Mechanism for the reactivation of the peroxidase activity of human cyclooxygenases: investigation using phenol as a reducing cosubstrate.

It has been known for many years that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro by the presence of phenol, which serves as a reducing compound, but the underlying mechanism is still poorly understood. In the present study, we use phenol as a model compound to investigate the mechanism by which the peroxidase activity of human COXs is reactivated after each catalytic cycle. Molecular docking and quantum mechanics calculations are carried out to probe the interaction of phenol with the peroxidase site of COXs and the reactivation mechanism. It is found that the oxygen atom associated with the Fe ion in the heme group (i.e., the complex of Fe ion and porphyrin) of COXs can be removed by addition of two protons. Following its removal, phenol can readily bind inside the peroxidase active sites of the COX enzymes, and directly interact with Fe in heme to facilitate electron transfer from phenol to heme. This investigation provides theoretical evidence for several intermediates formed in the COX peroxidase reactivation cycle, thereby unveiling mechanistic details that would aid in future rational design of drugs that target the peroxidase site.

Reactivity Study of a Pyridyl-1-azaallylgermanium(I) Dimer: Synthesis of Heavier Ether and Ester Analogues of Germanium.

The reactivity study of a pyridyl-1-azaallylgermanium(I) dimer LGe-GeL [1; L = N(SiMe3)C(Ph)C(SiMe3)(C5H4N-2)] with different stoichiometric ratios of elemental selenium and tellurium is described. The reactions of 1 with 1 equiv of selenium and tellurium afforded the first examples of heavier ether analogues of germanium, bis(germylene) selenide and telluride LGe(µ-E)GeL [E = Se (2) and Te (3)], respectively. Meanwhile, the reactions of 1 with 2 equiv of selenium and tellurium gave the heavier ester analogues LGe═E(µ-E)GeL [E = Se (4) and (5)]. All compounds have been characterized by X-ray crystallography and multinuclear NMR spectroscopy.

Synthesis and characterization of an octanuclear copper(I) methanediide cluster.

The reaction of [K{CH((i)Pr2P=S)2(C9H6N-2)}]n (1) with one equivalent of CuCl in THF afforded a rare octanuclear copper(I) methanediide cluster (3). The structure of compound 3 as determined by X-ray crystallography was found to have eight copper atoms that form a Gyrobifastigium (J26).

Synthesis and structural characterization of base-stabilized oligomeric heterovinylidenes.

Metalation of the (iminophosphoranyl)phosphine PPh2CH2(PPh2═NSiMe3) (1) with an equimolar amount of n-BuLi afforded the monolithium salt [Li{CH(PPh2)(PPh2═NSiMe3)}(THF)2] (2). The reaction of 2 with GeCl2·1,4-dioxane has led to the formation of a germavinylene moiety, which trimerized to form a new heterocyclic cage compound, [{(PPh2═NSiMe3)(PPh2)C═Ge:}{(PPh2═NSiMe3)(PPh2)C}2Ge→Ge:] (3). A similar reaction of the lithium methanide complex 2 with SnCl2 afforded the stannavinylidene moiety, which underwent a "head-to-tail" cycloaddition to form a stable 1,3-distannacyclobutane, 4. A trapping reaction of 4 with diiron nonacarbonyl gave the novel iron stannavinylidene complex 5. The solid-state structure analysis of 5 reveals that it contains two stannavinylidene moieties bonded in a Sn-P "head-to-tail" fashion, with one of the tin(II) centers coordinating to a Fe(CO)4 moiety. The X-ray structures of 2-5 have been determined by X-ray crystallography. In addition, the dynamic behavior of 5 has been studied by means of variable-temperature (31)P and (119)Sn NMR spectroscopy.

Synthesis of hetero-binuclear complexes from bisgermavinylidene.

Bisgermavinylidene [(Me3SiN═PPh2)2C═Ge→Ge═C(PPh2═NSiMe3)2] (1) has been used as a source of unstable germavinylidene for the synthesis of a series of heterobinuclear complexes. The reaction of 1 with stoichiometric amounts of transition metal chlorides MCl2 (M = Mn, Fe) yielded [(Me3SiN═PPh2)2(GeCl)CMn(µ-Cl)]2 (2) and [(Me3SiN═PPh2)2(GeCl)CFeCl] (3), respectively. Treatment of 1 with Me3SiN3 gave the [2 + 3] cycloaddition product [(Me3SiN═PPh2)2CGeN(SiMe3)N═N] (4). While similar reaction of 1 with ((n)Bu)3SnN3 ((n)Bu = n-butyl) and water-borane adduct H2O → B(C6F5)3 afforded the 1,2-addition products [(Me3SiN═PPh2){((n)Bu)3Sn}CPPh2NSiMe3GeN3] (5) and [HC(PPh2═NSiMe3)2Ge(OH)B(C6F5)3] (6), respectively. The results suggested that the germanium-carbon bond in germavinylidene is capable of forming addition reaction products. The X-ray structures of 2-6 have been determined.

Synthesis and structural characterization of a tin analogue of allene.

The reaction of [MgC(PPh(2)═S)(2)(THF)](2) (1; THF = tetrahydrofuran) with 1 equiv of SnCl(4) in THF afforded a novel tin analogue of allene [Sn{C(PPh(2)═S)(2)}(2)] (2). The structure of compound 2 has been characterized by X-ray crystallography and NMR spectroscopy.

Synthesis of a germanium analogue of a dithiocarboxylic acid anhydride from the Ge(i) pyridyl-1-azaallyl dimer.

The reaction of pyridyl-1-azaallyl germanium(ii) chloride RGeCl () [R = {N(SiMe(3))C(Ph)C(SiMe(3))(C(5)H(4)N-2)}] with lithium metal afforded the dimeric germanium(i) compound [(RGe)(2)] (); compound reacts with an excess of elemental sulfur to afford the novel germanium analogue of a dithiocarboxylic acid anhydride [{Ge(S)R}(2)S] () via the insertion of elemental sulfur into the Ge(i)-Ge(i) bond followed by the oxidative-addition of elemental sulfur to the germanium(ii) centres.

Synthesis of a manganese germavinylidene complex from bis(germavinylidene).

The reaction of bis(germavinylidene) [(Me3SiN=PPh2)2C=Ge-->Ge=C(PPh2=NSiMe3)2] (1) with CpMn(CO)2(THF) (Cp = eta5-C5H5) in THF afforded [(Me3SiN=PPh2)2C=Ge-->Mn(CO)2Cp] (2). Similar reaction of 1 with (cod)RhCl (cod = 1,5-cyclooctadiene) in THF gave [(Me3SiN=NPPh2)2{(cod)Rh}C-GeCl] (3). The results suggested that reactive germavinylidene may exist in solution. The X-ray structures of 2 and 3 have been determined.

A novel synthesis of metallogermacyclopropane and molybdenum bis(iminophosphorano)carbene complexes from bisgermavinylidene.

The reaction of bisgermavinylidene [(Me3SiN=PPh2)2C=Ge-->Ge=C(PPh2=NSiMe3)2] (1) with M(CO)5(THF) ( M = Cr, W, Mo) afforded the metallagermacyclopropane [(Me-3SiN=PPh2)2CGeM(CO)3[M(CO)5]] [M = W (2), Cr (3), Mo (4)]; in one of the reactions, compound 4 reacts further to give a "pincer" carbene complex [(CO)3Mo[C(Ph2P=NSi Me3)2]] (5); the X-ray structures of compounds 2 and 5 have been determined.

Bis(germavinylidene) [(Me3 SiN=PPh2 )2 C=Ge→Ge=C(Ph2 P=NSiMe3 )] and 1,3-Dimetallacyclobutanes [M{µ2 -C(Ph2 P=NSiMe3 )2 }]2 (M=Sn, Pb).

Low-valent metallavinylidenes :M=C/\ are scarce owing to the low stability of such species. Compound 1, prepared from [CH(Ph2 P=NSiMe3 )2 Li(thf)] and GeCl2 ⋅dioxane, represents the first stable bis(germavinylidene). The dimetallacyclobutanes 2 (M=Pb, Sn) were also prepared-they are believed to form by dimerization of the intermediate metallavinylidenes.