Interaction of Pd(II) and Pt(II) Amino Acid Complexes With Dinucleotides

The interaction of the dinucleotides d(ApG) and d(ApA) with [Pd(aa)Cl(2)], where aa = L- or D-histidine or the methyl ester of L-histidine, and with [Pt(Met)Cl(2)], where Met = L-methionine was studied by (1)H and (13)C NMR and CD measurements. In the case of the L-histidine and L-histidineOMe, the reaction with d(ApG) appeared to give the bifunctional adducts Pd(L-Histidine)N1(1)N7(2) and Pd(L-HisOMe)N1(1)N7(2), but the behavior with D-histidine suggested the formation of the monofunctional adduct Pd(D-His)N7(2). The reaction of L-histidine with d(ApA) seemed to form the bimetallic adduct (L-His)PdN7(1)N7(2)Pd(L-His). The Pt(II)-L-methionine complex in both reactions with d(ApG) and d(ApA) seemed to yield mainly adducts Pt(L-Met)N7(1)N7(2) but the existence of adducts Pt(L-Met)N1(1)N7(2) cannot be ruled out.     

Reactions of organic disulfides and gold(i) complexes

Gold-thiolate/disulfide exchange reactions of (p-SC(6)H(4)Cl)(2) with Ph(3)PAu(SC(6)H(4)CH(3)), dppm(AuSC(6)H(4)CH(3))(2), and dppe(AuSC(6)H(4)CH(3)) (2) were investigated. The rate of reactivity of the gold-thiolate complexes with (p-SC(6)H(4)Cl)(2) is: dppm(AuSC(6)H(4)CH(3))(2)> dppe(AuSC(6)H(4)CH(3))(2)>Ph(2)PAu (SC(6)H(4)CH(3)). This order correlates with conductivity measurements and two ionic mechanisms have been evaluated. (1)H NMR experiments demonstrate that in the reaction of dppm(AuSC(6)H(4)CH(3))(2) with (p-SC(6)H(4)Cl)(2), the mixed disulfide, ClC(6)H(4)SSC(6)H(4)CH(3), forms first, followed by the formation of (p-SC(6)H(4)CH(3))(2). The rate law is first order in (pp-SC(6)H (4)Cl)(2) and partial order in dppm(AuSC(6)H(4)CH(3))(2). Results from electrochemical and chemical reactivity studies suggest that free thiolate is not involved in the gold-thiolate/disulfide exchange reaction. A more likely source of ions is the dissociation of a proton from the methylene backbone of the dppm ligand which has been shown to exchange with D(2)O. The implications of this are discussed in terms of a possible mechanism for the gold-thiolate/disulfide exchange reaction.     

Synthesis of the Sulphonate and Phosphonate Derivatives of Mercaptoacetyltriglycine. X-Ray Crystal Structure of Na(2)[ReO(Mercaptoacetylglycylglycylaminomethanesulphonate)].3H(2)O

Mercaptoacetyltriglycine forms complexes with (186/188)Re and (99m)Tc radionuclides that are useful in nuclear medicine because they are substrates of the renal anion transport system. However, the renal clearance of [MO(MAG(3))](2-)(MAG(3) = penta-anionic form of mercaptoacetyltriglycine, M = Re, Tc) complexes are less than ideal. Organic sulphonates are also transported by the renal anion transport system and phosphonates are similar to sulphonates in size and shape. In an effort to develop new ligands that form Re and Tc complexes and have improved renal clearances compared to [MO(MAG(3))](2-) complexes, the sulphonate and phosphonate derivatives of mercaptoacetyltriglycine were synthesized. The dianion [ReO(MAG(2)-AMS)](2-) (MAG(2)-AMS = penta-anionic form of mercaptoacetylglycylglycylaminomethanesulphonic acid) was prepared for characterization by exchange reaction of ReOCl(3)(Me(2)S)(OPPh(3)) and isolated as the disodium salt. The structure of Na(2)[ReO(MAG(2)-AMS)].3H(2)O (6) was determined by X-ray diffraction. The coordination geometry is pseudo square pyramidal, with the nitrogen and sulfur donor atoms forming a square base and the oxo ligand at the apex. The deprotonated sulphonate group has a syn conformation with respect to the oxo ligand. The renal clearances of [(99m)TcO(MAG(2)-AMS)](2-) and [(99m)TcO(MAG(2)-AMP)](3-) were similar in rats and suggest that the difference in total charge between the SO(3) (-) and PO(3) (2-) groups is not important to renal clearance. However, their renal clearances were 40-50% less than that of [(99m)TcO(MAG(3))](2-) suggesting that the size and shape of the large tetrahedral SO(3) (-) and PO(3) (2-) groups of [(99m)TcO(MAG(2)-AMS)](2-) and [(99m)TcO(MAG(2)-AMP)](3-) inhibit recognition by the renal transport system compared to the small planar CO(2) (-) group of [(99m)TcO(MAG(3))](2-).     

Structure Determination and Anti-Inflammatory Activity of some Purine Complexes

Organomercury(II)-purine derivatives of the type, p-MeOC(6)H(4)HgL(1) (I), p-NO(2)C(6)H(4)HgCl(L(2))(II), p-MeC(6)H(4)HgCl(L(3))(III) and p-NO(2)C(6)H(4)HgCl(L(3))(IV) [ HL(1) = theophylline, L(2) = theobromine, L(3) = caffeine] have been synthesised and characterised on the basis of spectral studies (IR, UV, (1)H & (13)C NMR). The complexes have been screened for anti-inflammatory activity.     

Redox Chemistry and [Au(CN)(2)] in the Formation of Gold Metabolites

The role of hypochlorite ion, which can be generated by the enzyme myleoperoxidase, in the biochemistry of gold(I) anti-arthritic drugs was investigated. Sodium hypochlorite (OCl(-)) directly and rapidly oxidizes AuSTm, Au(CN)(2) (-), AuSTg (gold thioglucose) and auranofin (Et(3)PAuSATg). The resulting gold(III) species were detected by an Ion Chromotography Ion-Pairing technique that was developed to distinguish gold(I) and gold(III). Formation of Au(III) was also demonstrated spectrophotometrically after the conversion to AuCl(4) (-). The reactions of AuSTm, AuSTg, and auranofin are complex and gold(III) appears only after the initial oxidation of the thiolate (and phosphine) ligands.The enzymatic reaction, using MPO with H(2)O(2) and Cl(-) as substrates, leads to slow oxidation of Au(CN)(2) (-), AuSTm or AuSTg. The extent and rate of reaction depend on the concentrations of MPO, H(2)O(2), and Au(I). The continued presence of Au(I) during the initial stages of reaction (oxidation of the thiolates in AuSTm and AuSTg) and the conversion to Au(III) in the latter stages of the reaction were demonstrated. Au(CN)(2) (-), a gold metabolite, binds tightly to serum albumin. Unlike other gold(I) complexes, aurocyanide reacts almost negligibly at Cys-34 via ligand exchange. Instead, there is a strong association (K(1) = 5.5 x 10(4) and K(2) = 7.0 x 10(3); n(1) = 0.8 and n(2) = 3) of intact Au(CN)(2) (-). The full extent of binding is revealed only by equilibrium methods such as NMR or ultrafiltration; the bound gold dissociates extensively on conventional gel-exclusion columns and partially on Penefesky spun columns.The immunological and pharmacological significance of these results are discussed.     

Synthesis and "in Vitro" Trypanocidal Activity Evaluation of Some Organo-iron Compounds

Eight organo-iron ferrocene derivatives and arenocenium salts were prepared and evaluated by "in vitro" assay against one strain of Trypanosoma cruzi (Y). Six of the eight organo-iron compounds assayed, piperazinium diferrocenoate 1, eta(6)-(o-xylene)-eta(5)-(cyclopentadienyl) Iron(II) hexafluorophosphate 3, eta(6)-(mesitylene)-eta(5)-(cyclopentadienyl) iron(II) hexafluorphosphate 5, eta(6)-(durene)-eta(5)-(cyclopentadienyl) iron(II) hexafluorphosphate 6, eta(6)-(rho-chlorotoluene)-eta(5)-(cyclopentadienyl) Iron(II) hexafluorphosphate 7 and eta(6)-(chlorobenzene)-eta(5)-(cyclopentadienyl) iron(II) picrate 8 , were poorly active in the "in vitro" assays. Only two compounds 1,1'-(N-pyperidinocarbonyl) ferrocene 2(IC(50)=2.4 mug/mL) and eta(6)-(o-xylene)-eta(5)(cyclopentadienyl) iron(II) picrate 4 (IC(50)=12.08 mug/mL), were more active. Thus, some of the compounds are promising to be used against Chagas' disease as a prophylactic agents.     

Anionic Pd(0) and Pd(II) intermediates in palladium-catalyzed Heck and cross-coupling reactions

The anions of PdCl(2)L(2) and Pd(OAc)(2), precursors of palladium(0) used in cross-coupling and Heck reactions, play a crucial role in these reactions. Tricoordinated anionic complexes Pd(0)L(2)Cl(-) and Pd(0)L(2)(OAc)(-) are the effective catalysts instead of the usually postulated Pd(0)L(2) complex. The anion ligated to the palladium(0) affects the kinetics of the oxidative addition to ArI as well as the structure and reactivity of the arylpalladium(II) complexes produced in this reaction. Thus, pentacoordinated anionic complexes are formed, ArPdI(Cl)L(2)(-) or ArPdI(OAc)L(2)(-), the precursor of neutral trans-ArPd(OAc)L(2), instead of the usually postulated trans-ArPdIL(2) complex (L = PPh(3)).     

碳包覆对LiNi_(0.5)Mn_(1.5)O_4电化学性能的影响

以蔗糖为碳源,采用溶液沉积-真空热解法制备了LiNi_(0.5)Mn_(1.5)O_4/C复合材料。用热重与差热分析、X射线衍射分析、扫描电镜分析及电化学测试等手段对LiNi_(0.5)Mn_(1.5)O_4/C的微观结构、表面形貌和电化学性能进行了研究。结果表明,蔗糖热分解后在LiNi_(0.5)Mn_(1.5)O_4颗粒的表面包覆形成了一层无定形碳。无定形碳可以有效阻止LiNi_(0.5)Mn_(1.5)O_4颗粒的聚集,增加电极的导电面积,降低电池极化,从而改善LiNi_(0.5)Mn_(1.5)O_4的电化学性能。与未包覆的LiNi_(0.5)Mn_(1.5)O_4粉末相比,LiNi_(0.5)Mn_(1.5)O_4/C复合材料具有更高的可逆容量、更稳定的循环性能和更好的倍率性能。0.2C放电时,LiNi_(0.5)Mn_(1.5)O_4/C复合材料的首次放电容量达到144.8mA.h.g-1,经60次循环后平均每次循环的容量损失仅为0.0081%。而1.0C和2.0C放电时,LiNi_(0.5)Mn_(1.5)O_4/C复合材料的首次放电容量分别保持在131.9mA.h.g-1和122.4mA.h.g-1。     

Metallation of Isatin (2,3-Indolinedione). X-Ray Structure and Solution Behavior of Bis(Isatinato)Mercury(II)

The first X-ray structure of an isatin (2,3-indolinedione, isaH) metal complex, bis(isatinato)memury(II) (C(16)H(8)N(2)O(4)Hg) (1), was determined. (1) was obtained from the reaction of isaH with mercury(II) acetate in methanol. Analogously, treatment of sodium saccharinate and mercury(II) acetate in methanol yielded Hg(saccharinato)(2) (*)0.5CH(3)OH (3). (1) crystallizes in the monoclinic system, space group P2(1)/ a with a = 7.299(1) A, b = 8.192(1) A, c = 11.601(1) A , beta = 105.82(1) degrees , V = 667.4 A(3), Z = 2, D(calc) = 2.452 g cm(-3), MoKalpha radiation(lambda = 0.71073 A), mu = 115.5 cm(-1), F(000) = 460, 21(1) degrees C. The structure was refined on the basis of 2023 observed reflections to R= 0.044. The two deprotonated, non coplanar isa ligands are trans to each other in a head to tail orientation and bound to the Hg through the nitrogen in a linear N-Hg-N arrangement. The Hg atom is at the center of symmetry of the complex and displaced by 0.62 A from the two planes of the isa ligands (tau Hg-N1-C2-O2= -16 degrees ). The Hg-N bond length is 2.015 A. Nopi-aryl-memury(ll)-pi-aryl stacking interaction was observed either in the solid state or in the solution state. The IR, electronic, and (1)H and (13)CNMR spectral data of (1) and (3) suggest binding of the memury to the heterocyclic nitrogen, in agreement with the crystal structure determination of (1).     

Toxicity of Certain Penta-Coordinated Organotin(IV) and Tetra-Coordinated Tin(II) Complexes of Heterocyclic beta-Diketones Against the Larvae of Aedes Aegypti (Liston)

Some organotin(IV) and tin(II) complexes of composition R(3)Sn[R'COC:CON(C(6)H(5))N:CCH(3)] (where R=C(4)H(9), R'=CH(3), C(3)H(5), p-ClC(6)H(4); R=C(6)H(5), R'=C(6)H(5) and p-ClC(6)H(4)) and Sn[p-ClC(6)H(4)COC:CON(C(6)H(5))N:CCH(3)](2) were screened for their toxicity against Aedes aegypti larvae. Organotin(IV) complexes were more active than tin(II) complexes.     

Formation mechanism for hexagonal-structured self-assemblies of nanocrystalline titania templated by cetyltrimethylammonium bromide

Hexagonal-structured self-assemblies of nanocrystalline (anatase) titania templated by cetyltrimethylammonium bromide (C(16)H(33)N(CH(3))(3)Br; CTAB) (Hex-ncTiO(2)/CTAB Nanoskeleton) were formed after mixing of aqueous solutions containing CTAB spherical micelles and titanium oxysulfate acid hydrate (TiOSO(4).xH(2)SO(4).xH(2)O) as a titania precursor in the absence of any other additives. Formation mechanism of the Hex-ncTiO(2)/CTAB Nanoskeleton was examined in terms of the reaction temperature, titania precursor/CTAB mixing ratio, surfactant type, electrostatic interaction, micelle formation and molecular component. We found that crystal growth of crystalline (anatase) titania (polymorphic crystallization) was promoted with higher temperature and lower titania precursor content in aqueous solutions. In addition, we revealed that the crystalline (anatase) titania was formed in polycation, poly(allylamine hydrochloride ([CH(2)CH(CH(2)NH(2))HCl](n); PAH), and formamide (HCONH(2)) solutions. On the other hand, no titania formation was observed in anionic systems such as sodium dodecyl sulfate (CH(3)(CH(2))(11)OSO(3)Na; SDS) and poly(sodium 4-styrenesulfonate ([C(8)H(7)SO(3)Na](n); PSSS). This indicates that hydrolysis reaction of the titania precursor is initiated by not only cations but also nitrogen atoms in molecules and polymers. Hexagonally structure was formed in only cationic surfactant micellar solutions but not in polycation solutions and formamide.     

Controlled synthesis and optical spectroscopy of lanthanide-doped KLaF₄ nanocrystals

KLaF(4), as a good host matrix for trivalent lanthanide (Ln(3+)) ions to fabricate upconversion (UC) or downconversion (DC) phosphors, has been rarely reported. Herein, monodisperse (～10 nm) cubic-phase Ln(3+)-doped KLaF(4) nanocrystals (NCs) were synthesized via a facile thermal decomposition method. Upon excitation at 980 nm, UC luminescence properties of KLaF(4):Ln(3+)/Yb(3+) (Ln = Tm, Ho, Er) NCs were comprehensively surveyed. Particularly, after coating an inert KLaF(4) shell, the green and red UC luminescence intensity of KLaF(4):Er(3+)/Yb(3+) NCs was enhanced ～35 times, and the corresponding UC lifetimes of (4)S(3/2) and (4)F(9/2) levels of Er(3+) were observed significantly prolonged from 42 and 68 μs in core-only NCs to 87 and 136 μs in core/shell counterparts. Furthermore, intense DC luminescence was also achieved in Ce(3+)/Tb(3+) and Eu(3+) doped KLaF(4) NCs, with absolute quantum yields of 39.8% (Tb(3+)) and 17.3% (Eu(3+)). The luminescence lifetimes of (5)D(0) (Eu(3+)) and (5)D(4) (Tb(3+)) were determined to be 4.2 and 4.7 ms, respectively. Water-soluble Ln(3+)-doped KLaF(4) NCs featuring excellent monodispersion, long luminescence lifetime, and high UC/DC efficiency may have versatile and promising applications as luminescent nano-biolabels.     

Synthesis and physiological activity of ureas and amides with carvone residues

The synthesis and herbicidal activity of ureas and amides with carvone residues were examined. (S)-(+)-(1) and (R)-(-)-Carvone(2) were converted to the respectively, primary amines(3) and (4) by oximation and reduction with LiAlH(4). Primary amine derivatives were further converted into the urea and amide compounds (3a) approximately (3e) and (4a) approximately (4e). The herbicidal activity of products (3a) approximately (3e) and (4a) approximately (4e) towards weeds found in a paddy field and field was measured in the pot. Products (3a) showed a particularly strong inhibitory effect on the growth of Amaranthus retroflexus(AR) and Setaria viridis(SV).     

Synthesis and physiological activity of thiophenes and furans with 3- and 4-methoxyacetophenone derivatives

The synthesis and physiological activity of thiophenes and furans with methoxyacetophenone derivatives were examined. 3-Methoxyacetophenone (1) and 4-methoxyacetophenone (2) were converted, respectively, to the oximes (3) and (4) by oximation with hydroxylamine hydrochloride, and to the primary amines (5) and (6) by reduction with LiAlH(4). The primary amine derivatives were further converted into the thiophene and furan compounds (5a) approximately (5h) and (6a) approximately (6h), respectively. Bioassay of these compounds (5a) approximately (5h) and (6a) approximately (6h) on the germination of lettuce(Lactuca satiba) seeds showed that compound (5b) exhibits growthpromoting activity.     

Alternative Modes of Addition of Electrophilic Olefins to the Vinylcyclopropane Systems in 2,2-Ethano-1-Methylene-1,2,3,4-Tetrahydronaphthalene and 1,1-Ethano-2-Methylene-1,2,3,4-Tetrahydronaphthalene

The title compounds 2,2-ethano-1-methylene and 1,1-ethano-2-methylene-1,2,3,4-tetrahydronaphthalene ( 13 and 14 respectively) were synthesized by the Wittig reaction from the corresponding ethano-tetralones ( 16 ) and ( 19 ) which were, in turn, prepared from the respective α- and β-tetralones ( 15 ) and ( 18 ). It is shown that the reaction of ( 13 ) with TCNE at 0° yields the corresponding [2 + 2] cycloaddition adduct ( 20 ), isomerizing thermally to the formal [2 + 5] cycloaddition adduct ( 21 ). Compound ( 13 ) reacts with N-tosylisocyanate (TIC) and with N-phenylsulfonylisocyanate (PSI) to a 4:1-isomeric mixture of (Z)- and (E)-acryloamides ( 24 ) and ( 26 ), respectively. The reaction of ( 14 ) with TCNE at 0° leads to the [2 + 5] cycloadduct ( 30 ), while with (TIC) and (PSI) the corresponding tricyclic adducts ( 28a ) and ( 28b ) result. Bromination of ( 16 ) with NBS yielded the respective 4-bromo-2,2-ethano-1-tetralone ( 31 ) which gave, upon dehydrobromination with the aid of DBU, the naphtho-dihydrofurane derivative ( 34 ). The latter was formed most likely via facile cyclopropylketone upon dihydrofurane rearrangement of an initially formed 2,2-ethano-1-oxo-1,2-dihydronaphthalene ( 32 ) which was desired for the formation of ( 33 ). Structures of all new compounds were assigned on basis of analytical and spectroscopic data (IR, UV, mass spectra, ¹H-NMR).     

Behaviors of plutonium and neptunium in nitric acid solutions containing hydrazine and technetium ions

The valence behaviors of plutonium and neptunium in the interaction of Pu(IV) and Np(V) with hydrazine and tetravalent uranium in technetium(VII)-containing aqueous nitric acid are reported. At [HNO₃] = 1 mol/l and Pu(IV) and Tc(VII) concentrations of ～0.1 and 0.01–0.2 mol/l, respectively, Pu(IV) is reduced to Pu(III) and is then entirely reoxidized to Pu(IV). Neptunium(V) in 1–3 M HNO₃ undergoes reduction to Np(IV) and then turns back into Np(V). The resulting solution usually contains a mixture of Np(IV) and Np(V). The reduction of Pu(IV) to Pu(III) and the reduction of Np(V) to Np(IV) are accompanied by hydrazine decomposition and by the reduction of most of the Tc(VII) to its lower valence forms. The conversions of Pu(III) into Pu(IV) and of Np(IV) into Np(V) are accompanied by the oxidation of these forms of technetium to Tc(VII). The introduction of diethylenetriaminepentaacetic acid into the reaction system makes Pu(III) more stable against reoxidation into Pu(IV) by reducing the hydrazine decomposition rate, enhances the conversion of Np(V) into Np(IV), and hampers Np(IV) oxidation to Np(V).     

Developing Carrier Complexes for "Caged NO": RuCl(3)(NO)(H(2)O)(2) Complexes of Dipyridylamine, (dpaH), N,N,N'N'-Tetrakis (2-Pyridyl) Adipamide, (tpada), and (2-Pyridylmethyl) Iminodiacetate, (pida)

Delivery agents which can carry the {Ru(NO)}(6) chromophore ("caged NO") are desired for vasodilation and for photodynamic therapy of tumors. Toward these goals, complexes derived from [RuCl(3)(NO)(H(2)O)(2)]= (1) have been prepared using dipyridylamine (dpaH) as mono and bis adducts, [Ru(NO)Cl(3)(dpaH)] = (2) and [Ru(NO)Cl(dpaH)(2)]Cl(2) = (3). The dpaH ligands coordinate cis to the Ru(NO) axis.The mono derivative is a model for a potential DNA groove-spanning binuclear complex {[RuNO)Cl(3)](2)(tpada)} = (4) which has two DNA-coordinating Ru(II) centers, photo-labile {Ru(NO)}(6) sites, and a groove-spanning tether moiety.The binuclear assembly is prepared from the tethered dipyridylamine ligand N,N,N',N'-tetrakis(2-pyridylmethyl)adipamide (tpada) which has recently been shown to provide a binuclear carrier complex suited to transporting Ru(II) and Pd(II) agents. A related complex, [Ru(NO)Cl(pida)] = (5) with the {Ru(NO)}(6) moiety bound to (2-pyridylmethyl) iminodiacetate (pida(2-)) is also characterized as a potential "caged NO" carrier. Structural information concerning the placement of the pyridyl donor groups relative to the {Ru(NO)}(6) unit has been obtained from (1)H and (13)C NMR and infrared methods, noting that a pyridyl donor trans to NO+ causes "trans strengthening" of this ligand for [Ru(NO)Cl(pida)], whereas placement of pyridyl groups cis to NO+ causes a weakening of the N-O bond and a lower NO stretching frequency in the dpa-based complexes.     

Oligodeoxynucleotides containing 3-bromo-3-deazaadenine and 7-bromo-7-deazaadenine 2'-deoxynucleosides as chemical probes to investigate DNA-protein interactions

We describe the design and proof of concept of a pair of chemical probes for investigating DNA-protein interactions-specifically, the incorporation of 7-bromo-7-deazaadenine and 3-bromo-3-deazaadenine 2'-deoxynucleosides (Br(7)C(7)dA and Br(3)C(3)dA) into oligodeoxynucleotides (ODNs)-and their utility. Whereas the bromo substituent of the Br(7)C(7)dA unit in an ODN duplex acts sterically to inhibit binding with NF-kappaB, which interacts with the duplex in its major groove, the bromo substituent of the Br(3)C(3)dA unit acts sterically to inhibit binding with RNase H, which interacts with the duplex in its minor groove. In addition, the utilization of ODNs containing 7-deazaadenine and 3-deazaadenine 2'-deoxynucleosides (C(7)dA and C(3)dA), together with the pair of chemical probes, afforded valuable information on the requirement for nitrogen atoms located in either the major or minor grooves. Accordingly, we were able to show the utility of ODNs containing Br(7)C(7)dA, Br(3)C(3)dA, C(7)dA, and C(3)dA for the investigation of DNA-protein interactions.     

改性腐植酸新型阻垢缓蚀剂的制备及应用

采用溶液共混技术，制备了腐植酸钠（HA）和丙烯酰胺-烯丙基磺酸钠（SAS）共聚物（P(AM-SAS)的共混物（HA/P（AM-SAS）。与HA和P（AM-SAS）相比，HA/P（AM-SAS）共混物具有更好的阻垢，缓蚀和分散能力。当HA/P（AM-SAS）质量比超过1或2时，HA和P（AM-SAS）的共混对于CaCO3和Ca3(PO4)2的阻垢作用表现出了明显的协同效应。