Synthesis of Novel Bisphosphonate Inhibitors of Phosphoglycerate Kinase (3-PGK) (E.C.2.7.2.3)

Abstract

Novel, aromatic bisphosphonates have been synthesised as non-systematic analogues of 1,3-bisphosphoglyceric acid (1,3-BPG). These incorporate non-scissile α-halo and α-methylene phosphonates and have submicromolar K _i values for 3 -PGK.     

Mono and Bisphosphonates from Perfluoro Olefins and Polyfunctional Fluoro Ketones. Syntheses,Molecular Structure and Derivatives

Perfluoroalkenyl phosphonates were formed along with Me₃SiF using CF₃CF=CF₂, CF₃CH=CF₂, F₅SCF=CF₂ or F₅SCH=CF₂ and silylated phosphites, (R¹O)₂POSiMe₃ (R¹=Et, SiMe₃). This straightforward method could be extended to perfluorobutadienes CF₂=C(R^F)C(R^F)=CF₂ (R^F F=F, CF₃). The formation of CF₃C(=O)P(=O)(OSiMe₃)₂ and further reactions to yield bisphosphonates will be described. Acetylphosphonates, R²C(=O)P(=O)(OSiMe₃)₂ (R²=CH₃, CF₃) reacted with the ketimine, CH₃C(=NiPr)Ph to give α-hydroxy-γ-imino phosphonates. Trifluoroacetylphenol and 2,6-bis(trifluoracetyl)-4-methyl-phenol have been proven to be versatile precursors for α-and γ-hydroxy phosphonates. Intermediates in these reactions were found to be cyclic λ⁵σ⁵P species.     

Polycondensation of Tris(Trimethylsilylseleno)Phosphane

Abstract

Tris-(trimethylsilyl)phosphane and their organo substituted derivatives (Me₃Si)_3?nP(Me₃C)_n (n: 0, 1, 2) (la-c) had been found suitable for the insertion of selenium into the phosphorus-silicon bond. At deep temperatures all silylselenophosphanes of the series (Me₃SiSe)_3?nP(Me₃C_n) (2a-c) are formed in a nearly quantitative reaction, if no excess selenium is present. (Me₃C)(Me₃SiSe)₂P=Se (3b) and (Me₃C)₂(Me₃SiSe)P=Se (3c) are detectable in small quantities as the only by-products of the reaction of (Ib-c), whereas (la) end in the formation of (2a) and traces of the dimer (Me₃SiSe)₂P-P(SeSiMe₃)₂ (4). On exposure to light or at elevated temperatures (2a) undergoes a disproportionation, forming Se=P(SeSiMe₃)₃ (3a), and the heterocycles P₃Se₄(SeSiMe₃) (5) and α-P₄Se₃(SeSiMe₃)₂ (6). (Me₃Si)₂Se is spUt off as a condensation product. After further irradiation or prolonged standing at room temperature, an insoluble oligomer is formed. The constitutions of (2-6) were determined by the analysis of their ³¹P- and ⁷⁷Se-nmr spectra.     

The Reactivity of Hexafluorothioacetone and Hexafluoroacetone versus Phosphites

Abstract

The dimer of hexafluorothioacetone reacted with various phosphites to form thiophosphates and bis(trifluoromethyl)methylenphosphoranes, being unstable in the case of (Me₃SiO) P(OMe)_3-n, (n=1?3), where phosphonates (Me₃SiO)_n-1(MeO)_3-nP(O)[C(CF₃)=CF₂] (n=1-3) and Me₃SiF were observed. In general, cyclic phosphites behaved similar to acyclic ones. The resulting bis(trifluoromethyl)methylenphosphoranes were thermally stable except compound A, because of a new intramolecular fluorine transfer to phosphorus forming fluorophosphorane B.     

Synthesis of N-(alkoxycarbonyl or alkoxycarbonyl-methyl-alkoxyphosphonyl)-α-amino-O, O-diphenyl phosphonates and their bioactivities

With phosphonoformic acid (PFA) and its analog, phosphonoacetic acid (PAA), as the lead compounds, α-amino phosphonates were introduced into PFA and PAA. The derivatives of N-(alkoxycarbonyl-alkoxyphosphonyl)-α-amino phosphonates (I) and N-(alkoxycarbonyl-methyl-alkoxyphosphonyl)-α-amino phosphonates (II) with the N-terminal of amino phosphonates bonding to phosphorus atom of PFA andPAA were synthesized via the reaction of the corresponding phosphonyl chloride with α-amino phosphonates in the presence of a base. The³¹P NMR spectra of I and II were determined. It is found that the coupling constants³ J _pp with R³ being alkyl group were lower than those with R³ being (substituted) phenyl, and this result was discussed. The preliminary bioassay showed that some of the compounds I and II have better activities against tobacco mosaic virus (TMV). The inhibitory was higher than that of DHT (2, 4-dioxyhexahydro-1, 3, 5-triazine). In addition, some of the compounds showed the activity against cancer cells. Project supported by the National Natural Science Foundation of China.     

Phosphonic-Acid Analogues of the N-Acetyl-2-deoxyneiiraniinic Acids: Synthesis and Inhibition of Vibrio cholerae Sialidase

The phosphonic acids 3 and 4 were prepared to compare their inhibitory activity on Vibrio cholerae sialidase with the one of the corresponding N-acetyl-2-deoxyneuraminic acids 5 and 6 . Thus, hydrogenation and benzylation of methyl N-acetyl-2,3-didehydro-2-deoxyneuraminate (1MeNeu2en5Ac; 7) gave a mixture of the fully O-benzylated benzyl and methyl esters 9 and 10 , the partially O-benzylated benzyl and methyl esters 11 and 12 , and the fully O-and N-benzylated benzyl and methyl esters 13 and 14 (Scheme 1). Transesterification of 9 to 10 and hydrolysis of 10 gave the acid 15 . Oxidative decarboxylation of 15 with Pb(OAc)₄ gave a 1:9 mixture of the α-and β-D-glycero-D-galacto-acetates 16 and 17 . Phosphonoylation of 17 with P(OMe)₃ and Me₃SiOTf gave a 1.3:1 mixture of the phosphonates 18 and 19 , which were deprotected to give the (4-acetamido-2,4-dideoxy-D-glycero-α-and β-D-galacto-octopyranosyl)phosphonic acids 3 and 4 , respectively. The acid 6 was obtained by epimerization of the tert-butyl ester 23 with lithium N-cyclohexylisoproylamide and deprotection. The phosphonic acids 3 (K_i 5.5 10_-5 M) and 4 (K_i 2.3.10^?4 M ) are stronger inhibitors of Vibrio cholerae sialidase than the anomeric N-acetyl-2-deoxyneuraminic acids 5 (K_i 2.3 10^?3 M ) and 6 . Both 3 and 4 inhibit the Vibrio cholerae sialidase, while only the carboxylic acid 5 , possessing an equatorial COOH group is an inhibitor.     

Binary and Ternary Complexes of Copper(II) Involving N,N,N′,N′-Tetramethylethylenediamine (Me4en) and Various Biologically Relevant Ligands

Binary and ternary complexes of copper(II) involving N,N,N′,N′-tetramethylethylene-diamine (Me₄en) and various biologically relevant ligands containing different functional groups are investigated. The ligands (L) used are dicarboxylic acids, amino acids, peptides and DNA unit constituents. The ternary complexes of amino acids, dicarboxylic acids or peptides are formed by simultaneous reactions. The results showed the formation of Cu(Me₄en)(L) complexes with amino acids and dicarboxylic acids. The effect of chelate ring size of the dicarboxylic acid complexes on their stability constants was examined. Peptides form both Cu(Me₄en)(L) complexes and the corresponding deprotonated amide species Cu(Me₄en)(LH₋₁). The ternary complexes of copper(II) with (Me₄en) and DNA are formed in a stepwise process, whereby binding of copper(II) to (Me₄en) is followed by ligation of the DNA components. DNA constituents form both 1:1 and 1:2 complexes with Cu(Me₄en)²⁺. The concentration distribution of the complexes in solution was evaluated. [Cu(Me₄en)(CBDCA)] and [Cu(Me₄en)(malonate)] are isolated and characterized by elemental analysis and infrared measurements.     

Competing Pathways in the Photogeneration of Didehydrotoluenes from (Trimethylsilylmethyl)aryl Sulfonates and Phosphates

The scope of the photochemical generation of α,n‐didehydrotoluene diradicals from aryl sulfonates and phosphates and their chemistry are explored. The thermally inaccessible α,2‐ and α,4‐ intermediates are efficiently obtained by irradiation of ortho‐ and para‐(trimethylsilylmethyl)phenyl triflates through heterolytic splitting of the ester anion from the substrate in the triplet state. Triplet phenyl cations are formed and the loss of trimethylsilyl cation from them affords the desired diradicals (³Me₃SiCH₂C₆H₄‐OZ→³Me₃SiCH₂C₆H₄⁺→ ^? CH₂C₆H₄ ^? ). Triplet sensitization is required, for which acetone is used throughout. Direct irradiation leads, on the contrary, to photo‐Fries fragmentation (¹Me₃SiCH₂C₆H₄O‐Z→Me₃SiCH₂C₆H₄O ^? +Z ^? ). With mesylates, where ester cleavage is less convenient, a further competition from the triplet is direct desilylation. Didehydrotoluenes are also obtained from the corresponding phosphates, although with poor efficiency.     

Synthesis,structure, and reactivity of siloxides and germyloxides of iron(ii) and cobalt(ii)

Iron and cobalt siloxides and germyloxides [(Me₃Si)₃SiO]₂M (M = Fe (1), Co (2)), (Me₅Si₂O)₂Fe (3), (Prⁱ ₃SiO)₂M (M = Fe (4), Co (5)), (Prⁱ ₃GeO)₂Fe (6), (Ph₃SiO)₂Fe (7), (Me₃SiO)₂Fe (8), (Prⁱ ₃GeO)₂Fe(bpy) (9), and [(Me₃Si)₂NFe(-OSi₂Me₅)₂]₂Fe·C₆H₆ (10) were synthesized by the reactions of metal silylamides [(Me₃Si)₂N]₂M (M = Fe, Co) with the corresponding silanols or triisopropylgermanol. The reaction of pentamethyldisilanol with iron(ii) silylamide affords either polymeric complex 3 or coordination oligomer 10, depending on the ratio of the reactants. The structures of complexes 9 and 10 were established by X-ray diffraction analysis. The interaction of the prepared compounds with carbon oxides was studied. Low-coordination cobalt siloxide is the only among all prepared compounds that absorbs CO (2 mol) at room temperature and under 1 atm to form an unstable cluster. Compounds 1, 2, and 4—8 react with CO₂ to form carbonate complexes, and their reactivity decreases with a decrease in the electron-donating ability of the substituents at the central atom: (Me₃Si)₃SiO > Prⁱ ₃GeO Prⁱ ₃SiO > Me₃SiO Ph₃SiO.     

Enantioconvergent Reductive C(sp)−C(sp3) Cross-Coupling to Access Chiral α-Alkynyl Phosphonates Under Dual Nickel/Photoredox Catalysis

Transition-metal-catalyzed asymmetric carbon−carbon bond formation to forge phosphonates with an α-chiral carbon center through C(sp³)−C(sp³) and C(sp²)−C(sp³) couplings has been successful. However, the enantioselective C(sp)−C(sp³) coupling has not yet been disclosed. Reported herein is an unprecedented enantioconvergent cross-coupling of alkynyl bromides and α-bromo phosphonates to deliver chiral α-alkynyl phosphonates.     

Synthesis,characterization, DNA interaction,cytotoxicity, and apoptosis induction of a mixed-ligand copper(II) complex

A mixed-ligand complex, [Cu(Hptc)(Me₂bpy)(H₂O)]·3H₂O (1) (H₃ptc = pyridine-2,4,6-tricarboxylic acid; Me₂bpy = 4,4′-dimethyl-2,2′-dipyridine), has been synthesized and characterized by elemental analysis, IR, and single-crystal X-ray diffraction. In the discrete mononuclear structure of 1, the copper core is in a distorted octahedral environment (CuN₃O₃) derived from tridentate chelate Hptc^2?, bidentate chelate Me₂bpy and a coordinated water. The interaction of 1 with CT-DNA was investigated by UV–vis spectra, fluorescence spectra and viscosity, which reveals that 1 binds to CT-DNA by partial intercalation. Gel electrophoresis assay demonstrated that the complex displays efficient oxidative cleavage of supercoiled DNA with H₂O₂ as an oxidant. The in vitro cytotoxicity of 1 on HeLa cells was assessed by MTT and clonogenic assay, where IC₅₀ equals 4.24 ± 0.03 μM. Fluorescence microscopic observations indicated that 1 can induce apoptosis of HeLa cells.     

Unexpected results of the reactions of manganese and vanadium β-diketiminate halide complexes with Na[HBEt3]

The reaction of [(^Menacnac^Dipp)Mn(μ-Cl)]₂(2) (^Menacnac^Dipp = HC(C(Me)NDipp)₂; Dipp = 2,6-Prⁱ₂C₆H₃) with sodium triethylborohydride in a toluene—THF mixture afforded the complex [(^Menacnac^Dipp)Mn(μ-H)₂BEt₂(THF)] (3). The reaction of 2 with Na[HBEt₃] in toluene under THF-free conditions gave a mixture of products. The set and the ratio of these products in the resulting crystalline mixture were established by quantitative powder X-ray diffraction analysis: [(^Menacnac^Dipp)Mn(μ-H)]₂(1), [(^Menacnac^Dipp)?Mn(μ-H)₂BEt₂] (4), and unreacted compound 2 in the ratio of 15:4:1 and traces of an unknown crystalline phase. The reaction of [(^Menacnac^Dipp)VCl₂] (5) with Na[HBEt₃] yielded the compound [(^Menacnac^Dipp)V(μ-H)(μ,κ^1:1?C:C′?C₂H₄)BEt₂] (6) containing the unusual ligand [HBEt₂(CH₂CH₂)]^2?. The vanadium analog of compound 3, [(^Menacnac^Dipp)V(μ-H)₂BEt₂(THF)] (7), was isolated in one experiment. Besides. a small amount of the complex [(^Menacnac^Dipp)V(μ-H)BEt₃(THF)] (8) was detected in the mixture of crystalline products. The structures of compounds 3, 4, 6, 7, and 8 were determined by single-crystal X-ray diffraction.

     

Hydrogen-bonded mononuclear nickel(II) benzoate complexes: synthesis and structural studies

[Tp^Ph,MeNi(Cl)Pz^Ph,MeH] (1) has been synthesized by the reaction of hydrotris(3-phenyl-5-methyl-pyrazol-1-yl) borate [Tp^Ph,Me], NiCl₂ · 6H₂O and 3-phenyl-5-methyl-pyrazole [Pz^Ph,MeH]. The reaction of 1 with variously substituted sodium p–X–benzoates resulted in the formation of complexes of the type [Tp^Ph,MeNi(p–X–OBz)Pz^Ph,MeH] (X = H for 2, F for 3, Cl for 4, NO₂ for 5, Me for 6, OMe for 7, OH for 8, CHO for 9 and CN for 10). Single crystal X-ray studies suggest that all these complexes have a five-coordinate metal center and the benzoate groups are monodentate in a square pyramidal geometry. The X-ray studies also reveal that the uncoordinated oxygen atom of the benzoate forms intramolecular hydrogen-bonds with the NH group of the coordinated pyrazole. The substituents present on the benzoate ring are involved in different types of intermolecular interactions and the complexes exhibit different crystal packing. Complexes 2–10 were tested for superoxide dismutase activity. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Synthesis and structural characterization of nitrite-coordinating CoII and CoIII complexes as models for the reaction center of Co-substituted nitrite reductase

Co^II and Co^III complexes containing nitrite and tridentate aromatic amine compounds [bis(6-methyl-2-pyridylmethyl)amine (Me₂bpa) and bis(2-pyridylmethyl)amine (bpa)] have been prepared as models of the catalytic center in Co-substituted nitrite reductase: [Co^II(Me₂bpa)(NO₂)Cl]₂ · acetone (2), Co^II(Me₂bpa)(NO₂)₂ (3), Co^II(bpa)(NO₂)Cl (4), Co^II(bpa)(NO₂)₂ (5), Co^III(Me₂bpa)(NO₂)(CO₃) (6), and Co^III(bpa)(NO₂)₃ (7). The X-ray crystal structure analyses of these Co^II and Co^III complexes indicated that the geometries of the cobalt centers are distorted octahedral and the Me₂bpa and bpa with three nitrogen donors exhibit mer- (2, 3, and 7) and fac-form (4 and 6). The coordination mode of nitrite depends on the cobalt oxidation state, to Co^II through the oxygen (nitrito coordination, O- and O,O-coordination) and to Co^III through nitrogen (nitro coordination, N-coordination mode). These findings are consistent with the results of their IR spectra, except that another oxygen of the O-coordinated nitrito group in 3 might interact weakly with Co^II according to its IR spectrum. Reductions of the nitrite in 2, 3, 4, and 5 to nitrogen monoxide were not accelerated in the presence of proton, perhaps due to the nitrito coordination in these Co^II complexes.     

Iridium (III) and rhodium (III) triazoles by 1,3-dipolar cycloadditons to a coordinated azide in iridium (III) and rhodium (III) compounds

The reaction of [(η⁵-C₅Me₅)M(μCl)Cl]₂ with the ligand (L^∩L) in the presence of sodium methoxide yielded compounds of general formula [(η⁵-C₅Me₅)M(L^∩L)Cl] (1–10) (where M = Ir or Rh and L^∩L = N^∩O or O^∩O chelate ligands). Azido complexes of formulation [(η⁵-C₅Me₅)M(L^∩L)N₃] (11–20) have been prepared by the reaction of [(η⁵-C₅Me₅)M(μN₃)(X)]₂ (X = Cl or N₃) with the corresponding ligands or by the direct reaction of [(η⁵-C₅Me₅)M(L^∩L)Cl] with NaN₃. These azido complexes [(η⁵-C₅Me₅)M(L^∩L)N₃] undergo 1,3-dipolar cycloaddition reaction with substituted alkynes in CH₂Cl₂ and for the first time in ethanol at room temperature to yield iridium (III) and rhodium (III) triazoles (21–28). The compounds were characterized on the basis of spectroscopic data, and the molecular structures of 2 and 26 have been established by single crystal X-ray diffraction.     

The reaction of anthracenyl-α-hydroxyphosphonate with anthracene: Access to diverse (bis)-anthracenylmethylphosphonates as a suitable source for extensive π-conjugates

Abstract

Molecular anthracene has been used as an arene in the Friedel-Crafts (FC) type arylation reaction of anthracenyl-α-hydroxyphosphonate in the presence of acid. A diverse product formation is observed, in which anthracene unit is found to be linked through its C1 position with α-C of phosphonate. Interestingly, the molecular conformation (X-ray structure) of this phosphonate reveals one of the bond angles of a tetrahedral carbon as 118° which is close to the C of sp² character. Further, molecular anthracene is also recognized to attack at the C10 position of 9-anthracenylphosphonate through C1 or C2 or C9 atoms and the structures of three isomeric phosphonates are established with the help of ¹H and ³¹P NMR studies. The bis-anthracenyl compounds with a P-CH₂ unit have been successfully utilized in Horner-Wadsworth-Emmons (HWE) reactions to afford extensive bis-anthracenyl-linked π-conjugates.     

Methylbis(thiomethanolato)bismut(III) — Synthese,Charakterisierung und mikrobiologische Aktivität

The reaction of methyldibromobismuth(III),MeBiBr₂, with two equivalents of lithium thiomethanolate affords the new dithiolate complexMeBi(SMe)₂ (1). This compound is interesting in terms of its strong biological activity.¹H NMR and mass spectra of1 are discussed. As1 did not show characteristic metastable transitions in the MS under test conditions, ion genesis could partially be proved by using the isotopic labelled derivativeMe*Bi(SMe)₂ (1*) (Me*=¹³CH₃).

     

Routes to Higher Nuclearity Mixed-Metal Carbonyl Clusters Using the [Rh(η<Superscript>5</Superscript>-C<Subscript>5</Subscript>Me<Subscript>5</Subscript>)(NCMe)<Subscript>3</Subscript>]<Superscript>2+</Superscript> Dication as a Building Block

Reaction of the [Rh(η⁵-C₅Me₅)(NCMe)₃]²⁺ (1) dication with the hexaosmium [Os₆(CO)₁₇]²⁻ (2) dianion leads to the initial formation of [Os₆(CO)₁₇Rh(η⁵-C₅Me₅)] (3). This cluster readily adds CO to form [Os₆(CO)₁₈Rh(η⁵-C₅Me₅)] (4) which has been characterised crystallographically. 3 also adds dihydrogen to give [Os₆H₂(CO)₁₇Rh(η⁵-C₅Me₅)] (5) and undergoes a substitution reaction with PPh₃ to form [Os₆(CO)₁₆(PPh₃)Rh(η⁵-C₅Me₅)] (6). With the [Ru₆(CO)₁₈]²⁻ (7) dianion, [Rh(η⁵-C₅Me₅)(NCMe)₃]²⁺ (1) reacts to form three mixed-metal clusters [Ru₅(CO)₁₅Rh(η⁵-C₅Me₅)] (8), [Ru₆(CO)₁₈Rh(η⁵-C₅Me₅)] (9) and [Ru₆(CO)₁₈Rh₂(η⁵-C₅Me₅)₂] (10). The clusters have been characterised spectroscopically and the structures of 8 and 10 have been confirmed crystallographically. The cluster 8 undergoes a substitution reaction with P(OMe)₃ to form the disubstituted product [Ru₅(CO)₁₃(P(OMe)₃)₂Rh((η⁵-C₅Me₅)] (11) which has also been characterised crystallographically.     

Reactions of dimethyl(dimethylsulphoxide)pentamethylcyclopentadienyl-rhodium and -irridum with acids

The complexes [C₅Me₅MMe₂(Me₂SO)] (Ia, M = Rh; Ib, M = Ir) react with p-toluenesulphonic acid in acetonitrile to give [C₅Me₅MMe(Me₂SO)(MeCN)]⁺, (II), and with trifluoroacetic acid to give first [C₅Me₅MMe(Me₂SO)(O₂CCF₃)] and then [C₅Me₅M(Me₂SO)(O₂CCF₃)₂]. Complexes II react with halide (X^?) to give the halomethyl complexes [C₅Me₅MMe(X)(Me₂SO)]. The IR, far-IR, ¹H and ¹³C NMR spectra are all in agreement with structures proposed.     

Syntheses,characterizations and crystal structures of triorganotin(IV) complexes with amine derivatives of 6-amino-1,3,5-triazine-2,4-dithiol

Four new triorganotin(IV) complexes: Me₃SnL¹SnMe₃ (1), Ph₃SnL¹SnPh₃ (2), [Me₃SnL²] _n (3), Ph₃SnL²SnPh₃ (4) have been synthesized from 6-anilino-1,3,5-triazine-2,4-dithiol (L¹H₂) and 6-(dibutylamino)-1,3,5-triazine-2,4-dithiol (L²H₂). All were characterized by elemental analyses, IR and NMR spectra and X-ray diffraction analyses. Crystal structures show that 1, 2 and 4 are monomers with one ligand coordinated to two triorganotin moieties; complex 3 is a helical chain. Significant C–H ··· π, N–H ··· π interactions and intermolecular hydrogen bonds stabilize these structures.