Zinc(II) complexes with potent cyclin-dependent kinase inhibitors derived from 6-benzylaminopurine: synthesis, characterization, X-ray structures and biological activity

The synthesis, characterization and biological activity of the first zinc(II) complexes with potent inhibitors of cyclin-dependent kinases (CDKs) derived from 6-benzylaminopurine are described. Based on the results following from elemental analyses, infrared, NMR and ES+MS (electrospray mass spectra in the positive ion mode) spectroscopies, conductivity data, thermal analysis and X-ray structures, the tetrahedral Zn(II) complexes of the compositions [Zn(Olo)Cl(2)](n) (1), [Zn(iprOlo)Cl(2)](n) (2), [Zn(BohH(+))Cl(3)] x H(2)O (3) and [Zn(iprOloH(+))Cl(3)] x H(2)O (4) have been prepared, where Olo=2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine (Olomoucine), iprOlo=2-(2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (i-propyl-Olomoucine), Boh=2-(3-hydroxypropylamino)-6-benzylamino-9-isopropylpurine (Bohemine). The 1D-polymeric chain structure for [Zn(Olo)Cl(2)](n) (1) as well as the monomeric one for [Zn(BohH(+))Cl(3)] x H(2)O (3) and [Zn(iprOloH(+))Cl(3)] x H(2)O (4) have been revealed unambiguously by single crystal X-ray analyses. The 1D-polymeric chain of 1 consists of Zn(Olo)Cl(2) monomeric units in which the Zn(II) ion is coordinated by two chlorine atoms and one oxygen atom of the 2-hydroxyethylamino group of Olomoucine. The next monomeric unit is bonded to Zn(II) through the N7 atom of a purine ring. Thus, each of Zn(II) ions is tetrahedrally coordinated and a ZnCl(2)NO chromophore occurs in the complex 1. The complexes 3 and 4 are mononuclear species with a distorted tetrahedral arrangement of donor atoms around the Zn(II) ion with a ZnCl(3)N chromophore. The corresponding CDK inhibitor, i.e., both Boh and iprOlo, is coordinated to Zn(II) via the N7 atom of the purine ring in 3 and 4. The cytotoxicity of the zinc(II) complexes against human melanoma, sarcoma, leukaemia and carcinoma cell lines has been determined as well as the inhibition of the CDK2/cyclin E kinase. A relationship between the structure and biological activity of the complexes is also discussed.     

Growth of a Dehalococcoides-like microorganism on vinyl chloride and cis-dichloroethene as electron acceptors as determined by competitive PCR

A competitive PCR (cPCR) assay targeting 16S ribosomal DNA was developed to enumerate growth of a Dehalococcoides-like microorganism, bacterium VS, from a mixed culture catalyzing the reductive dehalogenation of cis-1,2-dichloroethene (cDCE) and vinyl chloride (VC), with hydrogen being used as an electron donor. The growth of bacterium VS was found to be coupled to the dehalogenation of VC and cDCE, suggesting unique metabolic capabilities. The average growth yield was (5.2 +/- 1.5) x 10(8) copies of the 16S rRNA gene/ micromol of Cl(-) (number of samples, 10), with VC being used as the electron acceptor and hydrogen as the electron donor. The maximum VC utilization rate (q) was determined to be 7.8 x 10(-10) micromol of Cl(-) (copy(-1) day(-1)), indicating a maximum growth rate of 0.4 day(-1). These average growth yield and q values agree well with values found previously for dechlorinating cultures. Decay coefficients were determined with growth (0.05 day(-1)) and no-growth (0.09 day(-1)) conditions. An important limitation of this cPCR assay was its inability to discriminate between active and inactive cells. This is an essential consideration for kinetic studies.     

Vitamin C induces periodontal ligament progenitor cell differentiation via activation of ERK pathway mediated by PELP1

The differentiation of periodontal ligament (PDL) progenitor cells is important for maintaining the homeostasis of PDL tissue and alveolar bone. Vitamin C (VC), a water-soluble nutrient that cannot be biosynthesized by humans, is vital for mesenchymal stem cells differentiation and plays an important role in bone remodeling. Therefore, the objective of this study was to determine the function and mechanism of VC in PDL progenitor cells osteogenic differentiation at the molecular level. We demonstrated that VC could induce the osteogenic differentiation and maturation of PDL progenitor cell without other osteogenic agents. During the process, VC preferentially activated ERK1/2 but did not affect JNK or p38. Co-treatment with ERK inhibitor effectively decreased the Vitamin C-induced expression of Runx2. ERK inhibitor also abrogated Vitamin C-induced the minimized nodules formation. PELP1, a nuclear receptor co-regulator, was up-regulated under VC treatment. PELP1 knockdown inhibited ERK phosphorylation. The overexpression of PELP1 had a positive relationship with Runx2 expression. Taken together, we could make a conclude that VC induces the osteogenic differentiation of PDL progenitor cells via PELP1-ERK axis. Our fi nding implies that VC may have a potential in the regeneration medicine and application to periodontitis treatment.     

Effects of vitamin E on serum enzymes and electrolytes in hypercholesterolemia

It is not known if vitamin E in hyperlipidemia and hypercholesterolemia of longer duration has any beneficial or adverse effects on electrolytes, and liver and kidney function. The objectives of this study are to determine (i) if long duration of mild hypercholesterolemia has any adverse effects on serum electrolytes, glucose and enzymes related to liver and kidney functions; (ii) if vitamin E has any effects on serum electrolytes, glucose and enzymes related to liver and kidney function in hypercholesterolemia. Blood samples were collected from the rabbits before and at various intervals during administration of a high cholesterol diet (0.25%) for 2 and 4 months, and while on a high cholesterol diet with vitamin E following a high cholesterol diet. Measurements of serum total cholesterol (TC), glucose, aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), albumin, creatinine, electrolytes [sodium (Na), potassium (K), chloride (Cl), and carbon dioxide (CO₂)] were made. High cholesterol diet for 2 months produced hypercholesterolemia which was associated with reductions in serum glucose, unaltered serum electrolytes, ALT, ALP, GGT, albumin and creatinine, and increased levels of AST. Hypercholesterolemia for 4 months had effects similar to hypercholesterolemia for 2 months except it lowered serum ALP. Vitamin E did not affect any of the parameters except serum glucose and Cl, which decreased compared to the values at month 2. Hypercholesterolemia for short and long term does not have adverse effects on liver or kidney function, and serum electrolytes. Vitamin E during hypercholesterolemia does not affect serum electrolytes or liver and kidney function.     

Oral administration of a zinc complex improves type 2 diabetes and metabolic syndromes

Previously, we reported that intraperitoneal injections of the Zn(II) complex (Zn(alx)(2)) with allixin, which is isolated from dry garlic, with a Zn(O(4)) coordination environment, exhibited high anti-diabetic effects in obesity-linked type 2 diabetic KKA(y) mice. However, this complex exhibited low activity when administered orally. To improve the effect of Zn(alx)(2), we prepared a novel Zn(II) complex with the allixin-derivative bis(1,6-dimethyl-3-hydroxy-5-methoxy-2-pentyl-1,4-dihydropyridine-4- thionato)Zn(II), abbreviated as Zn(II)-thioallixin-N-methyl (Zn(tanm)(2)), having a Zn(S(2)O(2)) coordination environment; this complex has extremely high in vitro insulin-like activity. Because Zn was extensively absorbed from the gastrointestinal tract when Zn(tanm)(2) was orally administered, its anti-diabetic effects were examined in KKA(y) mice. Daily oral administrations of Zn(tanm)(2) for 4 weeks in KKA(y) mice significantly improved hyperglycemia, glucose intolerance, insulin resistance, hyperleptinemia, obesity, and hypertension. Interestingly, Zn(tanm)(2) increased depressed plasma adiponectin levels in the mice. Here, we propose that Zn(tanm)(2) will be an orally active therapeutic for obesity-linked type 2 diabetes and metabolic syndromes.     

Stabilization of the non-canonical adenine-adeninium base pair by N(7) coordination of Zn(II)

A new zinc (II) compound with 9-ethyladenine (9-EtA) of formula [Zn(9-EtA-N7)Cl(3)](9-EtAH) has been synthesized and characterized by X-ray diffraction. Its X-structure consists of an Zn(II) anionic complex and 9-ethyladeninium as counteranion. The Zn(II) complex shows a distorted tetrahedral geometry in which three Cl and an 9-EtA coordinates through N(7) position are the ligands. An indirect chelation via intramolecular H-bond between N(6)H and an Cl ligand is present in the complex. The network of [Zn(9-EtA-N7)Cl(3)](9-EtAH) shows interesting features. Thus, self-association of coordinated adenine-adeninium takes place by H-bonding of N(6)-H...N(1) and N(6)-H...N(7), leading to a polymeric ribbon-like 1D supramolecular arrangement. Ab initio calculations have been applied in order to study the stability of the adenine-adeninium interaction due to the coordination of the Zn(II) to the N(7) position and to compare experimental and theoretical structural data.     

Interactions of Isolated C-terminal Fragments of Neural Wiskott-Aldrich Syndrome Protein (N-WASP) with Actin and Arp2/3 Complex

Wiskott-Aldrich syndrome proteins (WASP) are a family of proteins that all catalyze actin filament branching with the Arp2/3 complex in a variety of actin-based motile processes. The constitutively active C-terminal domain, called VCA, harbors one or more WASP homology 2 (WH2) domains that bind G-actin, whereas the CA extension binds the Arp2/3 complex. The VCA·actin·Arp2/3 entity associates with a mother filament to form a branched junction from which a daughter filament is initiated. The number and function of WH2-bound actin(s) in the branching process are not known, and the stoichiometry of the VCA·actin·Arp2/3 complex is debated. We have expressed the tandem WH2 repeats of N-WASP, either alone (V) or associated with the C (VC) and CA (VCA) extensions. We analyzed the structure of actin in complex with V, VC, and VCA using protein crystallography and hydrodynamic and spectrofluorimetric methods. The partial crystal structure of the VC·actin 1:1 complex shows two actins in the asymmetric unit with extensive actin-actin contacts. In solution, each of the two WH2 domains in V, VC, and VCA binds G-actin in 1:2 complexes that participate in barbed end assembly. V, VC, and VCA enhance barbed end depolymerization like profilin but neither nucleate nor sever filaments, in contrast with other WH2 repeats. VCA binds the Arp2/3 complex in a 1:1 complex even in the presence of a large excess of VCA. VCA·Arp2/3 binds one actin in a latrunculin A-sensitive fashion, in a 1:1:1 complex, indicating that binding of the second actin to VCA is weakened in the ternary complex.     

Zinc complexes of the biomimetic N,N,O ligand family of substituted 3,3-bis(1-alkylimidazol-2-yl)propionates: the formation of oxalate from pyruvate

The coordination chemistry of the 2-His-1-carboxylate facial triad mimics 3,3-bis(1-methylimidazol-2-yl)propionate (MIm(2)Pr) and 3,3-bis(1-ethyl-4-isopropylimidazol-2-yl) propionate (iPrEtIm(2)Pr) towards ZnCl(2) was studied both in solution and in the solid state. Different coordination modes were found depending both on the stoichiometry and on the ligand that was employed. In the 2:1 ligand-to-metal complex [Zn(MIm(2)Pr)(2)], the ligand coordinates in a tridentate, tripodal N,N,O fashion similar to the 2-His-1-carboxylate facial triad. However, the 1:1 ligand-to-metal complexes [Zn(MIm(2)Pr)Cl(H(2)O)] and [Zn(iPrEtIm(2)Pr)Cl] were crystallographically characterized and found to be polymeric in nature. A new, bridging coordination mode of the ligands was observed in both structures comprising N,N-bidentate coordination of the ligand to one zinc atom and O-monodentate coordination to a zinc second atom. A rather unique transformation of pyruvate into oxalate was found with [Zn(MIm(2)Pr)Cl], which resulted in the isolation of the new, oxalato bridged zinc coordination polymer [Zn(2)(MIm(2)Pr)(2)(ox)].6H(2)O, the structure of which was established by X-ray crystal structure determination.     

Vitamin C depletion increases superoxide generation in brains of SMP30/GNL knockout mice

Vitamin C (VC) has a strong antioxidant function evident as its ability to scavenge superoxide radicals in vitro. We verified that this property actually exists in vivo by using a real-time imaging system in which Lucigenin is the chemiluminescent probe for detecting superoxide in senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize VC in vivo. SMP30/GNL KO mice were given 1.5 g/L VC [VC(+)] for 2, 4, or 8 weeks or denied VC [VC(−)]. At 4 and 8 weeks, VC levels in brains from VC(−) KO mice were <6% of that in VC(+) KO mice. Accordingly, superoxide-dependent chemiluminescence levels determined by ischemia-reperfusion at the 4- and 8 weeks test intervals were 3.0-fold and 2.1-fold higher, respectively, in VC(−) KO mice than in VC(+) KO mice. However, total superoxide dismutase activity and protein levels were not altered. Thus, VC depletion specifically increased superoxide generation in a model of the living brain.     

Cultivation and metabolic insights of an uncultured clade,Bacteroidetes VC2.1 Bac22 (Candidatus Sulfidibacteriales ord. nov.), from deep-sea hydrothermal vents

Bacteroidetes VC2.1 Bac22 (referred to as VC2.1) is an uncultured clade that is widely distributed in marine ecosystems, including hydrothermal vents, oxygen-minimum zones and other anoxic, sulfide-rich environments. However, the lack of cultured representatives and sequenced genomes of VC2.1 limit our understanding of its physiology, metabolism and ecological functions. Here, we obtained a stable co-culture of VC2.1 with autotrophic microbes by establishing an autotrophy-based enrichment from a hydrothermal vent chimney sample. We recovered a high-quality metagenome-assembled genome (MAG) that belonged to VC2.1. Phylogenetic analyses of both 16S rRNA genes and conserved protein markers suggested that VC2.1 belongs to a novel order in the Bacteroidetes phylum, which we named Candidatus Sulfidibacteriales. The metabolic reconstruction of this MAG indicated that VC2.1 could utilize polysaccharides, protein polymers and fatty acids as well as flexibly obtain energy via NO/N₂O reduction and polysulfide reduction. Our results reveal the ecological potential of this novel Bacteroidetes for complex organic carbons mineralization and N₂O sinks in deep-sea hydrothermal vents. Furthermore, guided by the genome information, we designed a new culture medium in which starch, ammonium and polysulfide were used as the carbon source, nitrogen source and electron acceptor respectively, to isolate VC2.1 successfully.     

Unusual dimeric Zn(II)-cytosine complexes: new models of the interaction of Zn(II) with DNA and RNA

Synthesis and crystal structure of two Zn(II) dimer complexes with 1-methylcytosine (1-MeC) are reported. In complex [Zn(2)Cl(4)(mu-1-MeC-O2,N3)(2)] (1), two 1-MeC ligands are bridging two ZnCl(2) moieties. In [Zn(2)(1-MeC-N3)(4)(mu-SO(4))(2)].2H(2)O (2), the sulfates act as bridging ligands and 1-MeC are linked via N3 to Zn(II) as terminal ligands. Both complexes represent the first examples of Zn(II)-pyrimidine dimers. The potential biological significance of 1 and 2 is discussed.     

Photochemistry of metal complexes of 3-hydroxyflavone: towards a better understanding of the influence of solar light on the metal-soil organic matter interactions.

The photo-stability of 3-hydroxyflavone (3HF) and its complexes with Al(iii), Zn(ii) and Pb(ii) in methanol was investigated by a multi-disciplinary strategy, combining UV-Vis, fluorescence, Raman and FT-IR spectroscopies, DFT and time-dependent DFT calculations and a traditional organic photochemistry approach. We found that the presence of metals can slow down (in the case of Pb(ii)) or even block (in the case of Al(iii)) the photo-degradation of 3HF. The Zn(ii) complex shows a reactivity comparable to free 3HF. In all cases (except the Al(iii) complex) the photo-product is 3-hydroxy-3-phenyl-1,2-indandione, the same as reported in literature for 3HF photochemistry in methanol. This means that metallic cations do not modify the photochemical mechanism of the reaction. In addition, in the case of Zn(ii) and Pb(ii) complexes, the photo-produced 3-hydroxy-3-phenyl-1,2-indandione was found to exist in free form, i.e. without metal complexation. This means that similar photo-reactions occurring in soil organic matter under solar irradiation entail desorption of free Zn(2+) and Pb(2+) cations (the most toxic form) in the environment. The presence of external parameters-presence of water and oxygen-has also been studied. Interestingly, opposite effects have been found for free 3HF and Zn(ii) and Pb(ii) complexes. Tentative explanations for these effects are provided, relying on a detailed investigation on the structure and on the photophysical properties of the three complexes.     

Zinc bone loss in chronic renal failure and chronic metabolic acidosis

The effects of chronic metabolic acidosis (CMA) on zinc (Zn) bone content and urinary excretion were examined in the presence of normal or reduced renal function together with some aspects of calcium (Ca) metabolism. Four groups of rats were compared. All were fed a 30% protein and 9 mg Zn/100 g diet. Two were uremic (U): The first developed acidosis (UA), which was suppressed in the other (UNA) by NaHCO₃ supplement. Two other groups had normal renal function: One was normal (CNA), and the other had NH₄Cl in the drinking water and acidosis (CA). Femur total Zn and Ca content was markedly reduced by CMA and was not affected by uremia. Zn urinary excretion was increased by CMA and unaltered by uremia. Ca urinary excretion was markedly reduced in uremic rats, but was enhanced in both acidotic conditions. Urinary Ca and Zn showed a strong correlation in uremic and in control rats. Plasma parathormone and 1,25(OH)₂D₃ were unchanged by CMA. These data are in agreement with a direct primary effect of CMA on bone in releasing buffers. CMA induces bone resorption and a parallel decrease of mineral bone components, such as Ca and Zn, with little or no role of PTH, 1,25(OH)₂D₃ and of uremia itself.     

Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe

Further chemical optimization of the MLSCN/MLPCN probe ML077 (KCC2 IC(50)=537 nM) proved to be challenging as the effort was characterized by steep SAR. However, a multi-dimensional iterative parallel synthesis approach proved productive. Herein we report the discovery and SAR of an improved novel antagonist (VU0463271) of the neuronal-specific potassium-chloride cotransporter 2 (KCC2), with an IC(50) of 61 nM and >100-fold selectivity versus the closely related Na-K-2Cl cotransporter 1 (NKCC1) and no activity in a larger panel of GPCRs, ion channels and transporters.     

Antimicrobial activity of ZnII, CdII, and HgII complexes of 1,2-bis-[2-(5-R)-1H-benzimidazolyl]-1,2-ethanediols and 1,4-bis-[2-(5-R)-1H-benzimidazolyl]-1,2,3,4-butanetetraols

1,2-Bis-[2-(5-H/Me/Cl/NO2)-1H-benzimidazolyl]-1,2-ethanediols (L1-L4), 1,4-bis-[2-(5-H/Me/Cl)-1H-benzimidazolyl]-1,2,3,4-butanetetraols (L5-L7) and their complexes with ZnCl2, CdCl2 and HgCl2 were synthesized and antibacterial activity of the compounds was tested toward Staphylococcus aureus, S. epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri, Proteus mirabilis and antifungal activity against Candida albicans. HgII complexes have a considerably higher antimicrobial activity against all microorganisms. Some HgII complexes show higher antifungal activity than clotrimazole toward C. albicans. Zn2(L3)Cl4, Zn2(L4)Cl4, and Cd(L3)Cl2 were moderately effective against S. aureus and S. epidermidis; Cd(L4)Cl2 exhibited a weak activity only against S. epidermidis.     

Functions, applications and production of 2-O-d-glucopyranosyl-l-ascorbic acid

Vitamin C (VC) is an essential nutrient that cannot be synthesized by the human body. Due to its extreme instability, various VC derivatives have been developed in an attempt to improve stability while retaining the same biological activity. One of the most important VC derivatives, 2-O-D-glucopyranosyl-L-ascorbic acid (AA-2G), has attracted increasing attention in recent years with a wide range of applications in cosmetics, food, and medicine. In this mini-review, we first introduce the types and properties of different VC glycosyl derivatives. Next, we provide an overview of the functions and applications of AA-2G. Finally, we discuss in-depth the current status and future prospects of AA-2G production by biotransformation.     

Tracer Studies to Locate the Site of Platinum Ions Within Filamentous and Inhibited Cells of Escherichia coli

The distribution of platinum ions within Escherichia coli after the induction of filaments with cis-Pt(NH(3))(2)Cl(4), and after growth inhibition by PtCl(6) (2-), has been determined with radioactive metal compounds ((191)Pt, with a half-life of approximately 3 days) by the simple chemical procedure of Roberts et al. In the filamentous cells, the platinum metal is associated with metabolic intermediates, nucleic acids, and cytoplasmic proteins; whereas, in inhibited cells, the platinum is combined only with the cytoplasmic protein. Similar experiments with gram-positive cells of Bacillus cereus and Staphyloccus aureus, which show no filamentous growth in the presence of cis-Pt(NH(3))(2)Cl(4), reveal that the metal complex does penetrate the cell wall and subsequently becomes bound predominantly by metabolic intermediates.     

Kinetic study of catalytic CO(2) hydration by water-soluble model compound of carbonic anhydrase and anion inhibition effect on CO(2) hydration

A kinetic study of CO(2) hydration was carried out using the water-soluble zinc model complex with water-soluble nitrilotris(2-benzimidazolylmethyl-6-sulfonate) L1S, [L1SZn(OH(2))](-), mimicking the active site of carbonic anhydrase, in the presence and absence of anion inhibitors NCS(-) and Cl(-). The obtained rate constants k(cat) for CO(2) hydration were 5.9x10(2), 1. 7x10(3), and 3.1x10(3) M(-1) s(-1) at 5, 10, and 15 degrees C, respectively: the k(cat)=ca. 10(4) M(-1) s(-1) extrapolated towards 25 degrees C has been the largest among the reported k(cat) using zinc model complexes for carbonic anhydrase. It was also revealed that NCS(-), Cl(-) and acetazolamide play a role of inhibitors by the decrease of k(cat): 7x10(2) and 2x10(3) M(-1) s(-1) for NCS(-) and Cl(-) at 15 degrees C, respectively. The sequence of their magnitudes in k(cat) is Cl(-) approximately acetazolamide>NCS(-), where the sequence Cl(-)>NCS(-) is confirmed for native carbonic anhydrase. The difference of k(cat) or k(obs) between NCS(-) and Cl(-) resulted from that between the stability constants K(st)=2x10(3) for [L1SZn(NCS)](2-) and 1x10(2) M(-1) for [L1SZnCl](2-) in D(2)O: for water-insoluble tris(2-benzimidazolylmethyl)amine L1, K(st)=1.8x10(4) for [L1Zn(NCS)](2-) and 1.5x10(3) M(-1) for [L1ZnCl](2-)in CD(3)CN/D(2)O (50% v/v). The crystal structure of anion-binding zinc model complexes [L1Zn(OH(2))](0.5)[L1ZnCl](0.5) (ClO(4))(1.5) 1(0.5)2(0.5)(ClO(4))(1.5) was revealed by X-ray crystallography. The geometry around Zn(2+) in 1 and 2 was tetrahedrally coordinated by three benzimidazolyl nitrogen atoms and one oxygen atom of H(2)O, or Cl(-).     

Synthesis and structure-activity relationships of metal-ligand complexes that potently inhibit cell migration

We screened the National Cancer Institute Diversity Set compound collection for small molecules that affect mammalian cell migration and identified NSC 295642 as an inhibitor of cell motility with nanomolar potency. We found by LC-MS and X-ray crystallography that NSC 295642, a Cu(II) complex of the Schiff base product of condensation of S-benzyl dithiocarbazate and 2-acetylpyridine, has a bridged dimeric Cu2Cl2(L)2 structure with distorted square pyramidal geometry. Each of the two copper atoms is five-coordinated to one of the two tridentate chelating ligands and both bridging chlorine atoms. To define structure-activity relationships,we investigated the bioactivity of related metal-ligand complexes derived from different metal(II) atoms and different ligands. Complexation of the NSC 295642 ligand with Zn(II) or Ni(II), delivered as metal(II) chloride salts under conditions identical to those used for preparation of the original Cu(II) complex, instead results in distorted octahedral bis-chelate structures, where a single metal atom is six-coordinated to two ligands. The Zn(L)2 complex possesses a potency similar to that of the Cu2Cl2(L)2 complex, while the Ni(L)2 has no antimigratory activity at all. We carried out density functional theory calculations to obtain the electronic ground state geometry of the complexes, both in vacuum and implicit water solvent. The X-ray crystal and energy-minimized structures are very similar and exhibit a transoid orientation of the S-benzyl groups relative to the central metal-coordinated rings for both of the bioactive Cu2Cl2(L)2 and Zn(L)2 complexes, despite their different coordination geometries. In contrast, the biologically inactive Ni(L)2 complex adopts a cisoid conformation. Varying the ligand structure, we found that hydrophobic S-alkylaryl groups are required for activity. Complexes with a simple S-methyl group, S-benzyl groups with polar substitutions or a carboxylated pyridine ring exhibit dramatically reduced activity. We tested the most potent metal-ligand complex in a number of cancer cell lines and found cell-type selectivity in its effect on cell motility. Collectively, these results suggest that a two-ligand structure with bulky nonpolar S-substituents in a transoid conformation is important for the antimigratory activity of these metal-ligand complexes.