On the Synthesis of 1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is widely used as an intermediate in the preparation of medically important DO3A and DOTA metal chelators. Despite its commercial availability and importance, the literature describing the preparation and properties of the free base is limited and sometimes unclear. We present herein an efficient synthesis of the hydrobromide salt of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane, characterize this compound spectroscopically and by X-ray crystallographic analysis, describe its simple conversion to the corresponding free base, characterize this compound spectroscopically and by X-ray crystallographic analysis, and make observations on the reactivity of this interesting and useful compound.     

Rapid synthesis of 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester)

A three-step route was used to synthesize 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester) from 1,4,7,10-tetraazacyclododecane (cyclen). The overall time of reaction was reduced from a combined ∼56 h to 2.3 h with an overall yield comparable to previously reported methods.     

Synthesis and Crystal Structure of 1,4,7,10-Tetrakis （2-（（4-hydroxy）phenoxy）ethyl）-1,4,7,10- tetraazacyclododecane

A novel molecule tetra-N-alkylation of cyclen （1,4,7,10-tetraazacyclododecane）, 1,4,7,10-tetrakis（2-（（4-hydroxy）phenoxy）ethyl）-1,4,7,10-tetraazacyclododecane 2, was synthesized and structurally characterized by single-crystal X-ray diffraction. The molecule turned into chiral helical compound crystals grown from EtOH by slow diffusion at room temperature and three of the four hydroquinone groups of the benzene ring formed a g-electron-rich cavity by C-H…π stacking interaction. The crystal belongs to the monoclinic system, space group P21/C with a = 13.9192（9）, b = 13.2871（6）, c = 22.1894（15）A^°, β = 91.4600（10）°, V = 4102.5（4）A^°3, Z = 4, Dc = 1.219 g/cm^3, C40H52N4O8, Mr = 752.89, F（000） = 1616,μ = 0.088 mm^-1, MoKa radiation （λ = 0.71073）, R = 0.0578 and wR = 0.1389 for 5588 observed reflections with I 〉 2σ（I）. Moreover, compound 2 was characterized with ^1H NMR, ^13C NMR, IR spectra and MS.     

Synthesis, potentiometric, kinetic, and NMR Studies of 1,4,7,10-tetraazacyclododecane-1,7-bis(acetic acid)-4,10-bis(methylenephosphonic acid) (DO2A2P) and its complexes with Ca(II), Cu(II), Zn(II) and lanthanide(III) ions

A cyclen-based ligand containing trans-acetate and trans-methylenephosphonate pendant groups, H 6DO2A2P, was synthesized and its protonation constants (12.6, 11.43, 5.95, 6.15, 2.88, and 2.77) were determined by pH-potentiometry and (1)H NMR spectroscopy. The first two protonations were shown to occur at the two macrocyclic ring N-CH 2-PO 3 (2-) nitrogens while the third and fourth protonations occur at the two phosphonate groups. In parallel with protonation of the two -PO 3 (2-) groups, the protons from the NH (+)-CH 2-PO 3 (2-) are transferred to the N-CH 2-COO (-) nitrogens. The stability constants of the Ca (2+), Cu (2+), and Zn (2+) (ML, MHL, MH 2L, and M 2L) complexes were determined by direct pH-potentiometry. Lanthanide(III) ions (Ln (3+)) form similar species, but the formation of complexes is slow; so, "out-of-cell" pH-potentiometry (La (3+), Eu (3+), Gd (3+), Y (3+)) and competitive spectrophotometry with Cu(II) ion (Lu (3+)) were used to determine the stability constants. By comparing the log K ML values with those of the corresponding DOTA (H 4DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and DOTP (H 8DOTP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid) complexes, the order DOTA < DO2A2P < DOTP was found for all the metal ion complexes examined here with the exception of the Ca (2+) complexes, for which the order is reversed. The relaxivity of Gd(DO2A2P) decreases between pH 2 and 7 but remains constant in the pH range of 7 < pH < 12 ( r 1 = 3.6 mM (-1) s (-1)). The linewiths of the (17)O NMR signals of water in the absence and presence of Gd(DO2A2P) (at pH = 3.45 and 8.5) between 274 and 350 K are practically the same, characteristic of a q = 0 complex. Detailed kinetic studies of the Ce (3+) and Gd (3+) complexes with DO2A2P showed that complex formation is slow and involves a high stability diprotonated intermediate Ln(H 2DO2A2P)*. Rearrangement of the diprotonated intermediate into the final complex is an OH (-) assisted process but, unlike formation of Ln(DOTA) complexes, rearrangement of Ln(H 2DO2A2P)* also takes place spontaneously likely as a result of transfer of one of the protons from a ring nitrogen to a phosphonate group. The order of the OH (-) assisted formation rates of complexes is DOTA > DO2A2P > DOTP while the order of the proton assisted dissociation rates of the Gd (3+) complexes is reversed, DOTP > DO2A2P > DOTA. (1)H and (13)C NMR spectra of Eu(DO2A2P) and Lu(DO2A2P) were assigned using two-dimensional correlation spectroscopy (2D COSY), heteronuclear multiple quantum coherence (HMQC), heteronuclear chemical shift correlation (HETCOR), and exchange spectroscopy (EXSY) NMR methods. Two sets of (1)H NMR signals were observed for Eu(DO2A2P) characteristic of the presence of two coordination isomers in solution, a twisted square antiprism (TSAP) and a square antiprism (SAP), in the ratio of ~93% and ~7%, respectively. Line shape analysis of the (1)H NMR spectra of Lu(DO2A2P) gave lower activation parameters compared to La(DOTP) for interconversion between coordination isomers. This indicates that the Ln(DO2A2P) complexes are less rigid probably due to the different size and spatial requirements of the carboxylate and phosphonate groups.     

Synthesis and acid-base and complex-forming properties of 1,4,7,10-tetrakis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazacyclododecane

Conclusions A new complexone, 1,4,7,10-tetrakis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazacyclododecane, has been synthesized and its acid-base and complex-forming properties have been studied. It shows a very high complexing capability and marked selectivity for cations of large ionic radius (Cd²⁺, Hg²⁺, Pb²⁺, La³⁺).Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 844–849, April, 1984.     

Ion-pair interactions of lanthanide(III) complexes in aqueous solutions

The formation of ion-pair adducts between the cationic complex La(THP)3+ (THP = 1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane) and the anionic complexes Tm(DOTA)- (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetate), Tm(DTPA)2- (DTPA = diethylenetriamine-N,N,N',N",N"-pentaacetate), Tm(TTHA)3- (TTHA = triethylenetetraamine-N,N,N',N",N"',N"'-hexaacetate), and Tm(DOTP)5- (DOTP = 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetrakis(methylenephosphonate)) is examined by 13C NMR spectroscopy. The induced 13C shifts of the La(THP)3+ complex are followed by titration of the Tm(III) complexes of DOTA, DTPA, and TTHA at pH 7. From these data, the stability constants are calculated to be beta 1 = 64 M-1 (1:1), beta 1 = 296 M-1 (1:1), and beta 2 = 26,000 M-2 (2:1) for the ion pairs of La(THP)3+, with Tm(DOTA)-, Tm(DTPA)2-, and Tm(TTHA)3-, respectively. The La(THP)3+,Tm(DOTP)5- system elicits chiral resolution of the rapidly interconverting Tm(DOTP)5- isomers.     

A new zinc(II) fluorophore 2-(9-anthrylmethylamino)ethyl-appended 1,4,7,10-tetraazacyclododecane

A new 2-(9-anthrylmethylamino)ethyl-appended cyclen, L(3) (1-(2-(9-anthrylmethylamino)ethyl)-1,4,7,10-tetraazacyclododecane) (cyclen = 1,4,7,10-tetraazacyclododecane), was synthesized and characterized for a new Zn(2+) chelation-enhanced fluorophore, in comparison with previously reported 9-anthrylmethylcyclen L(1) (1-(9-anthrylmethyl)-1,4,7,10-tetraazacyclododecane) and dansylamide cyclen L(2). L(3) showed protonation constants log K(a)(i)() of 10.57 +/- 0.02, 9.10 +/- 0.02, 7.15 +/- 0.02, <2, and <2. The log K(a3) value of 7.15 was assigned to the pendant 2-(9-anthrylmethylamino)ethyl on the basis of the pH-dependent (1)H NMR and fluorescence spectroscopic measurements. The potentiometric pH titration study indicated extremely stable 1:1 Zn(2+)-L(3) complexation with a stability constant log K(s)(ZnL(3)) (where K(s)(ZnL(3)) = [ZnL(3)]/[Zn(2+)][L(3)] (M(-)(1))) of 17.6 at 25 degrees C with I = 0.1 (NaNO(3)), which is translated into the much smaller apparent dissociation constant K(d) (=[Zn(2+)](free)[L(3)](free)/[ZnL(3)]) of 2 x 10(-)(11) M with respect to 5 x 10(-)(8) M for L(1) at pH 7.4. The quantum yield (Phi = 0.14) in the fluorescent emission of L(3) increased to Phi = 0.44 upon complexation with zinc(II) ion at pH 7.4 (excitation at 368 nm). The fluorescence of 5 microM L(3) at pH 7.4 linearly increased with a 0.1-5 microM concentration of zinc(II). By comparison, the fluorescent emission of the free ligand L(1) decreased upon binding to Zn(2+) (from Phi = 0.27 to Phi = 0.19) at pH 7.4 (excitation at 368 nm). The Zn(2+) complexation with L(3) occurred more rapidly (the second-order rate constant k(2) is 4.6 x 10(2) M(-)(1) s(-)(1)) at pH 7.4 than that with L(1) (k(2) = 5.6 x 10 M(-)(1) s(-)(1)) and L(2) (k(2) = 1.4 x 10(2) M(-)(1) s(-)(1)). With an additionally inserted ethylamine in the pendant group, the macrocyclic ligand L(3) is a more effective and practical zinc(II) fluorophore than L(1).     

Synthesis of novel 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) derivatives for chemoselective attachment to unprotected polyfunctionalized compounds

A convenient synthesis of novel bifunctional poly(amino carboxylate) chelating agents allowing chemoselective attachment to highly functionalized biomolecules is described. Based on the well known chelator 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA), we synthesized novel bifunctional chelating agents bearing additional functional groups by alkylating 1,4,7,10-tetraazacyclododecane (cyclen) with one equivalent of para-functionalized alkyl 2-bromophenyl-acetate and three equivalents of tert-butyl 2-bromoacetate. The resulting compounds, which contain an additional carbonyl or alkyne functionality, allow site specific labeling of appropriately functionalized unprotected biomolecules in a rapid manner via click reactions. This was demonstrated by the attachment of our new DOTA derivatives to the somatostatin analogue Tyr3-octreotate by chemoselective oxime ligation and CuI-catalyzed azide-alkyne cycloaddition. Initial biodistribution studies in mice with the radiometalated compound demonstrated the applicability of the described DOTA conjugation.     

Monte Carlo simulation of a 1,4,7,10-tetraazacyclododecane/lithium complex in aqueous solution

Monte Carlo simulations have been carried out for the system consisting of a 1,4,7,10-tetraazacyclododecane (cyclen)-lithium complex in 201 water molecules. The volume of the periodic cube was calculated using the experimental density of pure water at 298 K and 1 atm of 1 g.cm(-)(3), plus additional space occupied by the complex. The geometry of the complex is the alternated form, where the ion is located at the center of the cyclen. The complex-water interaction was represented by the cyclen-water and lithium-water pair potentials, both of which were developed on the basis of ab initio calculations. The results show two layers of solvation shells consisting of 2 and 6.9 water molecules. Two water molecules in the first solvation shell (O(1) and O(2)) bind directly to the ion in which the ion-oxygen distance is 2.38 A, the dipole vector points to the ion, and rotation takes place around the ion-oxygen axis. In the next layer, 4 water molecules coordinate simultaneously to the first 2 water molecules in the first shell and the NH functional groups of cyclen. The remaining 2.9 water molecules in the second layer are also coordinated to be in the first half-hydration shell of O(1) and O(2).     

Equilibrium, 1H and 13C NMR spectroscopy,and X-ray diffraction studies on the complexes Bi(DOTA)- and Bi(DO3A-Bu)

Several Bi(III) complexes are used in medicine as drugs. Bi(DO3A-Bu) has recently been proposed as a nonionic contrast agent in X-ray imaging (H(3)DO3A-Bu = 10-[2,3-dihydroxy-(1-hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7,-triacetic acid). The solution equilibria and NMR structure and dynamics of Bi(DO3A-Bu) and of the similar Bi(DOTA)(-) have been investigated (H(4)DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The stability constants were determined with the study of the competition equilibria between Br(-) ions and the ligands DOTA or DO3A-Bu for the Bi(III) by spectrophotometry. The stability constants, obtained for Bi(DOTA)(-) and Bi(DO3A-Bu), are very high, log K = 30.3 and 26.8, respectively. Potentiometric titrations indicated the dissociation of one of the protons among the three alcoholic OH groups in Bi(DO3A-Bu). The dissociation constant is log K = 7.53 (0.09) indicating that at physiological pH about 50% of the species possess -1 charge. It was shown by (1)H and (13)C NMR spectroscopy that the OH group attached to the middle carbon atom of the "butriol" side chain is coordinated to the Bi(III) and starts to deprotonate at pH > 5.5. The crystal structure of NaBi(DOTA).H(2)O shows an octacoordinated arrangement of the donor atoms around the Bi(III), with no water in the inner sphere. The crystals belong to the centrosymmetric space group C2/c. The temperature dependent (1)H and (13)C NMR spectra indicate that both Bi(DOTA)(-) and Bi(DO3A-Bu)(-) complexes are fluxional. For Bi(DOTA), the Delta(deltadeltadeltadelta) right harpoon over left harpoon Lambda(lambdalambdalambdalambda) fluxionality was identified, and on the basis of the activation parameters, a synchronous motion was suggested for the fluxional motion resulting in the change of ring conformation and of the helicity of the complex. The transition state is supposed to be more symmetrical than the initial state. The deprotonated Bi(DO3A-Bu) has a highly asymmetric NMR structure in solution, and its fluxional motion is slower than that of Bi(DOTA)(-).     

Isotachophoretic determination of stability constants of Ho and Y complexes with diethylenetriaminepentaacetic acid and 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid

The method of capillary isotachophoresis with conductivity detection was applied for the determination of the physico-chemical characteristics (conditional stability constants log beta') of holmium and yttrium complexes with DTPA (diethylenetriaminepentaacetic acid) and DOTA (1,4,7,10-tetraazadodecane-N,N',N',N'-tetraacetic acid). The log beta' determination is based on the linear relation between the stability constants of lanthanide-DTPA (lanthanide-DOTA) complexes and the reduction of the zone of the complex owing to the bleeding phenomena (liberating free metal ion). The stability constants calculated using this relationship are comparable with the literary data obtained by other methods for both holmium (log beta'(Ho-DTPA)=21.9, log beta'(Ho-DOTA)=24.5) and yttrium complexes (log beta'(Y-DTPA)=21.2, log beta'(Y-DOTA)=24.4). Capillary isotachophoresis was applied for the determination of the optimum composition of the reaction mixture (metal:ligand ratio) as well.     

A new tetraazamacrocycle functionalized with pendant pyridyl groups: synthesis and crystal structure of a copper(II) complex of 1,4,7,10-tetrakis(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane (L), [CuL]·(ClO4)2

The [CuL](ClO4)2 complex, L=1,4,7,10-tetrakis- (2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane, was prepared in EtOH and characterized. The crystal structure of the complex was determined by single-crystal X-ray analysis. The coordination geometry about the copper ion can be described as a strongly distorted octahedron, with CuN distances ranging from 2.01(1)–2.82(1)AÅ.     

N,N',N",N"'-四对甲苯碘酰-1，4，7，10-四氮杂环十二烷的微小常压快速水解

N,N',N",N"'-四对甲苯磺酰-1,4,7,10-四氮杂环十二烷是Atkins法合成1, 4,7,10-四氮杂环十二烷的关键中间体,但其水解脱磺酰基比较困难,常规水解 一般需要采用96%-98%硫酸在140 ℃左右加热2-3d。报道了一种微波促进快速水解 法,即在稍加改装或未改装的家用微波炉中,采用95%-98%硫酸,控制火力2-5档, 全对甲苯碘酰化全氮冠醚仅需50-120 s即可完成水解,比常规加热水解所需时间缩 短约3000-8000倍,浓硫酸用量也比常规加热水解少,收率较常规水解高。     

Synthesis and Crystal Structure of 1,4,7,10-Tetrakis-（2-（2,3-difluorophenyl）-ethyl）-1,4,7,10-tetraazacyclododecane

The new compound 1,4,7,10-tetrakis-(2-(2,3-difluorophenyl) ethyl) -1,4,7,10-tetra-zacyclododecane 2 has been synthesized and structurally characterized by single-crystal X-ray diffraction. The molecule turned into diamond crystals grown from CH3CN by slow diffusion at room temperature. It crystallizes in the triclinic system,space group P1 with a = 9.543(2) ,b = 10.507(3) ,c = 10.734(3) ,α = 60.979(3) ,β = 81.870(4) ,γ = 84.279(4) o,V = 931.1(4) 3,Z = 1,Dc = 1.307 g/cm3,C40H44F8N4,Mr = 732.79,F(000) = 384,μ = 0.105 mm-1,T = 296(2) K,MoKa radiation(λ = 0.71073) ,R = 0.0494 and wR = 0.0989 for 1589 observed reflections with I > 2σ(I) . Hydrogen bonds and C-H···π stacking interactions in 2 contribute to a supramolecular structure. Moreover,compound 2 has been determined by 1H NMR,13C NMR,MS,IR spectra and elemental analysis.     

Short and straightforward synthesis of 1,7-dimethyl-1,4,7,10-tetraazacyclododecane

A novel, cost-effective, and efficient process for the synthesis of 1,7-dimethyl-1,4,7,10-tetraazacyclododecane 1 has been developed. The two-step process involved the selective conversion of commercially available cyclen to N1,N7-diethylcarbamate cyclen 3 that afforded the title compound in high yield after the reduction step.     

Direct excitation luminescence spectroscopy of Eu(III) complexes of 1,4,7-tris(carbamoylmethyl)-1,4,7,10- tetraazacyclododecane derivatives and kinetic studies of their catalytic cleavage of an RNA analog

The macrocycles 1,4,7-tris(carbamoylmethyl)-1,4,7,10-tetrazacyclododecane (1), 1,4,7-tris[(N-ethyl)carbamoylmethyl]-1,4,7,10-tetraazacyclododecane (2), 1,4,7-tris[(N,N-diethyl)carbamoylmethyl]-1,4,7,10-tetraazacyclododecane (3) and their Eu(III) complexes are prepared. Studies using direct Eu(III) excitation luminescence spectroscopy show that all three Eu(III) complexes exhibit only one predominant isomer with two bound waters under neutral to mildly basic conditions (Eu(X)(H(2)O)(2) for X = 1-3). There are no detectable ligand ionizations over the pH range 5.0-8.0 for Eu(3), 5.0-8.5 for Eu(2) or 5.0-9.5 for Eu(1). The three Eu(III) complexes show a linear dependence of second-order rate constants for the cleavage of 4-nitrophenyl-2-hydroxyethylphosphate (HpPNP) on pH in the range 6.5-8.0 for Eu(3), 7.0-8.5 for Eu(2) and 7.0-9.0 for Eu(1). This pH-rate profile is consistent with the Eu(III) complex-substrate complex being converted to the active form by loss of a proton and with Eu(III) water pK(a) values that are higher than 8.0 for Eu(3), 8.5 for Eu(2) and 9.0 for Eu(1). Inhibition studies show that Eu() binds strongly to the dianionic ligand methylphosphate (K(d) = 0.28 mM), and more weakly to diethylphosphate (K(d) = 7.5 mM), consistent with a catalytic role of the Eu(III) complexes in stabilizing the developing negative charge on the phosphorane transition state.     

Formation kinetics and stability studies on the lanthanide complexes of 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid by capillary electrophoresis

In this study, the kinetic behaviors of four lanthanide ions, Sm(3+), Dy(3+), Yb(3+) and Lu(3+), when mixed with a polyazamacrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), were investigated by capillary electrophoresis (CE) in the pH range of 2.0-6.0. At pH 2.0, the formation rate of DOTA-metal complex is extremely low as very little complex was detected after 5 days reaction, whereas almost no free DOTA was found in the mixture of metal ion and DOTA after 4 min at pH 6.0. The second-order kinetic association rate constants of the four lanthanide ions chelates at pH 4.2 were calculated as 1.44 x 10(-2) mM(-1)min(-1), 5.20 x 10(-2) mM(-1)min(-1), 4.56 x 10(-2) mM(-1)min(-1) and 4.54 x 10(-2) mM(-1)min(-1) at 25 degrees C with CE, respectively. In addition, the stability constants of the four lanthanide ions with DOTA were determined by CE at pH 3.0 where approximately 80-90% of the metal ions were associated with DOTA at 25 degrees C. The measured stability constants (log K(f)) of the four DOTA-metal complexes were 23.36, 23.93, 23.39 and 23.06, respectively, and correlated well with published data obtained by different methods. The percentage of metal ion bound with DOTA was evaluated as a function of reactant concentration in pH 6.0 buffer. After adding excess strong acid (0.1 M HCl) to each solution of DOTA-metal was formed at pH 6.0, no released DOTA was detected after 24 h; thus, dissociation of these lanthanide complexes did not occur under strongly acidic conditions. The Ln(DOTA)(-) species for the four DOTA-metal complexes were characterized by electrospray ionization-mass spectroscopy (ESI-MS), and the results correlated with proposed structures.     

A new,facile synthesis of 1,4,7,10-tetraazacyclododecane: cyclen

This report outlines a new and efficient synthesis of cyclen (1,4,7,10-tetraazacyclododecane, 1) utilizing bis-imidazoline, 6 (1,1'-ethylenedi-2-imidazoline), with 1,2-dibromoethane. General conditions were developed, allowing for the simple, three-step synthesis of 1 at the multigram scale with an isolated overall yield approaching 65%. The cyclization of 6 produced by the condensation of triethylene tetraamine (TETA) with N,N-dimethylformamide dimethyl acetal, gave the twelve-membered, imidazolinium, cyclized intermediate bromide salt, 7 (2,3,4,5,6,7,8,8c-octahydro-1H-4a,6a,8a-triaza-2a-azoniacyclopent[fg]acenaphthylene), which hydrolyzed to 1 with the use of hot, aqueous caustic. Hydrolysis of 7 under milder conditions formed the 1,4,7,10-tetraazabicyclo[8.2.1]tridecan-13-one (20). Mechanistically, the formation of 7 may be rationalized as involving a diaminocarbene that undergoes an intramolecular carbon-hydrogen insertion.     

Synthesis,structure and antitumor activities of a new macrocyclic ligand with four neutral pendent groups: 1,4,7,10-tetrakisbenzyl-1,4,7,10-tetraazacyclododecane (L) and its Co,Ni and Cu complexes

A new macrocyclic ligand, 1,4,7,10-tetrakisbenzyl-1,4,7,10-tetraazacyclododecane (L) and its three new divalent metal complexes of general formula: M(NO₃)₂(L)nH2O [M = Co(1), Ni(2), n = 0; M = Cu(3), n = 1.5] have been synthesized and characterized by elemental analysis, i.r., EI mass spectra and molecular conductance. Complex (2) has been characterized by X-ray diffraction. In complex (2), the central Ni^II atom coordinatively bonds to four nitrogen atoms of the macrocyclic ligand and two oxygen atoms of nitrate anion, to form a distorted octahedron. X-ray diffraction indicated that the bonds Ni–N(1), Ni–N(2), Ni–N(3) and Ni–N(4) are of almost equal length, i.e. 2.11(1), 2.12(1), 2.10(1) and 2.17(1)Å, respectively. Bond lengths of Ni–O(1) and Ni– O(2) are 2.11(1) and 2.10(1)Å. Preliminary pharmacological tests show that these complexes have high antitumor activity towards HL-60 tumor cell lines.     

Study of pH-dependent zinc(II)-carboxamide interactions by zinc(II)-carboxamide-appended cyclen complexes (cyclen = 1,4,7,10-tetraazacyclododecane)

To elucidate intrinsic recognition of carboxamides by zinc(II) in carbonic anhydrase (CA) (as inhibitors) and carboxypeptidase A (CPA) (as substrates), a new series of Zn(2+)-carboxamide-appended cyclen complexes have been synthesized and characterized (cyclen = 1,4,7,10-tetraazacyclododecane). Two types of Zn(2+)-carboxamide interactions have been found. In the first case represented by a zinc(II) complex of carbamoylmethyl-1,4,7,10-tetraazacyclododecane (L(1)), the amide oxygen binds to zinc(II) at slightly acidic pH (to form ZnL(1)), and the deprotonated amide N(-) binds to zinc(II) at alkaline pH (to form ZnH(-1)L(1)) with pK(a) = 8.59 at 25 degrees C and I = 0.1 (NaNO(3)), as determined by potentiometric pH titrations, infrared spectral changes, and (13)C and (1)H NMR titrations. The X-ray crystal structure of ZnH(-1)L(3) (where L(3) = N-(4-nitrophenyl)carbamoylmethyl cyclen, pK(a) = 7.01 for ZnL(3) <==> ZnH(-1)L(3)) proved that the zinc(II) binds to the amidate N(-) (Zn-N(-) distance of 1.974(3) A) along with the four nitrogen atoms of cyclen (average Zn-N distance 2.136 A). Crystal data: monoclinic, space group P2(1)/n (No. 14) with a = 10.838(1) A, b = 17.210(2) A, c = 12.113(2) A, b = 107.38(1) degrees, V = 2156.2(5) A(3), Z = 4, R = 0.042, and R(w) = 0.038. These model studies provide the first chemical support that carboxamides are CA(-) inhibitors by occupying the active Zn(2+) site both in acidic and alkaline pH to prevent the occurrence of the catalytically active Zn(2+)-OH(-) species. In the second case represented by a zinc(II) complex of 1-(N-acetyl)aminoethylcyclen, ZnL(6), the pendant amide oxygen had little interaction with zinc(II) at acidic pH. At alkaline pH, the monodeprotonation yielded a zinc(II)-bound hydroxide species ZnL(6)(OH(-)) (pK(a) = 7.64) with the amide pendant remaining intact. The ZnL(6)(OH(-)) species showed the same nucleophilic activity as Zn(2+)-cyclen-OH(-). The second case may mimic the Zn(2+)-OH(-) mechanism of CPA, where the nucleophilic Zn(2+)-OH(-) species does not act as a base to deprotonate a proximate amide.