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PubMed2004

Structural effects of the lone pair on lead(II), and parallels with the coordination geometry of mercury(II). Does the lone pair on lead(II) form H-bonds? Structures of the lead(II) and mercury(II) complexes of the pendant-donor macrocycle DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane).

The synthesis and structures of [Pb(DOTAM)](ClO4)2.4.5H2O (1) and [Hg(DOTAM)](ClO4)2.0.5CH3OH.1.5H2O (2) are reported, where DOTAM is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane. Compound 1 is triclinic, space group P, a = 12.767(3) A, b = 13.528(2) A, c = 18.385(3) A, alpha = 101.45(2) degrees, beta = 93.32(2) degrees, gamma = 90.53(2) degrees, Z = 4, R = 0.0500. Compound 2 is monoclinic, space group Cc, a = 12.767(3) A, b = 13.528(2) A, c = 18.385(3) A, beta = 101.91(2) degrees, Z = 4, R = 0.0381. The Pb(II) ion in 1 has an average Pb-N = 2.63 A to four N-donors from the macrocyclic ring, and four O-donors (average Pb-O = 2.77 A) from the amide pendant donors of the macrocycle, with a water molecule placed with Pb-O = 3.52 A above the proposed site of the lone pair (Lp) on Pb. The Hg(II) in 2 appears to be only six-coordinate, with four Hg-N bond lengths averaging 2.44 A, and two Hg-O from pendant amide donors at 2.41 A. The other two amide donors appear to be noncoordinating, with Hg-O distances of 2.74 and 2.82 A. A water situated 3.52 A above the proposed site of the lone pair on Pb(II) in 1 is oriented in such a way that it might be thought to be forming a Pb-Lp.H-O-H hydrogen bond. It is concluded that that this is not an H-bond, but that the presence of the lone pair allows a closer approach of the hydrogens to Pb than would be true otherwise. The structural analogy in the VSEPR sense between Pb(II), which has the 5d(10)6s(2) outer electron structure, and the Hg(II) ion, which has the 5d10 structure, is examined. The tendency of Hg(II) toward linear coordination, with two short Hg-L bonds (L = ligand) at 180 degrees to each other, and other donor groups at roughly 90 degrees to this and at much longer bond distances, is paralleled by Pb(II). One of the short Hg-L bonds is replaced in the Pb(II) structures by the lone pair (Lp), which is opposite the short Pb-L bond, or in some cases 2-4 shorter Pb-L bonds.

Journal Article↗
PubMed2003

Macrocyclization in the design of Grb2 SH2 domain-binding ligands exhibiting high potency in whole-cell systems.

While most SH2 domains bind phosphotyrosyl (pTyr) containing peptides in extended fashion, the growth factor receptor-bound protein 2 (Grb2) SH2 domain preferentially binds ligands in bend conformations. Accordingly, incorporation of bend-inducing functionality into synthetic ligands could potentially enhance their affinity for this SH2 domain. A macrocyclic tripeptide mimetic that contains a simplified pTyr surrogate lacking an alpha-nitrogen has recently been shown to exhibit high Grb2 SH2 domain-binding affinity in extracellular ELISA-based assays. However, the same compound is largely ineffective in whole-cell assays. It is known that acidic functionality originating from the alpha-nitrogen of pTyr residues or from the alpha-position of P0 pTyr mimetics not only increases binding affinity of peptides to Grb2 SH2 domains in extracellular assays but also enhances potency in cell-based systems. Such functionality is absent from the previously reported macrocycle. Therefore, the current study was undertaken to examine the effects of introducing carboxylic functionality at the pTyr mimetic alpha-position of macrocyclic ligands. It was found that such a modification not only enhanced Grb2 SH2 domain binding in extracellular assays but also conferred high efficacy in whole-cell systems. The most potent compound of the current study exhibited an IC(50) value of 0.002 microM in an extracellular ELISA-based assay, and in MDA-MB-453 cells, it both inhibited the association of Grb2 with p185(erbB-2) and exhibited antimitogenic effects with submicromolar IC50 values.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 1. Tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazine: a new macrocycle with remarkable electron-deficient properties.

A new pyrazinoporphyrazine macrocycle carrying externally appended pyridine rings, tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazine (hydrated), [Py(8)TPyzPzH(2)].2H(2)O, was prepared in high yield by direct cyclotetramerization of the precursor, 2,3-dicyano-5,6-di(2-pyridyl)-1,4-pyrazine, [(CN)(2)Py(2)Pyz], in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The single-crystal X-ray structure of [(CN)(2)Py(2)Pyz] shows a noncoplanar positioning of the pyrazine and pyridine rings in the two slightly different independent molecular units present in the crystal. UV-vis spectra of [Py(8)TPyzPzH(2)] were measured in two nondonor solvents (CHCl(3), CH(2)Cl(2)), a slightly basic solvent (pyridine), and an acidic solvent (CH(3)COOH). In all cases, the spectral changes are consistent with the occurrence of molecular aggregation and colloidal dispersions which break up with time to give clear solutions containing exclusively the monomeric form of the macrocycle, either neutral [Py(8)TPyzPzH(2)] (in CHCl(3), CH(2)Cl(2), and CH(3)COOH) or dianionic [Py(8)TPyzPz](2)(-) (in pyridine). A spectrally monitored titration of [Py(8)TPyzPzH(2)] in CH(2)Cl(2) with TBA(OH) shows the loss of two protons from the macrocyclic core and quantitative conversion of [Py(8)TPyzPzH(2)] to [Py(8)TPyzPz](2)(-). Cyclic voltammetry and thin-layer spectroelectrochemical measurements show that [Py(8)TPyzPzH(2)] is present in CH(2)Cl(2) while [Py(8)TPyzPz](2)(-) is present in pyridine, but both forms of the compound exhibit identical electrochemical behavior, consistent with a conversion of the dianion to the neutral porphyrazine in pyridine prior to electroreduction via four reversible one-electron transfer steps. No oxidations of the macrocycle are observed in either solvent containing 0.1 M tetrabuthylammonium perchlorate (TBAP). A comparison of the electrochemical behavior for [Py(8)TPyzPzH(2)] with what is reported for related phthalocyanine and porphyrazine analogues highlights the remarkable electron-accepting properties of the presently investigated free-base macrocycle.

Journal Article↗
PubMed1997

Mineral trioxide aggregate stimulates a biological response in human osteoblasts.

We report a novel material that appears to stimulate cytokine production in human osteoblasts and allow good adherence of the cells to the material. We have examined cultured osteoblasts (MG-63) in the presence of mineral trioxide aggregate (MTA) as set in moist conditions; secondly, we examined the behavior of these MG-63 cells with respect to cytokine and osteocalcin production and alkaline phosphatase activity. Standard ELISA assays were used for assessment of interleukin (IL)-1 alpha, IL-1 beta, IL-6, macrophage colony stimulating factor (M-CSF), and osteocalcin. Furthermore the levels of alkaline phosphatase were measured to establish the level of differentiation of the cells. Cells without MTA served as controls. Cells also were grown in the presence of polymethylmethacrylate (PMA), the commonly used orthopedic cement. In all dishes cells were seen adhering to the base and MTA at 6 h and had increased to confluence at 144 h. IL-1 alpha (175.1 +/- 32.6 pg/mL), IL-1 beta (154.0 +/- 26.7 pg/mL), and IL-6 (214.7 +/- 21.8 pg/mL) were raised when the cells were grown in the presence of MTA at 144 h, with raised values at all time intervals. M-CSF appeared to be unaffected although the overall value was high (7,045.0 +/- 89.5 pg/mL). In contrast, cells grown in the absence of MTA produced negligible amounts of these cytokines (< pg/mL) as did those cells grown in the presence of PMA. Osteocalcin production increased when cells were grown on MTA from 3.8 +/- 0.87 ng/mL to 19.7 +/- 2.8 ng/mL. No osteocalcin could be detected with PMA. Cells in contact with MTA also appeared to have levels of alkaline phosphatase similar to those reported elsewhere (4.3 +/- 0.21 mumol/mg protein/min). No cells could be found attached to PMA and so no alkaline phosphatase activity could be measured.

Alkaline Phosphatase↗
PubMed1998

Evaluation of the macrocyclic antibiotic avoparcin as a new chiral selector for HPLC.

Avoparcin is a macrocyclic glycopeptide antibiotic structurally related to vancomycin, teicoplanin, and ristocetin A. When attached to 5-microns spherical silica gel, the avoparcin proved to be an effective chiral stationary phase (CSP) that could be used in the reversed-phase, normal-phase, and polar-organic modes. The avoparcin CSP was complimentary to the other macrocyclic glycopeptide CSPs in that it could resolve some racemates that the others could not, and vice versa. Some important compounds resolved on the avoparcin CSP include verapamil, thyroxine, mephenytoin, and 2-imidazolidone-4-carboxylic acid. The use of this CSP and the optimization of separations on it are discussed. Avoparcin appears to be a useful addition to this family of CSPs.

Anti-Bacterial Agents↗
PubMed2004

Configurations of metallocyclams and relevance to anti-HIV activity.

Antiviral cyclam macrocycles block viral entry into cells by binding to the CXCR4 co-receptor. Cyclams bind transition metal ions strongly and can potentially form a range of trans (I-V) and cis configurations which may be recognised differently by co-receptor proteins. A survey of the CSD (crystallographic structural database) shows that the trans-III configuration is the most common in the solid state for complexes of cyclam itself. Other configurations can be induced by N-substitution or ternary complexation and by interaction with solvents in solution. We report X-ray structures for the square-planar trans-III complexes [Pd(cyclam)]Cl(2).2MeOH and the C-C linked dimer [Pd(2)(2,2'-bi-(1,4,8,11-tetraazacyclotetradecane))](ClO4)(4), in which the planes of the two cyclam rings are close to perpendicular (100.1 degrees ), and for tetra-N-benzyl-cyclam and its 5-coordinate Ni(II) complex [Ni(Bz(4)-cyclam)Cl]Cl which has the unusual trans-I configuration.

Anti-HIV Agents↗
PubMed2006

A new type of steroids with a cyclobutane fragment in the AB-ring moiety.

The synthesis of a 5,10-seco steroid containing two double bonds in a AB-macrocycle as well as the preparation of a steroidal skeleton with a cyclobutane fragment is described. The structures of these compounds are different from those of natural steroids, but they are very similar with respect to conformation of the carbon skeleton.

Cyclobutanes↗
PubMed2000

Permeation liquid membrane metal transport: studies of complex stoichiometries and reactions in Cu(II) extraction with the mixture 22DD-laurate in toluene/phenylhexane

The role of lauric acid (LAH) in the transport of copper(II) through a permeation liquid membrane (PLM) comprising 1,10-didecyldiaza-18-crown-6 (22DD) and lauric acid (ratio 1:1) in 1:1 v/v toluene/phenylhexane has been investigated by determining the stoichiometry of metal extraction and of the metal complex formed in the organic phase by performing 1H NMR and liquid/liquid and liquid/membrane extraction measurements. In the absence of copper(II), the 1H NMR data suggest that there is a strong interaction between the proton of LAH and the nitrogen of the 22DD macrocycle but no interaction between the aliphatic long chains of LAH and 22DD. Thus, in the organic solution, the two compounds are associated as (22DD-H)(+)-LA-, the laurate being away from (22DD-H)+. The signal intensity of the acidic proton was found to decrease when the metal Pb(II) was incorporated by the carrier after its extraction from the aqueous phase. Additionally, liquid/liquid as well as liquid/membrane extraction results reveal that Cu(II) extraction proceeds via the loss of two protons from the organic phase. The Cu(II) is found to be located in the 22DD cavity and the stoichiometry of the complex in the organic phase is (22DD-Cu)(2+)-2LA-. Metal extraction is governed by 22DD and laurate acts only as counteranion. An unexpected feature was observed in the liquid/liquid extraction which was that, at low 22DD and LAH concentrations, the slope for log(Kp) = f(pH) was 2 whereas it was much lower at high carrier concentration. This unexpected result seems to stem from impurities present in 22DD: only 0.1 mol% of impurity can indeed influence the exchange ratio of Cu(II) and H+. This type of anomaly, however, is not found in the normal procedure of liquid/membrane extraction possibly due to the lower carrier/metal molar ratio which is used in the classical PLM conditions.

Journal Article↗
PubMed2003

Synthesis and characterization of cationic iodonium macrocycles.

A synthetic strategy for the high-yield preparation of iodonium containing macrocycles such as rhomboids, a square, and a pentagon is described, with the long-term objective of preparing iodonium compounds for potential molecular electronics applications. Two cationic rhomboid shaped molecules were prepared for the first time (55-70%) by the treatment of compounds 11 and 12a or 12b with Me3SiOTf. The reaction of dication 8 with 6 in the presence of Me3SiOTf gave an iodonium containing molecular square in 70% yield. In addition, a pentagon-shaped macromolecule was prepared in 60% yield. These iodonium-containing charged macromolecules were characterized by multinuclear NMR, mass spectrometry, and physical means.

Cations↗
PubMed1996

New macrocyclic spermine (budmunchiamine) alkaloids from Albizia gummifera: with some observations on the structure--activity relationships of the budmunchiamines.

The CH2Cl2 extract of the stem bark of Albizia gummifera yielded four macrocyclic spermine alkaloids (budmunchiamines), three of them being new analogues. On the basis of spectral analysis and comparison with related compounds they were identified as budmunchiamine G (1) and the new analogues budmunchiamine K (2), 6'xi-hydroxybudmunchiamine K (3), and 9-normethylbudmunchiamine K (4). The four isolated alkaloids and other related budmunchiamines isolated from Albizia schimperana were all active against two Gram-positive and two Gram-negative bacteria at MIC levels below 80 micrograms mL(-1), and showed toxicity to brine shrimp larvae (with LC50 values below 100 micrograms mL(-1)). The negative impact of side chain hydroxylation and N-demethylation on both measures of biological activity was shown to be considerable.

Alkaloids↗
PubMed1999

Stereochemistry of the roridins. Diastereomers of roridin E.

A careful investigation of cultures of Myrothecium verrucaria has shown that this fungus produces all four roridin E isomers (3a-d), diastereomeric at the C-6' and C-13' centers. The stereochemistries at these centers were established by a combination of X-ray crystallographic analysis, NMR spectroscopy, and chemical transformations. NMR data from these and other macrocyclic trichothecenes allows for the assignment of configurations at the C-6' and C-13' centers for most of these compounds, the exceptions being those congeners having a C-4' ketone group in the macrolide ring.

Crystallography, X-Ray↗
PubMed2002

In vitro inhibition of 1,3-beta-glucan synthase by glycolipids from convolvulaceous species.

Sixteen convolvulaceous glycolipids selected from the tricolorin (1 - 7) and orizabin (8 - 16) series, proved to be strong in vitro inhibitors of the enzyme that catalyzes the synthesis of 1,3-beta-D-glucan, a major polymer of fungal cell-walls. Results provide an insight into function of the specific structures of these complex macrocyclic lactones as inhibitors of the 1,3-beta-D-glucan synthase and open the possibility of using these compounds as starting points for the development of antifungal agents that act by inhibiting fungal cell-wall synthesis.

Antifungal Agents↗
PubMed1989

Mass spectral investigations on trichothecene mycotoxins. VIII--Thermospray ionization and collisionally activated dissociation of macrocyclic trichothecenes.

Several structurally similar, biologically active macrocyclic trichothecenes were ionized under thermospray conditions followed by collisionally activated dissociation of the ammonium adducts. Most of the observed daughter ions were formed by bond cleavage at the exocyclic ester bridges. Compounds with similar ester bridges formed several common daughter ions and underwent similar neutral losses. Fragmentation pathways proposed for the dissociation of the adducts were confirmed from the corresponding neutral loss spectra. Simple experiments designed for the sequential monitoring of the characteristic daughter ions were used for the rapid, direct and accurate analysis of macrocyclic trichothecenes in real samples. The primary drawback of the method is its inability to distinguish between isomers.

Chemical Phenomena↗
PubMed1988

LL-F28249 antibiotic complex: a new family of antiparasitic macrocyclic lactones. Isolation, characterization and structures of LL-F28249 alpha, beta, gamma, lambda.

A new family of antiparasitic macrolides has been isolated from Streptomyces cyaneogriseus sp. noncyanogenus. The compounds, designated LL-F28249 alpha, beta, gamma and lambda, possess potent antiparasitic activity. The isolation, purification and structure determination by spectroscopic methods are presented.

Anti-Bacterial Agents↗
PubMed2006

Neomycin-capped aromatic platforms: quadruplex DNA recognition and telomerase inhibition.

A series of aminoglycoside-capped macrocyclic structures has been prepared using intramolecular bis-tethering of neomycin on three aromatic platforms (phenanthroline, acridine, quinacridine). Based on NMR and calculations studies, it was found that the cyclic compounds adopt a highly flexible structure without conformational restriction of the aminoglycoside moiety. FRET-melting stabilization measurements showed that the series displays moderate to high affinity for the G4-conformation of human telomeric repeats, this effect being correlated with the size of the aromatic moiety. In addition, a FRET competition assay evidenced the poor binding ability of all macrocycles for duplex DNA and a clear binding preference for loop-containing intramolecular G4 structures compared to tetramolecular parallel G4 DNA. Finally, TRAP experiments demonstrated that the best G4-binder (quinacridine ) is also a potent and selective telomerase inhibitor with an IC(50) in the submicromolar range (200 nM).

Acridines↗
PubMed2005

The diazo route to diazonamide A. Studies on the indole bis-oxazole fragment.

[structure: see text] Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl compounds in key steps. Thus, 3-bromophenylacetaldehyde is converted into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Boc-valinamide resulted in N-H insertion of the intermediate rhodium carbene to give a ketoamide that readily underwent cyclodehydration to give (S)-2-(1-tert-butoxycarbonylamino)-2-methylpropyl]-5-(3-bromobenzyl)oxazole-4-carboxamide, after ammonolysis of the initially formed ester. This aryl bromide was then coupled to a 3-formyl-indole-4-boronate under Pd catalysis to give the expected biaryl. Subsequent conversion of the aldehyde group into a second alpha-diazo-beta-ketoester gave a substrate for an intramolecular carbene N-H insertion, although attempts to effect this cyclization were unsuccessful. A second approach to an indole bis-oxazole involved an intermolecular rhodium carbene N-H insertion, followed by oxazole formation to give (S)-2-[1-tert-(butoxycarbonylamino)-2-methylpropyl]-5-methyloxazole-4-carboxamide. A further N-H insertion of this carboxmide with the rhodium carbene derived from ethyl 2-diazo-3-[1-(2-nitrobenzenesulfonyl)indol-3-yl]-3-oxopropanoate gave a ketoamide, cyclodehydration of which gave the desired indole bis-oxazole. Finally, the boronate formed from 4-bromotryptamine was coupled to another diazocarbonyl-derived oxazole to give the corresponding biaryl, deprotection and cyclization of which produced a macrocyclic indole-oxazole derivative. Subsequent oxidation and cyclodehydration incorporated the second oxazole and gave the macrocyclic indole bis-oxazole.

Heterocyclic Compounds, 4 or More Rings↗
PubMed2001

Synthesis and biological evaluation of nonylprodigiosin and macrocyclic prodigiosin analogues.

Nonylprodigiosin (4) and various of its analogues have been prepared by Suzuki cross-coupling reactions of a well accessible pyrrolyl triflate with (hetero)aryl boronic acid derivatives bearing alkenyl side chains. The resulting alkenes or dienes were subjected to metathesis dimerization or ring-closing metathesis (RCM) reactions, respectively, by using a ruthenium indenylidene complex as the catalyst. The biological activity of the products thus obtained was tested in two different assays monitoring i) the proliferation of murine spleen cells induced by lipopolysaccharides (LPS) and concanavalin A (Con A), and ii) the vacuolar acidification of baby hamster kidney (BHK) cells. Compounds 4 and 21 suppressed Con A-induced T-cell proliferation much more potently than LPS-induced B-cell proliferation. Furthermore, compounds 4 and 26 markedly inhibited vacuolar acidification, although other compounds exhibited no or only marginal effects. Thus, the immunosuppressive activity of prodigiosins toward T-cell proliferation seems to be mediated through cellular targets distinct from vacuolar acidification, and the prodigiosin analogues might be powerful tools to dissect these biological responses. The X-ray crystal structure of the macrocyclic product 25 has been determined, showing that the replacement of one pyrrole ring of the parent compound 4 by a phenyl group does not alter the overall electronic features of the remaining heterocyclic ring system of these alkaloids.

Animals↗