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PubMed1998

The in vivo behavior of copper-64-labeled azamacrocyclic complexes.

The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomolecules. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomolecule conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biological behavior of 64Cu complexes, a series of macrocyclic 64Cu complexes have been prepared, and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivatives, and cyclam, TETA, and et-cyclam were tetradecane backbone derivatives. The biodistributions of the 64Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compounds showed uptake and clearance through the liver and kidneys; however, the positively charged 64Cu complexes showed significantly higher uptake in both of these organs than did the negatively charged or neutral complexes. 64Cu-TETA, a negatively charged complex with the tetradecane backbone, had the most efficient clearance by 24 hours' postinjection. These data suggest that negatively charged complexes may have more favorable clearance properties when used as BFCs.

Animals↗
PubMed2002

Organization of the interior of molecular capsules by hydrogen bonding.

The enclosure of functional entities within a protective boundary is an essential feature of biological systems. On a molecular scale, free-standing capsules with an internal volume sufficiently large to house molecular species have been synthesized and studied for more than a decade. These capsules have been prepared by either covalent synthesis or self-assembly, and the internal volumes have ranged from 200 to 1,500 A(3). Although biological systems possess a remarkable degree of order within the protective boundaries, to date only steric constraints have been used to order the guests within molecular capsules. In this article we describe the synthesis and characterization of hexameric molecular capsules held together by hydrogen bonding. These capsules possess internal order of the guests brought about by hydrogen bond donors within, but not used by, the framework of the capsule. The basic building blocks of the hexameric capsules are tetrameric macrocycles related to resorcin[4]arenes and pyrogallol[4]arenes. The former contain four 1,3-dihydroxybenzene rings bridged together by -CHR- units, whereas the latter contain four 1,2,3-trihydroxybenzene rings bridged together. We now report the synthesis of related mixed macrocycles, and the main focus is on the macrocycle composed of three 1,2,3-trihydroxybenzene rings and one 1,3-dihydroxybenzene ring bridged together. The mixed macrocycles self-assemble from a mixture of closely related compounds to form the hexameric capsule with internally ordered guests.

Benzene↗
PubMedDate not supplied

Analysis of HSF-1 phosphorylation in A549 cells treated with a variety of stresses.

In the absence of stress, heat shock transcription factor-1 (HSF-1) exists as a monomer. After the treatment of cells with variety of stresses, HSF-1 forms a trimer and binds to the heat shock element (HSE), a motif consisting of three consecutive NGAAN sequences located in an inverted orientation upstream of the heat shock genes. HSF-1 is then phosphorylated causing transactivation of heat shock mRNAs. Treatment of cells with some of the stresses has been shown to increase HSF binding to HSE without detectably increasing the synthesis of heat shock mRNAs. Here we used antibody specific to HSF-1 to detect its phosphorylation status following exposure of A549, a human lung carcinoma cell line to a variety of stresses in order to correlate HSF-1 phosphorylation with its transactivation ability. Our studies show that HSF-1 is phosphorylated following heat shock (43 degrees C for 1 h), hypoxia (5 h exposure to 0.02% oxygen), 8% ethanol (1 h exposure at 37 degrees C), or 200 microM sodium arsenite (1 h exposure at 37 degrees C). All such stresses have previously been shown to increase the synthesis of heat shock proteins (hsps). However, there are no detectable increases in HSF-1 phosphorylation after the treatment of cells with X-irradiation (2-8 Gy) or 100 microM canavanine, an amino acid analogue (1 h exposure at 37 degrees C). Treatment of cells with X-irradiation increases HSF binding to HSE without increasing the synthesis of hsps, while treatment of cells with canavanine has been shown to increase the synthesis of hsps.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed1995

CD28 cross-linking augments TCR-mediated signals and costimulates superantigen responses.

The CD28 molecule expressed on the surface of T cells plays a pivotal role in transducing costimulatory signals necessary for cell activation. CD28 coligation enhances tyrosine phosphorylation and phosphoinositol 3-kinase association in responsive cells. CD28 cross-linking has also been reported to activate inositol phospholipid turnover and to cause release of intracellular calcium. Here we examine the effects of CD28 cross-linking on early activation of protein kinase C (PKC). We have reported recently that either PMA or CD28 cross-linking synergizes with signals delivered by superantigen and cytokines to induce the proliferation of APC-depleted T cells. Unlike PMA, CD28 cross-linking alone failed to induce an increase in membrane-associated PKC activity. However, PKC activation was seen in resting T cells when CD28 was cross-linked in the presence of superantigen plus APC-derived supernatant, which by themselves had no effect on PKC activity. Inhibition of PKC activity using calphostin C blocked the response of pure T cells to superantigen in the presence of either autologous APC, PMA, or CD28 cross-linking. This effect was specific; it was only seen when calphostin C was added within the first hour of stimulation. Assays of [Ca2+]i levels showed that CD28 cross-linking augmented and prolonged the rise in [Ca2+]i induced in T cells by superantigen and APC-derived cytokines. In the presence of superantigen, the proliferative response of T cells costimulated by CD28 cross-linking was cyclosporin A-sensitive, whereas in the presence of PMA, CD28 cross-linking conferred resistance to cyclosporin A. Both the phosphorylation of phospholipase C gamma 1 at tyrosine and the rise in [Ca2+]i induced by CD28 cross-linking in preactivated T cells were blocked by herbimycin A. Herbimycin A treatment also blocked the ability of CD28 cross-linking to induce a rise in [Ca2+]i in resting T cells. We conclude that CD28 costimulatory signals augment superantigen-induced TCR signals by converging onto common TCR effector pathways involving the activation of phospholipase C gamma 1 and PKC and by generating a cyclosporin A-sensitive pathway.

Antigen-Presenting Cells↗
PubMed2006

Characterization of isomeric cationic porphyrins with beta-pyrrolic substituents by electrospray mass spectrometry: the singular behavior of a potential virus photoinactivator.

Electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (ESI-MS/MS) have been used to differentiate the 2- and 4-methylpyridyl isomers of free-base and metallated cationic beta-vinylpyridylporphyrins. The analysis by ESI-MS/MS of the deuterated analogs and semiempirical calculations of structural and electronic parameters were also undertaken. The two free-base isomers are easily differentiated by ESI-MS/MS but the presence of a metallic center renders differentiation of the metallated isomers less effective. The data acquired show that of all the studied compounds, the free-base 2-methylpyridyl isomer, which was operative in the in vitro photoinactivation of Herpes simples virus, has a different gas-phase behavior. Local distortion of the macrocycle due to the presence of the beta-vinylpyridyl substituent occurs for all the compounds, but a different electron density distribution can account for the observed gas-phase behavior of this potential virus photoinactivator.

Antiviral Agents↗
PubMed1999

Synthesis and cytostatic activities of didemnin derivatives.

The highly cytostatic didemnins contain a 23-membered cyclopeptolide with a side chain attached to the backbone through the amine group of threonine. Thirty-six derivatives varying the side chain were prepared, but only compounds with D-MeLeu attached to threonine show remarkable biological activities. To protect the macrocycle from degradation by lipases the two ester bonds were replaced successively by amide bonds. Although these variations have a major effect on the conformation and rigidity of the ring, the compound which contains exclusively amide bonds is highly active, equivalent to acetyl-didemnin A.

Antineoplastic Agents↗
PubMedDate not supplied

On-line HPLC-electrospray ionization mass spectrometry: a pharmacological tool for identifying and studying the stability of Gd3+ complexes used as magnetic resonance imaging contrast agents.

The identification of MRI contrast agents (CAg) as gadolinium complexes often used at very low concentrations in Pharmacology was carried out by ESI-MS or HPLC-ESI-MS. Firstly, Omniscan, Dotarem and Magnevist were tested. In these compounds, the Gd3+ ion must be solidly chelated by linear or macrocyclic ligands because of the severe toxicity of the free Gd3+. Spectra were obtained at low voltage, preserving the non-covalent binding integrity of the complexes, and at various higher voltages showing the progressive destruction of the complexes. Secondly, a direct reaction of these drugs with the oxidative human neutrophil production, induced in vitro by Phorbol 12-myristate 13-acetate enhancing the respiratory burst, was investigated. This was done to mimic what happens in the case of inflammatory diseases, or infection, or when people are likely to develop anaphylactoid reactions, as the i.v. injection of CAg causes contact between the complexes and neutrophils in the blood. Analysis by HPLC-ESI-MS coupling did not show any direct reaction between Gd complexes and the chemical compounds in the neutrophil oxidative metabolism, even if uncertainty remains as regards meglumine salt. HPLC-ESI-MS is a good way of visualizing characteristic, Gd isotopic distribution and of following its associations in biological samples.

Chromatography, High Pressure Liquid↗
PubMed2005

Protein recognition of macrocycles: binding of anti-HIV metallocyclams to lysozyme.

The macrocyclic antiviral drug xylyl-bicyclam blocks entry of HIV into cells by targeting the CXCR4 coreceptor, a seven-helix transmembrane G-protein-coupled receptor. Its affinity for CXCR4 is enhanced by binding to Cu2+, Ni2+, or Zn2+. Metallocyclams have a rich configurational chemistry and proteins may bind selectively to specific metallocyclam configurations. Our studies of lysozyme reveal structural details of protein-metallocyclam interactions that are important for receptor recognition. Solution NMR studies show that Cu-cyclam interacts with specific tryptophan residues of lysozyme (Trp-62, Trp-63, and Trp-123). Two major binding sites for both Cu-cyclam and Cu2-xylyl-bicyclam were detected by x-ray crystallography. In the first site, Cu2+ in one cyclam ring of Cu2-xylyl-bicyclam adopts a trans configuration and is coordinated to a carboxylate oxygen of Asp-101, whereas for Cu-cyclam two ring NH groups form H bonds to the carboxylate oxygens of Asp-101, stabilizing an unusual cis (folded) cyclam configuration. For both complexes in this site, a cyclam ring is sandwiched between the indole side chains of two tryptophan residues (Trp-62 and Trp-63). In the second site, a trans cyclam ring is stacked on Trp-123 and H bonded to the backbone carbonyl of Gly-117. We show that there is a pocket in a model of the human CXCR4 coreceptor in which trans and cis configurations of metallobicyclam can bind by direct metal coordination to carboxylate side chains, cyclam-NH...carboxylate H bonding, together with hydrophobic interactions with tryptophan residues. These studies provide a structural basis for the design of macrocycles that bind stereospecifically to G-coupled and other protein receptors.

Animals↗
PubMedDate not supplied

Isolation and characterization of two verrucarins from Myrothecium roridum.

In the course of a screening for compounds inhibiting the growth of two human breast cancer cells lines, two highly cytotoxic compounds were isolated from fermentations of Myrothecium roridum. The elucidation of their structures revealed that they are macrocyclic trichothecenes of the verrucarin type, 16-hydroxyverrucarin A (1), reported here as a natural product for the first time, and verrucarin X (2), a new compound. Both 1 and 2 exhibit moderate antifungal activity and pronounced cytotoxic activity, with IC50 values in the nanomolar (1) and micromolar (2) range. Both compounds preferentially inhibit in vivo protein biosynthesis.

Adenocarcinoma↗
PubMed2003

UV photostability of metal phthalocyanines in organic solvents.

Kinetic studies of photochemical reactions induced by UV radiation in solutions of metal phthalocyanines have been carried out to determine the factors which might have influenced the stability of photosensitized phthalocyanines. Complexes of the molecular type Mpc, M'(2)pc, and Lnpc(2) (where M = Li, Mg, Fe, Co, Zn, Pb; M'= Tl; Ln = rare earth; pc = phthalocyanine ligand, C(32)H(16)N(8)(2-)) were investigated in DMF, DMSO, and pyridine. Progressive decay of the phthalocyanine macrocycle due to absorption of UV light was observed. Phthalimide found in the final photolysis product may indicate some chemically bonded oxygen involved in the solid phthalocyanine material. Fluorescence lifetimes determined for the studied compounds (2.91-5.98 ns) have shown no particular relation to the stability of the excited macrocyclic system. The bonding strength of the photosensitized phthalocyanine moiety appears to rely on typical chemical factors, rather than on the properties of the excited states. Kinetics of the degradation process has proved to depend on the molecular structure of the complex and seems to be controlled by interactions of the macrocycle bridging nitrogen atoms with the solvent molecules. The use of electron acceptor solvents such as DMSO may enhance the molecular stability of phthalocyanines excited by UV radiation. Sandwich-type rare earth diphthalocyanines dissolved in DMSO displayed the highest photostability.

Journal Article↗
PubMed2000

Enzyme-mimetic model compounds: conformational analysis and far-IR study of Cu(TAAB)2+.

Many enzymes occurring in nature like superoxide dismutase are systems rather too big to be accessible for vibrational and quantum chemical investigations. Thus, enzyme-mimetic model compounds consisting of a biological active metal centre surrounded by a macrocyclic ligand are used to shed light on binding properties of the active metal centre. Far- and mid-range IR spectroscopic investigations and a conformational analysis with the semi-empirical ZINDO/1 method of superoxide dismutase-mimetic complex Cu[TAAB]2+ are performed (TAAB = [b,f,j,n][1,5,9,13]tetra-aza-cyclohexadecine (tetra-anhydroamino benzaldehyde)). A distorted tetrahedral copper(II) centre with slightly twisted phenyl subunits is determined as the most stable conformation. Calculated mid- and far-IR spectra are in good agreement with the experimental data and confirm the proposed structure. A harmonic normal-coordinate analysis is used to assign the vibrational modes of the observed spectra.

Binding Sites↗
PubMed2004

Differential protein acetylation induced by novel histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors induce the hyperacetylation of nucleosomal histones in carcinoma cells resulting in the expression of repressed genes that cause growth arrest, terminal differentiation, and/or apoptosis. In vitro selectivity of several novel hydroxamate HDAC inhibitors including succinimide macrocyclic hydroxamates and the non-hydroxamate alpha-ketoamide inhibitors was investigated using isolated enzyme preparations and cellular assays. In vitro selectivity for the HDAC isozymes (HDAC1/2, 3, 4/3, and 6) was not observed for these HDAC inhibitors or the reference HDAC inhibitors, MS-275 and SAHA. In T24 and HCT116 cells these compounds caused the accumulation of acetylated histones H3 and H4; however, the succinimide macrocyclic hydroxamates and the alpha-ketoamides did not cause the accumulation of acetylated alpha-tubulin. These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase.

Amides↗
PubMed2003

Acyclic congener of cucurbituril: synthesis and recognition properties.

The cucurbit[n]uril (CB[n]) family of macrocycles occupies a prominent role in molecular recognition and self-assembly studies despite the current inability to access specific cucurbit[n]uril homologues, derivatives, and analogues by straightforward tailor-made synthetic procedures. In this paper, we explore an approach that circumvents the challenges posed by the tailor-made synthesis of macrocyclic CB[n] by preparing 1, which functions as an acyclic CB[6] congener. The o-xylylene connections to the glycoluril rings preorganize 1 into the (a,a,a,a)-1 conformation required for binding and reduce its tendency to undergo self-association. We surveyed the binding properties of 1 toward 16 amines (K(a) <or= 1.52 x 10(4) M(-)(1)) and diol, diacid, guanidinium, and pyridinium species in pD 7.4 phosphate-buffered D(2)O. We find that the recognition properties of 1 parallel those of CB[6], binding tightly to alkaneammonium species in water and exhibiting length-dependent selectivity and competitive binding with alkali metals present in solution. Compound 1 binds hexanediammonium ion only 180-fold less tightly than CB[6]. The modular synthesis of 1 suggests synthetic methods toward the preparation of acyclic CB[n] congeners with complex functional groups on the edges of their aromatic rings and cavity volumes similar to CB[7] and CB[8]. In combination, these results suggest that acyclic CB[n] congeners hold promise in molecular recognition and self-assembly studies that complements that of macrocyclic CB[n].

Bridged-Ring Compounds↗
PubMed1978

Induction of plasminogen activator in cultured cells by macrocyclic plant diterpene esters and other agents related to tumor promotion.

In vitro systems that are responsive to tumor-promoting agents may facilitate the identification of such agents and the analysis of their mode of action. We have previously reported that the potent tumor promoter phorbol-12-myristate-13-acetate induces the synthesis of the enzyme plasminogen activator in cultured chick embryo fibroblasts. We have, therefore, tested various compounds for their ability to induce plasminogen activator in chicken embryo fibroblasts. Among these, phorbol esters and other macrocyclic diterpene esters isolated from species of the families Euphorbiaceae and Thymelaeaceae were potent inducers of plasminogen activator. These compounds maximally induced enzyme to the same levels, although they differed in their relative molar potencies. Structural requirements for in vitro activity paralleled the requirements for activity in vivo. These results indicate that induction of plasminogen activator is a useful marker for the biologically active macrocyclic diterpene esters. On the other hand, tumor-promoting agents such as anthralin, cantharidin, Tween 60, and tobacco leaf extract failed to induce plasminogen activator.

Cells, Cultured↗
PubMed1987

Identification of novel erythromycin derivatives in mother liquor concentrates of Streptomyces erythraeus.

The identification of five novel compounds, pseudo-erythromycin A-6,9-hemiketal, 8,9-anhydro-pseudo-erythromycin A-6,9-hemiketal, 8,9-anhydro-pseudo-N-demethylerythromycin A-6,9-hemiketal, 5-O-beta-D-desosaminylerythronolide A and 15-nor-erythromycin C, in mother liquor concentrates of Streptomyces erythraeus is described. The pseudo-erythromycin derivatives are characterized by a 12-membered macrocyclic ring as a result of C13----C11 trans-lactonization. The five compounds have very little antimicrobial activity.

Bacteria↗
PubMed2006

Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin.

The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. Neither compound seemed to induce an aberrant tubulin assembly reaction, as occurs with vinblastine (tight spirals) or dolastatin 10 (aggregated rings and spirals). We modeled the two compounds into a shared binding site on tubulin consistent with their biochemical properties. Of the two tubulin structures available, we selected for modeling the complex of a stathmin fragment with two tubulin heterodimers with two bound colchicinoid molecules and a single bound vinblastine between the two heterodimers (Nature (Lond) 435:519-522, 2005). Halichondrin B and NSC 707389 fit snugly between the two heterodimers adjacent to the exchangeable site nucleotide. Fitting the compounds into this site, which was also close to the vinblastine site, resulted in enough movement of amino acid residues at the vinblastine site to cause the latter compound to bind less well to tubulin. The model suggests that halichondrin B and NSC 707389 most likely form highly unstable, small aberrant tubulin polymers rather than the massive stable structures observed with vinca alkaloids and antimitotic peptides.

Binding Sites↗