A Synthetic Pathway for an Unsymmetrical N(5) O(2) Heptadentate Ligand and Its Heterodinuclear Iron(III)Zinc(II) Complex: A Biomimetic Model for the Purple Acid Phosphatases

One major field of interest in bioinorganic chemistry is the design and synthesis of inorganic compounds with low molecular mass, showing structural, spectroscopic, and reactivity properties that mimic enzymes, such as purple acid phosphatases (PAPs). In this study, the unsymmetrical heptadentate ligand 2-[(4,7-diisopropyl-1,4,7-triazacyclonon-1-yl)methyl]-6-{[(2-hydroxybenzyl)(pyridin-2-ylmethyl)-amino]methyl}-4-methylphenol (H(2) L) and its first mixed-valence complex [Fe(III) Zn(II) (L)(μ-OAc)(2) ]ClO(4) (1) were synthesized. Physical and chemical measurements (crystal structure, conductometry, IR and UV/VIS spectroscopy, and electrochemistry) were performed for 1, and these properties are compared with those presented by the kbPAPs active sites. Potentiometric titration studies of 1 have confirmed its acid/base properties that are crucial for the understanding of the phosphodiester and DNA catalytic cleavage in future studies.     

Microwave-assisted synthesis of 4'-azaflavones and their N-alkyl derivatives with biological activities

4'-Azaflavone (=2-(pyridin-4-yl)-4H-1-benzopyran-4-one; 4) and 3-[(pyridin-4-yl)methyl]-4'-azaflavone (5) were synthesized by a simple environmentally friendly microwave-assisted one-pot method through the cyclization of 3-hydroxy-1-(2-hydroxyphenyl)-3-(pyridin-4-yl)propan-1-one (1), (E)-2'-hydroxy-4-azachalcone (2; chalcone=1,3-diphenylprop-2-en-1-one), and 2'-hydroxy-2-[(hydroxy)(pyridin-4-yl)methyl]-4'-azachalcone (3) under solventless conditions using silica-supported NaHSO(4), followed by treatment with base. In addition, N-alkyl-substituted 4'-azaflavonium bromides 6 and 7 were prepared from compounds 4 and 5, respectively. The antimicrobial and antioxidant activities of compounds 1-7 were tested. The N-alkyl-substituted 4'-azaflavonium bromides 6 and 7 showed high antimicrobial activity against the Gram-positive bacteria and the fungus tested, with MIC values close to those of reference antimicrobials ampicilline and fluconazole. The alkylated compounds 6 and 7 also showed a good antioxidant character in the two antioxidant methods, DPPH (=1,1-diphenyl-2-picrylhydrazyl) radical-scavenging and ferric reducing/antioxidant power (FRAP) tests.     

Iron(III) complexes using NNS reduced Schiff bases and NNOS coordinating tetradentate ligands: Synthesis, structure and catecholase activity

The orange-red colored complexes of the type [Fe(L_SB)Cl₃], 1, have been synthesized in excellent yields by reacting FeCl₃·6H₂O with L_SB in methanol. Here, L_SB is (2-(ethylthio)-N-(pyridin-2-ylmethyl)ethanamine), (L_SB¹) and (2-(benzylthio)-N-(pyridin-2-ylmethyl)ethanamine) (L_SB²). Similarly, FeCl₃·6H₂O reacted with 2-(((2-(ethylthio) ethyl) (pyridin-2-ylmethyl)amino)methyl)phenol (HL¹), 2-(((2-(ethylthio)ethyl)(pyridin-2 ylmethyl)amino)methyl)-4-nitrophenol (HL²), 4-chloro-2-(((2-(ethylthio)ethyl)(pyridin-2-ylmethyl)amino)methyl)phenol (HL³), 2-(((2-(benzylthio)ethyl)(pyridin-2-ylmethyl) amino)methyl)phenol (HL⁴), 2-(((2-(benzylthio)ethyl)(pyridin-2-ylmethyl)amino)methyl) -4-nitrophenol (HL⁵), and 4-chloro-2-(((2-(benzylthio)ethyl)(pyridin-2-ylmethyl)amino) methyl)phenol (HL⁶) to give dichloro complexes of the type [Fe(L)Cl₂], 2. The solid and solution structure of the complexes, as well as their properties, were probed using X-ray diffraction, spectroscopic and electrochemical methods. The Mössbauer spectral study at 80 K for complexes reveals the existence of (III) oxidation state and high-spin state of the metal center in the complex. Dioxygenase activity of the complexes has been studied and both 1 and 2 have been found to display the intradiol-cleaving pathway. However, no extradiol cleavage products have been isolated.     

Mononuclear manganese(III) catechol compounds as substrate adduct complexes for manganese-substituted intradiol cleaving catechol dioxygenases

The complexes [Mn(L₁)(tcc)] (1), [Mn(L₂)(tcc)] · H₂O · 0.5CH₃OH (2), [Mn(L₃)(tcc)] · CH₂Cl₂ (3), [Mn(L₄)(tcc)] · 1.5CH₂Cl₂ (4), [Mn(L₅)(tcc)] (5), and (HN(C₂H₅)₃)[Mn(L₆)(tcc)] · CH₂Cl₂ (6) have been synthesized using the ligands HL₁ (2-[(bis(pyridin-2-ylmethyl)amino)methyl]phenol), HL₂ (2-[[((6-methylpyridin-2-yl)methyl)(pyridin-2-ylmethyl)amino]methyl] phenol), HL₃ (2-[[((6-methylpyridin-2-yl)methyl)(pyridin-2-ylmethyl)amino]methyl]-4-nitrophenol), HL₄ (2-[(bis(pyridin-2-ylmethyl)amino)methyl]-4-bromophenol), HL₅ (2-[(bis(pyridin-2-ylmethyl)amino)methyl]-6-methoxyphenol) and H₂L₆ ([(bis(2-hydroxy-5-nitrobenzyl))(pyridin-2-ylmethyl)]amine) and characterized by X-ray crystallography, mass spectrometry, IR, UV-Vis spectroscopy, cyclic voltammetry, and elemental analysis. Compounds 1 and 6 crystallize in the monoclinic space groups P2₁/n and P2₁/c, respectively, whereas the crystal structures of complexes 2, 3, and 4 were solved in the triclinic space group . Complex 5 crystallizes in the orthorhombic space group P2₁2₁2₁. Complexes 1-6 are structural related to the proposed active site of intradiol cleaving catechol dioxygenase exhibiting a distorted octahedral N₃O₃ (1-5) and N₂O₄ (6) donor set, respectively. Complexes 1-6 can be regarded as structural manganese analogous for substituted forms of iron-containing intradiol cleaving catechol dioxygenases, where the substrate tetrachlorocatechol (tcc) is asymmetrically bound to the metal center.     

In Silico Analog Design for Terbinafine Against Trichophyton rubrum: A Preliminary Study

The diseases caused by dermatophytes are common among several other infections which cause serious threat to human health. It is evident that enzyme squalene epoxidase is responsible for prolonged dermatophyte infection and it is appealing to note that this enzyme is also responsible for fatty acid synthesis in these groups of fungi. In the present study, terbinafine drug which targets enzyme squalene epoxidase has been explored to design its various novel analogues. The present study suggests that many more prominent drug analogues could be constituted which may be crucial towards designing new drug candidates. In the present study, we have designed a series of such analogues viz. [(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)(naphthalen-1-ylmethyl)amine, N-[8-({[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]-2-(sulfoamino) acetamide, {[4-(dihydroxyamino)-8-({[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]sulfanyl}methanol and (R)-{[4-({[(2E,6R)-6,7-dimethyloct-2-en-4-yn-1-yl](methyl)amino}methyl)-5-[(hydroxysulfamoyl)amino]naphthalen-1-yl]amino}sulfinic acid. Moreover, further by molecular docking approach the binding between enzyme and designed analogues was further analysed. The present preliminary report suggested a considerably good docking interaction score of −338.75 kcal/mol between terbinafine and squalene epoxidase from Trichophyton rubrum. This preliminary study implies that few designed candidate ligands can be effectual towards the activity of this enzyme and can play crucial role in pathogenesis control of T. rubrum.     

Delivery of floxuridine derivatives to cancer cells by water-soluble organometallic cages

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (pPr(i)C(6)H(4)Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) or 5,8-dioxydo-1,4-naphthoquinonato (donq) bridges, in the presence of a pyrenyl-nucleoside derivatives (pyreneR), affords the triangular prismatic host-guest compounds [(pyrene-R)?Ru(6)(pPr(i)C(6)H(4)Me)(6)(tpt)(2)(dobq)(3)](6+) ([(pyrene-R)?1](6+)) and [(pyrene-R)?Ru(6)(pPr(i)C(6)H(4)Me)(6)(tpt)(2)(donq)(3)](6+) ([(pyrene-R)?2](6+)), respectively. The inclusion of six monosubstitutedpyrenyl-nucleosides (pyrene-R1 = 5'-(1-pyrenyl butanoate)-2'-deoxyuridine, pyrene-R2 = 5-fluoro-5'-(1-pyrenyl butanoate)-2'-deoxyuridine, pyrene-R3 = 5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-glycyl}-2'-deoxyuridine, pyrene-R4 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-glycyl}-2'-deoxyuridine, pyrene-R5 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-phenylalanyl}-2'-deoxyvuridine, pyrene-R6 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-phenylalanyl}-2'-deoxyuridine) has been accomplished. The carceplex nature of [(pyrene-R)?1](6+) with the pyrenyl moiety firmly encapsulated in the hydrophobic cavity of the cage with the nucleoside groups pointing outward was confirmed by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS), while the host-guest nature of [(pyrene-R)?2](6+) was studied in solution by NMR techniques. In contrast to the floxuridine compounds used in the clinic, the host-guest complexes are highly water-soluble. Consequently, the cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 and A2780cisR cancer cells. All the host-guest systems are more cytotoxic than the empty cages alone [1][CF(3)SO(3)](6) (IC(50) = 23 μM) and [2][CF(3)SO(3)](6) (IC(50) = 10 μM), the most active compound [pyrene-R4?1][CF(3)SO(3)](6)being 2 orders of magnitude more cytotoxic (IC(50) = 0.3 μM) on these human ovarian cancer cell lines (A2780 and A2780cisR).     

Inhibition of Src kinase activity by 7-ethynyl-4-phenylamino-3-quinolinecarbonitriles: identification of SKS-927

Of a series of 7-ethynyl-3-quinolinecarbonitriles, the most potent Src inhibitory activity was observed with 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methylpiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927). Variation of the solubilizing amine tail or removal of the methoxy group from either C-6 of the quinoline core or C-5 of the aniline headpiece led to reduced activity.     

Identification of a novel class of selective Tpl2 kinase inhibitors: 4-Alkylamino-[1,7]naphthyridine-3-carbonitriles

We have previously reported the discovery and initial SAR of the [1,7]naphthyridine-3-carbonitriles and quinoline-3-carbonitriles as Tumor Progression Loci-2 (Tpl2) kinase inhibitors. In this paper, we report new SAR efforts which have led to the identification of 4-alkylamino-[1,7]naphthyridine-3-carbonitriles. These compounds show good in vitro and in vivo activity against Tpl2 and improved pharmacokinetic properties. In addition they are highly selective for Tpl2 kinase over other kinases, for example, EGFR, MEK, MK2, and p38. Lead compound 4-cycloheptylamino-6-[(pyridin-3-ylmethyl)-amino]-[1,7]naphthyridine-3-carbonitrile (30) was efficacious in a rat model of LPS-induced TNF-alpha production.     

Development of a potent and orally active activator of adenosine monophosphate-activated protein kinase (AMPK), ASP4132, as a clinical candidate for the treatment of human cancer

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a key role in maintaining cellular metabolism. AMP or adenosine diphosphate (ADP) levels rise during metabolic stress, such as during nutrient starvation, hypoxia and muscle contraction, and bind to AMPK to induce activity. Recently, activation of AMPK has been considered an attractive therapeutic strategy in the field of human oncology. Structural optimization of lead compound 2, a new type of AMPK activator with potent AMPK activation activity and attractive selective growth inhibition against human cancer cells, improved aqueous solubility, metabolic stability and animal pharmacokinetics (PK) and culminated in the identification of (5-{1-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}-1H-benzimidazol-2-yl)(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)methanone ditosylate, ASP4132 (28). Studies on ASP4132 had advanced to clinical trials for the treatment of cancer.     

The role of the oximes HI-6 and HS-6 inside human acetylcholinesterase inhibited with nerve agents: a computational study

The oximes 4-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HI-6) and 3-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HS-6) are isomers differing from each other only by the position of the carbamoyl group on the pyridine ring. However, this slight difference was verified to be responsible for big differences in the percentual of reactivation of acetylcholinesterase (AChE) inhibited by the nerve agents tabun, sarin, cyclosarin, and VX. In order to try to find out the reason for this, a computational study involving molecular docking, molecular dynamics, and binding energies calculations, was performed on the binding modes of HI-6 and HS-6 on human AChE (HssAChE) inhibited by those nerve agents.     

A homo-isoflavonoid and a cytotoxic saponin from Dracaena draco

Two new compounds, dracol (= (3R)-2,3-dihydro-3,5-dihydroxy-7-methoxy-3-[(4-methoxyphenyl)methyl]-8-methyl-4H-[1]benzopyran-4-one; 1) and icodeside (= (1beta,3beta,23S,24S)-3,23-dihydroxy-1-{[2-O-(2,3,4-tri-O-acetyl-alpha-L-rhamnopyranosyl)-alpha-L-arabinopyranosyl]oxy}spirosta-5,25(27)-dien-24-yl alpha-L-arabinopyranoside; 2), were isolated from the EtOH extract of the leaves of Dracaena draco, together with 17 known constituents. The structures of 1 and 2 were elucidated by in-depth spectroscopic analysis, and those of the known compounds were identified by comparison of their NMR and MS data with those reported in the literature. Icodeside (2) showed moderate cytotoxicity against human HL-60 and A-431 cells (Table 3).     

Synthesis and NMR properties of novel 5,6-dihydroborauracil derivatives

Novel boron compounds - 5,6-saturated borauracil derivatives (4-bromo-5,6-dihydroborauracil, 4-hydroxy-5,6-dihydroborauracil and 4-methoxy-5,6-dihydroborauracil) are presented along with other boron compounds obtained from N-vinylurea: N-substituted β-boronic amino acid - 2-{[(dihydroxyborano-amino)(dihydroxyboranooxy)methyl]-amino}ethylboronic acid and substituted methoxy-borane O-[(1-amino-1-N-vinylamino)methyl]dihydroxyboronate.     

New N-pyridinyl(methyl)-indolalkanamides acting as topical inflammation inhibitors

The authors have described the synthetic way to new N-pyridinyl(methyl)indolylpropanamides acting as non acidic NSAIDs. Pharmacomodulation was carried out at N-1 and C-5 of the indole ring and at the level of the propanamide chain. N-(pyridin-3-ylmethyl)-3-[5-chloro-1-(4-chlorobenzyl)-indol-3-yl]propanamide 32 represents one of the most potent compounds evaluated in the TPA-induced mouse ear swelling assay, with a level of activity higher than that of ibuprofen and comparable to that of dexamethasone.     

A remarkable anion effect on the crystal packing of two analogous copper complexes from a thiophene-containing phenol-based ligand

The new asymmetric phenol-based N,O,S-ligand Hpy2th1as was prepared by the straightforward reductive amination of 3-{[bis(pyridin-2-ylmethyl)amino]methyl}-2-hydroxybenzaldehyde with (thiophen-2-yl)methylamine. This potentially hexadentate ligand was used to coordinate to copper(II) chloride. Two dinuclear copper complexes were thus synthesised and fully characterized. Although the two coordination compounds exhibit identical complex cations, the crystal packings of both molecules significantly differ, which is most likely induced by the distinct, but geometrically related anions, namely tetrachlorocuprate(II) and perchlorate.     

Design,synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor

Here we describe the design, synthesis, and pharmacological evaluation of a set of compounds structurally related to the high affinity serotonin 5-HT₇ receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT_1A and adrenergic α₁ receptors. The synthesized compounds have chemical features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabeled on the methoxy group with carbon-11. Positron emission tomography (PET) analysis revealed that [¹¹C]-23a and [¹¹C]-26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests.     

New Phenylpropanoid Glycosides from Illicium majus and Their Radical Scavenging Activities

Chemical investigation of the ethanol extract of the branch and leaves of Illicium majus resulted in the isolation of four new phenylpropanoid glycosides ( 1 – 4 ) and one new phenolic glycoside ( 9 ), along with 13 known ones. Spectroscopic techniques were used to elucidate the structures of the new isolates such as 3-[(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-yl]propyl β-D-glucopyranoside ( 1 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-glucopyranoside ( 2 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-xylopyranoside ( 3 ), 3-[(2R,3S)-3-({[2-O-(4-O-acetyl-α-L-rhamnopyranosyl)-β-D-xylopyranosyl]oxy}methyl)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-2,3-dihydro-1-benzofuran-5-yl]propyl acetate ( 4 ), and 4-(2-hydroxyethyl)phenyl 3-O-β-D-glucopyranosyl-β-D-glucopyranoside ( 9 ). Free radical scavenging activities of the isolates were elucidated through the DPPH assay method. The most active compounds, 1-O-caffeoyl-β-D-glucopyranose ( 17 ) and soulieana acid 1 ( 18 ), exhibited moderate radical scavenging activities (IC₅₀=37.7±4.4 μM and IC₅₀=97.2±3.4 μM, respectively). The antibacterial activities of the isolates against Staphylococcus aureus and Escherichia coli were also assessed, and no activity was shown at the measured concentration (<32 μg/mL).     

Microbial Asymmetric Reduction. Preparation of Optically Active Methyl trans-3-(4-Methoxyphenyl)Glycidates

As a result of screening of microorganisms, Mucor ambiguus IFO 6742 was found to reduce methyl 2-chloro-3-(4-methoxyphenyl)-3-oxopropionate (2) to give methyl (2S,3R)-2-chloro-3-hydroxy-3-(4-methoxyphenyl)propionate [(2S,3R)-3] in good yield with high enantioselectivity. The resulting (2S, 3R)-3 was converted into methyl (2S,3R)-3-(4-methoxyphenyl)glycidate [(2S,3R)-4] by treatment with sodium methoxide. On the other hand, its enantiomer, (2R,3S)-4 was obtained by the Mitsunobu esterification of (2S,3R)-3 and subsequent treatment with sodium methoxide. Also (2R,3S)-4 was obtained by the treatment of (2RS,3S)-3, which was obtained from 2 by Trichoderma viride OUT 4642, with sodium methoxide.     

Polyazacyclophanes incorporating two pyridine units and a heteroaromatic pendant group as potential cleaving agents of mRNA 5'-cap structure

Four hexaazacyclophanes, 16a-d, incorporating two pyridine units and a (pyridin-2-yl)methyl or (quinolin-2-yl)methyl pendant group at one of the ring N-atoms have been prepared. The key step of the synthesis is an intermolecular cyclization of N,N-bis{[6-(tosyloxymethyl)pyridin-2-yl]methyl}-2-nitrobenzenesulfonamide (7) with either tert-butyl bis{2-[(2-nitrophenylsulfonyl)amino]ethyl}carbamate (2a) or tert-butyl bis{3-[(2-nitrophenylsulfonyl)amino]propyl}carbamate (2b) in the presence of anhydrous Cs(2)CO(3). Removal of the acid-labile tert-butoxycarbonyl protection then allows attachment of the pendant group by reductive alkylation to the exposed secondary amino group, and deprotection of the remaining aliphatic ring N-atoms completes the synthesis. The ability of the cyclophanes and their dinuclear Cu(2+) and Zn(2+) complexes to cleave the mRNA cap structure, m(7)G(5')pppG(5') (1), has been studied.     

Manganese(II) complexes of a set of 2-aminomethylpyridine-derived ligands bearing a methoxyalkyl arm: syntheses, structures and magnetism

Four new ligands, N-(2-methoxyethyl)-N-(pyridin-2-ylmethyl)amine (mepma), N-(3-methoxypropyl)-N,N-bis(pyridin-2-ylmethyl)amine (mpbpa), N-(2-methoxyethyl)-N,N-bis(pyridin-2-ylmethyl)amine (mebpa) and 2-{[(2-methoxyethyl)(pyridin-2-ylmethyl)amino]methyl} phenol (Hmepap), and four of their complexes with manganese(II) halides, [MnCl₂(mepma)₂] (1), [MnCl(μ-Cl)(mpbpa)]₂ (2), [MnBr₂(mebpa)] (3) and [MnBr₂(MeOH)(Hmepap)] (4) have been synthesized and characterized. Single-crystal Xray studies revealed that in all four complexes, the Mn(II) coordination spheres are distorted octahedral. In 1 and 2, the ether oxygen atom does not coordinate to the Mn(II) centre, but in 3 and 4 it does. The mononuclear molecules of 1 are linked by double hydrogen bonds to form linear chains. Temperature dependent magnetic susceptibility measurements revealed that the Mn(II) ions in 1 interact antiferromagnetically, with J=−1.06 cm⁻¹. Compound 2 crystallizes as a double chloride-bridged dimer in which there is a weak ferromagnetic interaction (J=0.55 cm⁻¹) between the Mn(II) pair. The solution EPR spectrum of 2 suggests that in methanol compound 2 decomposes to a great extent to mononuclear species. In compound 3, mebpa acts as a tetradentate ligand with all of its nitrogen and oxygen atoms coordinated to the Mn(II) ion. Unexpectedly, in complex 4, the phenolic oxygen of Hmepap remains protonated and does not coordinate to the metal ion. Instead the oxygen from a methanol molecule coordinates the manganese centre. Hydrogen bonds between one of the two bromide ions, and the methanol and phenol hydroxyl groups, respectively, connect the mononuclear molecules of 4 into chains. No magnetic interactions were observed between the Mn(II) ions in 3 or 4.     

p53 is not directly relevant to the response of Polo-like kinase 1 inhibitors

Polo-like kinase 1 (Plk1) is elementary for cell proliferation and its deregulation is involved in tumorigenesis. Plk1 has been established as one of the most attractive targets for molecular cancer therapy. In fact, multiple small molecule inhibitors targeting either the kinase domain or the Polo-box binding domain (PBD) of Plk1 have been identified and intensively investigated. Intriguingly, Plk1 depletion affects more cancer cells than normal cells. It is also reported that the cytotoxicity induced by Plk1 inhibition is elevated in cancer cells with defective p53. The data lead to the hypothesis that p53 might be a predictive marker for the response of Plk1 inhibition. In this study, we demonstrate that there is no obvious different cytotoxic response between cancer cells with and without functional p53, including the isogenic colon cancer cell lines HCT116p53(+/+) and HCT116p53(-/-), breast cancer cell line MCF7, lung cancer cell line A549 and cervical carcinoma cell line HeLa, after treatment with either siRNA against Plk1, the kinase domain inhibitors BI 2536 and BI 6727 or the PBD inhibitor Poloxin. We suggest that the p53 status is not a predictor for the response of Plk1 inhibition, at least not directly. Yet, the long-term outcomes of losing p53, such as genome instability, could be associated with the cytotoxicity of Plk1 inhibition. Further studies are required to investigate whether other circumstances of cancer cells, such as DNA replication/damage stress, mitotic stress, and metabolic stress, which make possibly the survival of cancer cells more dependent on Plk1 function, are responsible for the sensitivity of Plk1 inhibition.