction by a silyl ligand to give such a metallaheterocyclic moiety is new. Theoretical investigations of the gamma-H abstraction by silyl ligands have been conducted by density functional theory calculations at the Becke3LYP (B3LYP) level, and they revealed that the formation of the metallacyclic complexes through gamma-H abstraction is entropically driven. X-ray crystal structures of (Me(2)N)(3)Ta[N(SiMe(3))(2)](SiPh(2)Bu(t)) (1), (Me(2)N)Zr[N(SiMe(3))(2)](2)Cl (5a), and (M = Zr, 4a, and Hf, 4b) are also reported.     

Synthesis and characterization of dimetallic oxorhenium(V) and dioxorhenium(VII) compounds, and a study of stoichiometric and catalytic reactions

Chelating dithiolate ligands--e.g., mtp from 2-(mercaptomethyl)thiophenol, edt from 1,2-ethanedithiol, and pdt from 1,3-propanedithiol--stabilize high-valent oxorhenium(V) against hydrolytic and oxidative decomposition. In addition to the dithiolate chelating to a single rhenium, one sulfur forms a coordinate bond to the other rhenium. In one arrangement this gives a dimer with a nearly planar diamond core with different internal Re-S distances. The new compounds are [MeReO(edt)](2) (2) and [MeReO(pdt)](2) (3), which can be compared to the previously known [MeReO(mtp)](2) (1). Another mode of synthesis leads to [ReO](2)(mtp)(3) (5) and [ReO](2)(edt)(3) (6). They, too, have similar Re(2)S(2) cores that involve donor atoms from two of the dithiolate ligands; the third dithiolate chelates one of the rhenium atoms. Gentle hydrolysis of 1 affords [Bu(n)4][[MeReO(mtp)](2)(mu-OH)] (7) in low yield. It appears to be the first example of this structural type for rhenium. The use of dithioerythritol as a starting material allowed the synthesis of a dioxorhenium(VII) compound, [MeReO(2)](2)(dte) (8). Its importance lies in understanding the role such compounds are believed to play as intermediates in oxygen atom catalysis. Ligation of the dimers 1-3 converts them into monomeric compounds, MeReO(dithiolate)L. These reactions go essentially to completion for L = PPh(3), but reach an equilibrium for L = NC(5)H(4)R. With R = 4-Ph, the values of K/10(3) L mol(-1) for the reactions (1-3) + 2L = 2MeReO(dithiolate)L are identical within 3 sigma: 1.15(3) (1), 1.24(4) (2), and 1.03(16) (3). The rates of monomer formation follow the rate law -d ln [dimer]/dt = k(a)[L] + k(b)[L](2). These trends were found: (1) phosphines are slow to react compared to pyridines, (2) the edt dimer 2 reacts much more rapidly than 1 and 3. Dimer 1 and MeReO(mtp)PPh(3) both catalyze oxygen atom transfer: PicO + PPh(3) --> Pic + Ph(3)PO. Compound 1 is ca. 90 times more reactive, which can be attributed to its lability toward small ligands as opposed to the low rate of displacement of PPh(3) from the mononuclear catalyst. The kinetics of this reaction follows the rate law -d[PicO]/dt = k[PicO][1]/[1 + kappa[PPh(3)]], with k = 5.8 x 10(6) L mol(-1) s(-1) and kappa = 3.5 x 10(2) L mol(-1) at 23 degrees C in benzene. A mechanism has been proposed to account for these findings.