Cytotoxic and Antimicrobial Properties of Copper(II) Complexes of Pyridine and Benzimidazole Derivatives

The cytotoxic and antimicrobial activity of a series of six copper(II) complexes with phosphate and hydroxymethyl derivatives of pyridine and benzimidazole were investigated. The complexes and the corresponding free ligands were tested against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Pseudomonas aeruginosa ATCC 15442, Escherichia coli ATCC 25922, Proteus hauseri ATCC 13315, and Candida albicans ATCC 10231. Among the tested copper(II) complexes, compounds 2 and 5 containing 1H‐benzimidazol‐2‐ylmethyl diethyl phosphate and 2‐(hydroxymethyl)benzimidazole as ligands, respectively, were most active and limited the growth of S. aureus, E. coli, and C. albicans by 30–60 % according to concentration and microorganism. The in vitro cytotoxic activity of the Cu^II complexes and free ligands towards cancerous B16 (murine melanoma) and non‐cancerous 10T1/2 (murine fibroblasts) cell lines was determined. The 10T1/2 cells were treated with the compounds at concentrations equal to IC₅₀ values for B16 cells. In spite of the use of relatively high concentrations of the complexes, the viability of 10T1/2 cells was very high, ca. 80 % in some cases. Stability of the Cu^II complexes was evaluated in water solutions by UV/Vis spectroscopy. The copper(II) complex of 4‐(hydroxymethyl)pyridine was synthesized and identified.     

Ethyl (2‐pyridyl­methyl)­phospho­nate

Molecules of the title compound, C₈H₁₂NO₃P, exist as zwitterions. The positive charge formally located on the N atom is spread over the pyridyl ring. A partial delocalization of negative charge within the O—P—O system is observed. The conformational features and hydrogen‐bonding network of the title compound are compared with the structure of (2‐pyridyl­methyl)­phosphonic acid.     

Synthesis and spectroscopy of phosphonate derivatives of uracil and thymine. X-ray crystal structure of diethyl 6-uracilmethylphosphonate

A new class of phosphonate ligands, derived from uracil and thymine was designed, prepared and characterised. Dimethyl ( 4, 7 ) and diethyl ( 5, 8 ) uracilmethylphosphonates have been prepared by the reaction of chloromethyluracil isomers 2 and 3 with trimethyl phosphite and triethyl phosphite, respectively. The corresponding free acids, 5-uracilmethylphosphonic acid 6 and 6-uracilmethylphosphonic acid 9 , have also been isolated. The structure of the compounds has been assigned by nmr spectroscopy and, in the case of 8 , confirmed by X-ray analysis.     

Properties of the Magnesium(II) and Calcium(II) Complexes of 5‐ and 6‐Uracilmethylphosphonate (5 Umpa2– and 6 Umpa2–) in Aqueous Solution

The stability constants of the 1 : 1 complexes formed between Mg²⁺ or Ca²⁺ and 5 Umpa^2– or 6 Umpa^2– were determined by potentiometric pH titrations in aqueous solution (25 °C; I = 0.1 M, NaNO₃). Based on previously established log K^M_M(R‐PO3) versus pK^H_H(R‐PO3) straight‐line plots (M²⁺ = Mg²⁺ or Ca²⁺; R‐PO₃^2– = simple phosphate monoester or phosphonate ligands where R is a non‐interacting residue), it is shown that the Mg(5 Umpa), Ca(5 Umpa), Mg(6 Umpa) and Ca(6 Umpa) complexes have the stability expected on the basis of the basicity of the phosphonate group in 5 Umpa^2– and 6 Umpa^2–. This means, these ligands may be considered as simple analogues of nucleotides, e. g. of uridine 5′‐monophosphate. In the higher pH range deprotonation of the uracil residue in the M(5 Umpa) and M(6 Umpa) complexes occurs and this leads to the negatively charged M(5 Umpa–H)^– and M(6 Umpa–H)^– species. Based on the comparison of various acidity constants it is shown that the M(5 Umpa) complexes are especially acidic; or to say it differently, the M(5 Umpa–H)^– species are especially stable. This increased stability is attributed to the formation of a seven‐membered chelate involving next to the phosphonate group also the carbonyl oxygen atom at C4 (after deprotonation of the (N3)H site). The formation degree of this chelated isomer reaches about 45% for the Mg(5 Umpa–H)^– and Ca(5 Umpa–H)^– species. No indication for chelate formation was observed for the M(6 Umpa–H)^– complexes.     

Complexes of Uracil (2,4-Dihydroxypyrimidine) Derivatives

Equilibrium studies have been carried out on complex formation of M²⁺ ions (M=Co, Ni, and Zn) with L = thymine, 6-chloromethyluracil, 5-hydroxymethyluracil, uracil, 6-methyluracil, and 6-umpm (dimethyl 6-uracilmethylphosphonate) in aqueous solution, at 25 ^∘;C and an ionic strength of I=0.1 mol⋅L⁻¹ (KNO₃). Potentiometric results indicate the formation of ML species (coordination via N3) for Co(II) and Ni(II) as well as a hydroxo complex MLH₋₁—with a deprotonated water of the inner coordination sphere. Titrations of Zn(II) confirmed both the existence of ML and MLH₋₁ species with 6-chloromethyluracil as well as 5-hydroxymethyluracil, whereas for uracil, thymine, and 6-methyluracil the only species accepted pH-metrically was MLH₋₁. For all the ligands under study the complexation with Zn(II) was reinvestigated by means of ion-selective electrodes (ISE). The role of substituents is discussed.     

Metal ion-binding properties of (1H-benzimidazol-2-yl-methyl)phosphonate (Bimp2-) in aqueous solution. Isomeric equilibria, extent of chelation, and a new quantification method for the chelate effect

The acidity constants of the 2-fold protonated (1H-benzimidazol-2-yl-methyl)phosphonate, H2(Bimp)(+/-), are given, and the stability constants of the M(H;Bimp)+ and M(Bimp) complexes with the metal ions M2+ = Mg2+, Ca2+, Ba2+, Mn2+, Co2+, Cu2+, Zn2+, or Cd2+ have been determined by potentiometric pH titrations in aqueous solution at I = 0.1 M (NaNO3) and 25 degrees C. Application of previously determined straight-line plots of log KM(M(Bi-R)) versus pKH(H(Bi-R)) for benzimidazole-type ligands, Bi-R, where R represents a residue which does not affect metal ion binding, proves that the primary binding site in the M(H;Bimp)+ complexes is (mostly) N3 and that the proton is located at the phosphonate group; outersphere interactions seem to be important, and the degree of chelate formation is above 60% for all metal ion complexes studied, except for Zn(H;Bimp)+. A similar evaluation based on log KM(M(R-PO3)) versus pKH(H(R-PO3)) straight-line plots for simple phosph(on)ate ligands, R-, where R represents a residue which cannot participate in the coordination process, reveals that the primary binding site in the M(Bimp) complexes is (mostly) the phosphonate group with all metal ions studied. In this case, the formation degree of the chelates varies more widely in dependence on the kind of metal ion involved, i.e., from 17 +/- 11% to nearly 100% for Ba(Bimp) and Cu(Bimp), respectively. For all the M(H;Bimp)+ and M(Bimp) systems, the intramolecular equilibria between the isomeric complexes are evaluated in a quantitative manner. The fact that for Bimp2- the metal ion affinity of the two binding sites, N3 and PO3(2-), can be calculated independently, i.e., the corresponding micro stability constants become known, allows us to present for the first time a method for the quantification of the chelate effect solely based on comparisons of stability constants which carry the same dimensions. This effect is often ill defined in textbooks because equilibrium constants of different dimensions are compared, which is avoided in the present case. For the M(Bimp) complexes, it is shown that the chelate effect is close to zero for Ba(Bimp) whereas for Cu(Bimp) it amounts to about four log units. This method is also applicable to other chelating systems. Finally, considering that benzimidazole as well as phosphonate derivatives are employed as therapeutic agents, the potential biological properties of Bimp, especially regarding nucleic acid polymerases, are briefly discussed.     

Comparison of the surprising metal-ion-binding properties of 5- and 6-uracilmethylphosphonate (5Umpa2- and 6Umpa2-) in aqueous solution and crystal structures of the dimethyl and di(isopropyl) esters of H2(6Umpa)

5- and 6-Uracilmethylphosphonate (5Umpa(2-) and 6Umpa(2-)) as acyclic nucleotide analogues are in the focus of anticancer and antiviral research. Connected metabolic reactions involve metal ions; therefore, we determined the stability constants of M(Umpa) complexes (M(2+)=Mg(2+), Ca(2+), Mn(2+), Co(2+), Cu(2+), Zn(2+), or Cd(2+)). However, the coordination chemistry of these Umpa species is also of interest in its own right, for example, the phosphonate-coordinated M(2+) interacts with (C4)O to form seven-membered chelates with 5Umpa(2-), thus leading to intramolecular equilibria between open (op) and closed (cl) isomers. No such interaction occurs with 6Umpa(2-). In both M(Umpa) series deprotonation of the uracil residue leads to the formation of M(Umpa-H)(-) complexes at higher pH values. Their stability was evaluated by taking into account the fact that the uracilate residue can bind metal ions to give M(2)(Umpa-H)(+) species. This has led to two further important insights: 1) In M(6Umpa-H)-cl the H(+) is released from (N1)H, giving rise to six-membered chelates (degrees of formation of ca. 90 to 99.9 % with Mn(2+), Co(2+), Cu(2+), Zn(2+), or Cd(2+)). 2) In M(5Umpa-H)$-cl the (N3)H is deprotonated, leading to a higher stability of the seven-membered chelates involving (C4)O (even Mg(2+) and Ca(2+) chelates are formed up to approximately 50 %). In both instances the M(Umpa-H)-op species led to the formation of M(2)(Umpa-H)(+) complexes that have one M(2+) at the phosphonate and one at the (N3)(-) (plus carbonyl) site; this proves that nucleotides can bind metal ions independently at the phosphate and the nucleobase residues. X-ray structural analyses of 6Umpa derivatives show that in diesters the phosphonate group is turned away from the uracil residue, whereas in H(2)(6Umpa) the orientation is such that upon deprotonation in aqueous solution a strong hydrogen bond is formed between (N1)H and PO(3) (2-); replacement of the hydro gen with M(2+) gives the M(6Umpa-H)-cl chelates mentioned.     

trans‐Di­aqua­tetrakis(3,5‐di­methyl­pyrazole‐N2)­nickel(II) dichloride

The X‐ray structure analysis of [Ni(C₅H₈N₂)₄(H₂O)₂]Cl₂ was undertaken to elucidate the geometry around the Ni²⁺ ion. The molecule lies on a twofold axis which runs through the O—Ni—O atoms. The geometry around the Ni²⁺ ion is best described as slightly distorted tetragonal bipyramidal.     

Polydiacetylenes: supramolecular smart materials with a structural hierarchy for sensing, imaging and display applications

While a large variety of conjugated polymers exist, polydiacetylenes (PDAs) remain a major research area among scientists due to their interesting optical, spectral, electronic, and structural properties. Heavily reviewed in regards to their stimuli responsive properties, much is known about the assortment of sensing and detection capabilities of PDAs. In this article, we look more upon the structural diversities of polydiacetylenes that have been achieved in recent years, particularly from a hierarchical perspective of 1, 2, and 3-dimensional configurations. In addition, we examine how these different dimensional arrangements of PDAs have heralded clear applications in several key areas. Successful integration of these stimuli-responsive "smart" materials into various geometries has required researchers to have a comprehensive understanding of both the fabrication and synthesis processes, as well as the signalling mechanism for the optical, fluorogenic or spectral transitions. The on-going discovery of new PDA formulations continues to provide interesting structural manifestations such as liposomes, tubes, fibres, organic/inorganic incorporated hybrids and composite structures. By highlighting some of the recent conceptual and technological developments, we hope to provide a measure of the current pace in new PDA derivative development as core components in efficient sensor, imaging and display systems.