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PubMed2026

Recent advances in supramolecular macrocycle-based artificial light-harvesting systems.

Artificial light-harvesting systems (ALHSs) inspired by the antenna function of natural photosynthesis provide molecular platforms for collecting excitation energy and directing it to emissive or reactive acceptors. In many supramolecular ALHSs, however, practical performance is limited by poorly defined donor-acceptor orientation, aggregation-caused quenching (ACQ), interfacial defects, and limited stability in aqueous or complex media. Supramolecular macrocycles-particularly pillar[n]arenes (PAs), cucurbit[n]urils (CBs), calixarenes (CAs), cyclodextrins (CDs), and supramolecular coordination complexes (SCCs)-offer a useful design space because their cavities, pre-organized scaffolds, and reversible non-covalent interactions can confine chromophores, tune local donor/acceptor ratios, and modulate Förster resonance energy transfer (FRET). This Review systematically examines the unique structural advantages and assembly mechanisms of the five macrocyclic families, with an emphasis on their use in constructing ALHSs-from single-step to cascaded FRET-and in advancing aqueous photocatalysis, near-infrared bioimaging, panchromatic fluorescence modulation, and singlet oxygen generation. The resulting structure-property-application framework is intended to guide the rational design of macrocycle-assisted photofunctional materials while avoiding overextension of the photosynthesis analogy.

Journal Article↗
PubMed2002

The inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase by macrocyclic lactones and cyclosporin A.

The pharmacology of macrocyclic lactones is varied, with many beneficial effects in treating disease processes. FK-506, rapamycin and ascomycin have been utilized as immunosuppressant agents. Ivermectin is typically used to treat parasitic worm infections in mammals. Another immunosuppressant, cyclosporin A, is a cyclic oligotide that has similar immunosuppressant properties to those exerted by macrocyclic lactones. Here we report on the inhibition by these compounds of sarcoplasmic/endoplasmic-reticulum Ca(2+)-ATPase (SERCA) Ca(2+) pumps. Ivermectin, cyclosporin A and rapamycin all inhibited the skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1). In addition, although ivermectin inhibited brain microsomal endoplasmic reticulum (type 2b) Ca(2+)-ATPase, cyclosporin A and rapamycin did not. As cyclosporin A also did not inhibit cardiac Ca(2+)-ATPase activity, this would suggest that it could be an isoform-specific inhibitor. Ivermectin was shown to be the most potent Ca(2+)-ATPase inhibitor of the macrocyclic lactones (IC(50)=7 microM). It appears to show a 'competitive' inhibition with respect to high concentrations of ATP by increasing the regulatory binding site K(m) but without affecting the catalytic site K(m). In addition, ivermectin stabilizes the ATPase in an E1 conformational state, and inhibits Ca(2+) release from the enzyme during turnover. This would suggest that ivermectin inhibits Ca(2+) release from the luminal binding sites of the phosphoenzyme intermediate, a step that is known to be accelerated by high [ATP].

Adenosine Diphosphate↗
PubMed2003

Insulin mimetic effects of macrocyclic binuclear oxovanadium complexes on streptozotocin-induced experimental diabetes in rats.

AIM: The vanadium complexes so far tested for their insulin mimetic effects are either mono- or binuclear and contain only acyclic ligands. The leaching or hydrolysis of vanadyl ions from these complexes is much easier, and hence they elicit side effects. In the present study, a new binuclear macrocyclic oxovanadium complex was synthesized, and its efficacy was studied on streptozotocin (STZ)-induced diabetic rats over a period of 30 days. METHODS: The insulin mimetic effect of the complex was tested on the blood sugar level in the STZ-diabetic rats and on the activities of the carbohydrate-metabolizing enzymes present in the liver. RESULTS: Administration of vanadium complex to STZ-induced diabetic rats decreased blood glucose levels from hyperglycaemic to normoglycaemic when compared to diabetic rats. The activity of carbohydrate-metabolizing enzymes such as hexokinase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen content were increased to near normal in vanadium complex-administered diabetic rats. The biochemical studies such as assay of blood urea and glutamate oxaloacetate transaminases revealed that the complex is not toxic to the system. CONCLUSION: The nontoxic nature of this complex may be due to the presence of the vanadyl ions in an intact macrocyclic form. Further, the vanadyl ions present in the macrocyclic binuclear oxovanadium complex are very close to each other, and this may enhance the insulin mimetic activity by synergic effect.

Animals↗
PubMed1999

Effects of satratoxins and other macrocyclic trichothecenes on IL-2 production and viability of EL-4 thymoma cells.

The macrocyclic trichothecenes are a group of potent protein synthesis inhibitors that have been encountered in indoor air and food as a result of infestation by the fungus Stachybotrys. To evaluate the capacity of these mycotoxins to alter immune functions, the effects of satratoxin G, H, F, roridin A, and verrucarin A on interleukin 2 (IL-2) production and viability were evaluated in a murine T-cell model. EL-4 thymoma cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin and concurrently exposed to various concentrations of the trichothecenes. Enzyme-linked immunosorbent assay (ELISA) of supernatants revealed that IL-2 concentrations at 24 and 72 h were significantly increased in cultures that were incubated in the presence of 0.5 to 1 ng/ml of satratoxin H, 1 to 5 ng/ml of isosatratoxin F, 0.1 to 0.5 ng/ml of roridin A, and 0.25 to 0.5 ng/ml of verrucarin A. However, IL-2 levels at these time points were significantly depressed when incubated in the presence of higher concentrations of satratoxin G (> or =2.5 ng/ml), satratoxin H and isosatratoxin F (> or =5 ng/ml), and roridin A and verrucarin A (> or =1 ng/ml). Cell viability, as measured by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, was depressed by each of the trichothecenes in a concentration-dependent manner. MTT responses were significantly decreased by as little as 0.5 ng/ml satratoxin G, roridin A, and verrucarin A and by 2.5 ng/ml of isosatratoxin F and satratoxin H. When these data were compared to those found in EL-4 cells for the 8-ketotrichothecene vomitoxin (deoxynivalenol), a common food contaminant, the macrocyclic trichothecenes were at least 100 times more potent. The results indicate that, at low concentrations, macrocyclic trichothecenes as a group could superinduce IL-2 production even while partially decreasing cell viability, whereas higher concentrations suppressed cytokine production and were markedly cytotoxic. The capacity of these compounds to dysregulate cytokine production in a biphasic fashion may play an etiologic role in outbreaks of human illnesses associated with indoor Stachybotrys contamination.

Air Microbiology↗
PubMed1994

The synthesis and evaluation of macrocyclic gadolinium-DTPA-bis(amide) complexes as magnetic resonance imaging contrast agents.

The authors found that DTPA bis(amide) macrocycles can be prepared in reasonable yields using simple methods and readily available starting materials. Gadolinium complexation is facile and gives rise to monomeric and dimeric species. The "pocket size" influences the solid state structure of the final complex, with Gd-DTPA-EAM existing as a dimer wherein the macrocycle bridges between two metal centers. Increasing the size of the bridging diamide moiety yields a macrocycle with a sufficiently large pocket to allow for the formation of nine-coordinant monomeric complexes. The solution behavior of all the complexes studied is consistent with the complex being present as monomers. All complexes display kinetic lability comparable to Gd-DTPA-BMA. The measured KTherm and KSel values of the complexes vary with the size of the pocket. Values similar to those observed for Gd-DTPA-BMA have been obtained with Gd-DTPA-OAM. There appears to be a good correlation between log K(Gd/Zn) and the acute toxicity for the complexes studied, with Gd-DTPA-OAM showing a toxicity value similar to that of Gd-DTPA-BMA. Although many of these complexes are chemically interesting, they do not offer any unique advantages as new magnetic resonance imaging contrast agents compared with the DOTA- and DTPA-based products currently used clinically.

Animals↗
PubMed1989

Toxicology of novel macrocyclic trichothecenes, baccharinoid B4, myrotoxin B, and roritoxin B.

Baccharinoid B4, Myrotoxin B and Roritoxin B, some recently identified macrocyclic trichothecenes, were tested in Swiss mice with respect to their toxicity after oral and topical application. For oral dosing, the mycotoxins were dissolved in propylene glycol, and doses from 0 to 8.0 mg/kg body weight (BW) were employed. For topical application, toxins were dissolved in DMSO. A dose of 40 mg/kg BW was applied, except for Roritoxin B, where a dose of 10 mg/kg BW was also utilized. Animals were observed until death, or until 14 days after application and histopathological examinations were performed. It was found that Baccharinoid B4 was only moderately toxic, but this macrocyclic trichothecene appeared to exert its toxicity particularly on the intestine. Myrotoxin B was found to be quite toxic, and Roritoxin B was determined to be the most potent and toxic macrocyclic trichothecene of the three investigated. Oral administration of Roritoxin B resulted in death of 70-90% of mice at doses up to 1.0 mg/kg BW, and topical application of 10 or 40 mg/kg BW caused 100% death within 18 hours after application.

Administration, Oral↗
PubMed2004

DNA-templated organic synthesis and selection of a library of macrocycles.

The translation of nucleic acid libraries into corresponding synthetic compounds would enable selection and amplification principles to be applied to man-made molecules. We used multistep DNA-templated organic synthesis to translate libraries of DNA sequences, each containing three "codons," into libraries of sequence-programmed synthetic small-molecule macrocycles. The resulting DNA-macrocycle conjugates were subjected to in vitro selections for protein affinity. The identity of a single macrocycle possessing known target protein affinity was inferred through the sequence of the amplified DNA template surviving the selection. This work represents the translation, selection, and amplification of libraries of nucleic acids encoding synthetic small molecules rather than biological macromolecules.

Amides↗
PubMed2005

Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins in the indoor environment.

The existence of airborne mycotoxins in mold-contaminated buildings has long been hypothesized to be a potential occupant health risk. However, little work has been done to demonstrate the presence of these compounds in such environments. The presence of airborne macrocyclic trichothecene mycotoxins in indoor environments with known Stachybotrys chartarum contamination was therefore investigated. In seven buildings, air was collected using a high-volume liquid impaction bioaerosol sampler (SpinCon PAS 450-10) under static or disturbed conditions. An additional building was sampled using an Andersen GPS-1 PUF sampler modified to separate and collect particulates smaller than conidia. Four control buildings (i.e., no detectable S. chartarum growth or history of water damage) and outdoor air were also tested. Samples were analyzed using a macrocyclic trichothecene-specific enzyme-linked immunosorbent assay (ELISA). ELISA specificity was tested using phosphate-buffered saline extracts of the fungal genera Aspergillus, Chaetomium, Cladosporium, Fusarium, Memnoniella, Penicillium, Rhizopus, and Trichoderma, five Stachybotrys strains, and the indoor air allergens Can f 1, Der p 1, and Fel d 1. For test buildings, the results showed that detectable toxin concentrations increased with the sampling time and short periods of air disturbance. Trichothecene values ranged from <10 to >1,300 pg/m3 of sampled air. The control environments demonstrated statistically significantly (P < 0.001) lower levels of airborne trichothecenes. ELISA specificity experiments demonstrated a high specificity for the trichothecene-producing strain of S. chartarum. Our data indicate that airborne macrocyclic trichothecenes can exist in Stachybotrys-contaminated buildings, and this should be taken into consideration in future indoor air quality investigations.

Air Microbiology↗
PubMed1986

Paramagnetic macrocyclic complexes as contrast agents for MR imaging: proton nuclear relaxation rate enhancement in aqueous solution and in rat tissues.

Paramagnetic macrocyclic chelates show promise as magnetic resonance (MR) imaging contrast agents due to stability and relaxivity comparable to those of DTPA-type chelates. For the three copper and manganese macrocyclic complexes studied in aqueous solution, T1 and T2 relaxivities ranged from 0.14 to 5.88 mM-1sec-1 at 6.25 MHz. In rats, the intravenous administration of 16 mumol/kg of Mn(cyclam) caused the liver T1 relaxation rate to double at 15 minutes after injection. T1 measurements by pulsed MR imaging and manganese analyses on excised tissue showed that both relaxation rate (1/T1) and manganese content of liver and kidney increase linearly with the dosage of Mn(cyclam). The linear relationship between 1/T1 and manganese content can be considered an "in tissue" relaxivity plot for the agent. The resulting relaxivity is 54 mM-1sec-1 in liver, compared with 3.1 mM-1sec-1 in aqueous solution. Although this work is preliminary, the implication for medical MR imaging applications is that macrocyclic contrast agents can be effective at approximately one-tenth the current typical dose used for gadolinium DTPA.

Animals↗
PubMed2003

Novel archaeal macrocyclic diether core membrane lipids in a methane-derived carbonate crust from a mud volcano in the Sorokin Trough, NE Black Sea.

A methane-derived carbonate crust was collected from the recently discovered NIOZ mud volcano in the Sorokin Trough, NE Black Sea during the 11th Training-through-Research cruise of the R/V Professor Logachev. Among several specific bacterial and archaeal membrane lipids present in this crust, two novel macrocyclic diphytanyl glycerol diethers, containing one or two cyclopentane rings, were detected. Their structures were tentatively identified based on the interpretation of mass spectra, comparison with previously reported mass spectral data, and a hydrogenation experiment. This macrocyclic type of archaeal core membrane diether lipid has so far been identified only in the deep-sea hydrothermal vent methanogen Methanococcus jannaschii. Here, we provide the first evidence that these macrocyclic diethers can also contain internal cyclopentane rings. The molecular structure of the novel diethers resembles that of dibiphytanyl tetraethers in which biphytane chains, containing one and two pentacyclic rings, also occur. Such tetraethers were abundant in the crust. Compound-specific isotope measurements revealed delta13C values of -104 to -111/1000 for these new archaeal lipids, indicating that they are derived from methanotrophic archaea acting within anaerobic methane-oxidizing consortia, which subsequently induce authigenic carbonate formation.

Archaea↗
PubMed2002

[From new molecular science to new supramolecular science with macrocyclic polyamines].

Exploitation of saturated macrocyclic polyamines has led to the discovery of numerous novel functions and new molecules such as 1) unique proton sponge properties; 2) uptake of biological polyanions; 3) peptide-like metal uptake properties; 4) stabilization of unusual oxidation states of metal ions (e.g., CuIII, NiIII); 5) novel uptake and activation of O2 by new NiII-macrocyclic complexes; 6) a new synthetic pathway to functionalize macrocyclic polyamines; 7) the first gold(III) complex that is a new candidate for gold-plating agents; 8) intrinsic zinc(II) properties pertinent to zinc enzymes; 9) selective recognition of thymine by ZnII complexes; and 10) new cage supermolecules. These newly discovered molecules and properties have opened up a new field of supramolecular science.

Crystallography, X-Ray↗
PubMed2001

Macrocycles mimic the extended peptide conformation recognized by aspartic, serine, cysteine and metallo proteases.

It has been previously demonstrated that aspartic, serine, metallo and cysteine proteases bind to their inhibitors and substrate analogues in a single conformation, the saw-tooth or extended beta-strand. Consequently a generic approach to the development of protease inhibitors is the use of constraints that conformationally restrict putative inhibitor molecules to an extended form. In this way the inhibitor is pre-organized for binding to a protease and does not need to rearrange its structure. One constraining device that has proven to be effective for such pre-organization is macrocyclization. This article illustrates the general principle that macrocycles, especially those composed of 3-4 amino acids and usually 13-17 ring atoms, can effectively mimic the extended conformation of short peptide sequences. Such structure-stabilising macrocycles are stable to degradation by proteases, valuable components of potent protease inhibitors, and in many cases they are also bioavailable.

Aspartic Acid Endopeptidases↗
PubMed1992

Development of humoral immune responses against a macrocyclic chelating agent (DOTA) in cancer patients receiving radioimmunoconjugates for imaging and therapy.

The development of stable immunoconjugates by the advent of macrocyclic metal chelating agents (DOTA) has enabled us to study the ability of 111In-DOTA-labeled monoclonal antibodies to detect tumor lesions in a pilot radioimmunolocalization study, as well as to evaluate the kinetics, toxicity, and efficacy of i.p. administered 90Y-DOTA-labeled murine monoclonal antibody in a Phase I/II clinical trial of advanced ovarian cancer. The development of serum sickness-like reactions in three of six treated patients, in the absence of previous monoclonal antibody administration, led us to study the potential immunogenicity of the new chelate. Six patients with ovarian cancer received 25 mg of HMFG1 monoclonal antibody coupled with 90Y-DOTA (doses of radioactivity, 15 to 25 mCi), administered i.p. Eight patients with various malignant tumors received low doses (220 micrograms to 1 mg) of monoclonal antibodies, labeled with 111In-DOTA, i.v. for imaging studies. Using a solid-phase enzyme-linked immunosorbent assay method, the immunogenicity of DOTA was evaluated. Serial dilutions of patients' sera, before and after imaging or therapy with DOTA-coupled monoclonal antibodies, as well as sera from patients who did not receive DOTA-coupled antibody, were screened on enzyme-linked immunosorbent assay plates coated with human serum albumin (HSA), HSA-2-iminothiolane, and HSA-2-iminothiolane-benzyl-DOTA. All patients treated with i.p. monoclonal antibody developed anti-DOTA antibodies. Four of eight patients who received i.v. "imaging" doses of DOTA-coupled monoclonal antibody developed antibodies against DOTA. The levels of anti-DOTA response correlated with the amount of injected radioimmunoconjugate (r = 0.889, P less than 0.001). None of the patients who received DOTA-coupled antibody had detectable antibodies against the macrocycle before immunoconjugate administration. We then addressed further the restriction of the immune response against the macrocycle. We found that there was no or very low response against the aromatic ring attached to DOTA. Most, if not all, of the immune response is directed against the DOTA ring structure. Affinity purification of anti-DOTA antibody from serum enabled quantitation of these antibodies in the serum of patients. An inverse, statistically significant correlation was observed between the percentage of binding inhibition of a patient's serum to DOTA, by HSA-2-iminothiolane-DOTA (100 micrograms/ml) and the level of anti-DOTA immunoglobulin in the serum.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMedDate not supplied

Mass spectral investigations on trichothecene mycotoxins. II. Detection and quantitation of macrocyclic trichothecenes by gas chromatography/negative ion chemical ionization mass spectrometry.

A general, sensitive gas chromatographic/negative ion chemical ionization mass spectrometric (GC/NICIMS) method of analysis was developed for the detection and quantitation of several polar, thermally labile, toxic macrocyclic trichothecenes. The procedure involves the conversion of the molecules to their corresponding alcohols (verrucarols) by alkaline hydrolysis, followed by derivatization of the hydrolysate with heptafluorobutyrylimidazole and analysis by GC/MS technique under negative ion chemical ionization conditions. Nanogram (250 ng) quantities of several macrocyclic trichothecenes with different verrucarol and ester moieties were analyzed successfully with good precision by this procedure. The method was applicable for the accurate determination of at least low ppb levels of these macrocyclic trichothecenes in environmental samples, such as fungal products, fermentation broths, and plant samples. This is the first reported, well developed, sensitive, and applicable method for the detection and quantitation of these compounds in naturally occurring samples.

Fermentation↗
PubMedDate not supplied

[Quantitative dependence of structure-antiseizure activity in a series of macrocyclic compounds].

In the present study we have further examined the influence of some structure parameters of macrocyclic polyethers upon their anticonvulsant activity in order to determine basic pharmacophore fragments. The anticonvulsant activity was studied experimentally for 25 new macrocyclic compounds, and their structure, physico-chemical properties, electron donor factors and atom charges were calculated using programs HyperChem-ChemPlus and HYBOT. The data about atomic properties were presented as a set functions of inter-atomic distances (Program MOLTRA). The cluster analysis revealed that studied compounds represent two independent groups which differ from chemical and pharmacological viewpoints. For first group, we have found that anticonvulsant activity of macrocycles is determined by their polarizability and spatial orientation of electron donor atoms. For another cluster the correlation was found between activity and spatial orientation of two hydrophobic fragments and electron donor atoms as well.

Animals↗
PubMed2006

Amino acid derived macrocycles--an area driven by synthesis or application?

The synthesis, structure, and physical properties of macrocycles have fascinated chemists for many years. Their inherent properties make them useful in areas as diverse as ion transport across membranes, development of new antibiotics, and catalysis. In this Review, the authors examine the chemistry of macrocycles containing non-peptidic amino acid derived molecules; the analysis is discussed in terms of function, rather than structure or synthesis. It is revealed that the diverse and imaginative structures created by synthetic chemists are not being fully exploited in application-driven endeavors.

Amino Acids↗
PubMed2006

Macrocyclization by ring-closing metathesis in the total synthesis of natural products: reaction conditions and limitations.

The construction of macrocycles by ring-closing metathesis (RCM) is often used as the key step in the synthesis of natural products containing large rings. This reaction is attractive because of its high functional group compatibility and the possibility for further transformations. The finding of suitable reaction conditions is critical for the success of the synthesis. In this Minireview we summarize the efforts of many research groups to develop efficient RCM reactions on their way towards the total synthesis of natural macrocyclic products. Their findings should help in future synthesis to reduce the time-consuming phase of the optimization of the reaction conditions.

Biological Products↗
PubMed2005

Metal ion complexes of macrocyclic polyamines enhance both the phosphate hydrolysis and imidazole ring opening of RNA 5'-cap structure.

The cleavage of P1-(7-methylguanosyl-5') P3-(guanosyl-5') triphosphate, a RNA 5'-cap model, by 2-hydroxyethyl- (6a-6c) and 2-aminoethyl- (7a-7c) substituted macrocycles in the presence and absence of Zn2+ and Cu2+ ions has been studied at pH 7.2 and 60 degrees. In the presence of the metal ions, hydrolysis of the phosphate group is enhanced. The mono- and dinuclear Zn2+ complexes promote solely the phosphate hydrolysis, whereas the corresponding Cu2+ complexes accelerate both the phosphate hydrolysis and the imidazole ring opening of the 7-methylguanine base. In the absence of the metal ions, the macrocycles mainly promote breakdown of the 7-methylguanine base, most probably by enhancing the nucleophilic attack of hydroxide ion on the C(8)-atom by shielding the repulsive negative charge on the phosphate moiety. The 2-hydroxyethyl and 2-aminoethyl side arms exhibit a two- to three-fold rate acceleration. Opening of the imidazole ring eventually results in cleavage of the triphosphate bridge.

Copper↗