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PubMed2001

A novel binucleating macrocyclic ligand with two alcohol pendants.

A novel binucleating 24-membered macrocyclic ligand, 6,20-bis(2-hydroxyethyl)-3,6,9,17,20,23-hexazatricyclo[23.3.1.1(11,15)]triaconta-1(29),11(30),12,14,25,27-hexaene (L), was synthesized and crystallized as the tetrahydrobromide salt, i.e. 6,20-bis(2-hydroxyethyl)-6,20-diaza-3,9,17,23-hexaazoniatricyclo[23.3.1.1(11,15)]triaconta-1(29),11(30),12,14,25,27-hexaene tetrabromide tetrahydrate, C28H50N6O2(4+)*4Br(-)*4H2O. A crystallographic inversion center is located in the macrocyclic cavity and the two hydroxyethyl pendants are on opposite sides of the macrocyclic plane. The benzene rings of the macrocycle are parallel to each other and a pi-pi-stacking interaction exists between the benzene rings of adjacent macrocycles, which are separated by 3.791 (9) A. An infinite intermolecular hydrogen-bond network stabilizes the crystal.

Journal Article↗
PubMed1985

Macrocyclic trichothecene toxins produced by Stachybotrys atra strains isolated in Middle Europe.

A total of 17 strains of Stachybotrys atra isolated in Hungary and Czechoslovakia were cultured on Sabouraud agar, and the toxins produced by them were chemically analyzed by gas-liquid chromatography, high-pressure liquid chromatography, and mass spectroscopy. Furthermore, brine shrimp (Artemia salina) bioassay was used for the determination of toxicity of the compounds examined. Macrocyclic trichothecenes (satratoxins H and G, roridin E, and verrucarin J as well as two other unidentified macrocyclic trichothecenes) were found in all of the cultures tested. The identities of satratoxins H and G, roridin E, and verrucarin J were qualitatively determined by high-pressure liquid chromatography and gas-liquid chromatography. The ratio of satratoxins H and G and roridin E was found to be similar in each of the strains tested, but the amount of verrucarin J found was different in each of them. One of the unidentified macrocyclic trichothecenes was equivalent to the compound isolated by Harrach et al. (Harrach et al., Appl. Environ. Microbiol. 41:1428-1433, 1981). The other one proved to be a newly isolated macrocyclic trichothecene toxin. Stachybotryotoxicosis, one of the oldest mycotoxicoses known, and a serious problem in Middle Europe (Gy. Danko, Magy. Allatorv. Lapja 31:226-232, 1976), is believed to be caused by macrocyclic trichothecene toxins produced by Stachybotrys atra (R. M. Eppley, in Rodricks et al., ed., Mycotoxins in Human and Animal Health, p. 285-293, 1977). Forty years ago, the death of animals in the Soviet Union was associated with this fungus (C. U. Ruhliada, in Proceedings of the All-Union Sci. and Tech. Conf., p. 47-51, 1980).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Structural elucidation of a unique macrocyclic membrane lipid from a new, extremely thermophilic, deep-sea hydrothermal vent archaebacterium, Methanococcus jannaschii.

The membrane lipid of a new deep-sea hydrothermal vent methanogen, Methanococcus jannaschii, was isolated, purified, and structurally characterized. The total lipid extract, amounting to 32.2 micrograms/mg, dry cell weight, was fractionated on silica gel into a neutral lipid and polar lipid fraction. The neutral lipid fraction consisted of a series of isoprenoid hydrocarbons and free (nonphospholipid) alkylglycerol ethers. The polar phospholipid and glycolipid fraction (8.44 micrograms/mg, dry cell weight) was hydrolyzed with methanolic HCl, and the resulting alkylglycerol ethers were analyzed by a combination of chemical and spectroscopic techniques. The hydrolyzed polar lipid was primarily (95%) a unique, macrocyclic glycerol diether, heretofore unknown. High-field (250 MHz) proton nuclear magnetic resonance and infrared spectra of this novel macrocyclic compound are nearly identical and overlapping those of the known bis-(phytanyl)glycerol diether and bis-(diphytanyl)diglycerol tetraether. A field desorption mass spectrum revealed a molecular weight of 650 for the macrocyclic glycerol diether, 2 mass units less than that of bis-(phytanyl)glycerol diether. Degradation of the macrocyclic ether with boron tribromide resulted in diphytanyl dibromide, and further reaction of this dibromide with lithium aluminium hydride resulted in diphytane as determined by gas chromatography-mass spectrometry. The significance of the predominance of this structure in M. jannaschii is discussed. A survey of selected methanogenic Archaebacteria, including three thermophiles, failed to indicate the presence of the macrocyclic glycerol diether in any other microorganism, including two species of order Methanococcales, one species of Methanobacteriales, and three strains belonging to the order Methanomicrobiales.

Chemical Phenomena↗
PubMed1996

Antibody responses to macrocycles in lymphoma.

UNLABELLED: Metallic radioimmunoconjugates have promise for radioimmunoimaging and therapy. Macrocyclic chelating agents allow formation of stable metallic radioimmunoconjugates but have been reported to be immunogenic. This study assesses human antibody responses in patients that were imaged or treated with radiolabeled Lym-1 containing the macrocyclic chelators 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA) or 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA). METHODS: One to six doses (median 1) and 6 to 285 mg (median 33) 67Cu-2IT-BAT (2-iminothiolane bromoacetamidobenzyl TETA)- or 111In-2IT-BAD (2-iminothiolane bromoacetamidobenzyl DOTA)-Lym-1 were administered to each of 18 patients with lymphocytic malignancies. Solid-phase ELISA, utilizing unchelated Lym-1 or human serum albumin conjugated to DOTA, TETA or 2IT-bromoacetamidobenzyl-ethylenediaminetetraacetic acid (BABE) as coating antigens, was used to characterize antibody responses against 67Cu-2IT-BAT-Lym-1 and 111In-2IT-BAD-Lym-1 by quantitating antibodies against the Lym-1, DOTA, TETA or 2IT moieties, respectively. RESULTS: None of the patients had evidence for serum sickness. No patient that received 111In-2IT-BAD-Lym-1 developed antibodies to Lym-1 or DOTA. Two (15%) of the 13 patients that received 67Cu-2IT-BAT-Lym-1 developed antibodies against both TETA and Lym-1, and an additional patient developed antibodies against Lym-1 only. No patient developed an antibody response solely against the macrocycle, nor did any of the patients generate antibodies against the 2IT molecule. HAMA levels were many times greater in amount than HATA levels even when their relative molecular masses were considered. CONCLUSION: Although macrocycles such as DOTA and TETA, and other chelates, can be haptens and thus potentially immunogenic, our findings do not support the view that macrocycles are more immunogenic than other radiometal chelating agents.

Animals↗
PubMed2005

What can a chemist learn from nature's macrocycles?--a brief, conceptual view.

Macrocyclic natural products often display remarkable biological activities, and many of these compounds (or their derivatives) are used as drugs. The chemical diversity of these compounds is immense and may provide inspiration for innovative drug design. Therefore, a database of naturally occurring macrocycles was analyzed for ring size, molecular weight distribution, and the frequency of some common substructural motifs. The underlying principles of the chemical diversity are reviewed in terms of biosynthetic origin and nature's strategies for diversity and complexity generation in relation to the structural diversity and similarities found in the macrocycle database. Finally, it is suggested that synthetic chemists should use not only nature's molecules, but also nature's strategies as a source of inspiration. To illustrate this, the biosynthesis of macrocycles by non-ribosomal peptide synthetases and terpene and polyketide cyclases, as well as recent advances of these strategies in an integrated synthesis/biotechnology approach are briefly reviewed.

Biological Factors↗
PubMed2004

Syntheses and bioactivities of macrocyclic paclitaxel bis-lactones.

Five macrocyclic paclitaxel bis-lactones and their corresponding open chain taxoids were synthesized as models of the tubulin-binding conformation of paclitaxel. Macrocyclic lactones with a 19-21-membered ring underwent isomerization to form smaller rings. The lactones were evaluated for cytotoxicity and tubulin-polymerization ability. All five macrocyclic paclitaxel lactones were active, but less so than paclitaxel, while the rearranged macrocyclic lactones and the corresponding open-chain taxoids were much less active or inactive.

Antineoplastic Agents↗
PubMed2004

Spectroscopic, redox and biological activities of transition metal complexes with ons donor macrocyclic ligand derived from semicarbazide and thiodiglycolic acid.

A novel macrocyclic Schiff base ligand (2,5,9,12,14,18-hexaoxo-7,16-dithia-1,3,4,10,11,13-hexaazacycloocta-decane (H6L) with N4S2 coordinating sites was prepared by the reaction of the semicarbazide and thiodiglycolic acid. The transition metal complexes with macrocyclic ligand were synthesized and characterized by elemental analyses, magnetic susceptibility measurements, molar conductance, IR, electronic, and EPR spectral studies. Mass, 1H NMR and IR spectral techniques suggest the structural features of macrocyclic ligand. Magnetic and electronic spectral studies suggest an octahedral geometry of complexes. Electrochemical behaviour of cobalt, nickel and copper complexes were determined by cyclic voltammetry. The cyclic voltammogram of the copper complex at room temperature shows a quasi-reversible peaks for Cu(III)-->Cu(II) and Cu(II)-->Cu(I) couples. The macrocyclic ligand and its complexes show growth inhibitory activity against pathogenic bacteria and plant pathogenic fungi A. niger, A. alternata and P. variotii. Most of the complexes have higher activities than that of free ligand.

Anti-Bacterial Agents↗
PubMed2005

Reaction pathways leading to arylene ethynylene macrocycles via alkyne metathesis.

Mechanistic studies on the direct formation of arylene ethynylene macrocycles via alkyne metathesis catalyzed by a molybdenum complex are reported. Gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry on the products from metathesis of monomer 1 show the initial formation of linear oligomers and large macrocycles (n > 6), followed by their transformation into the thermodynamically most stable product distribution-mainly the cyclic hexamer. Variable temperature and scrambling experiments reveal the reversibility of macrocycle formation. Nearly identical product distributions are observed from the cross metathesis of hexacycle 2 with diphenylacetylene and from the metathesis of bis(phenylethynyl) substituted monomer 4, demonstrating that macrocycle formation is thermodynamically rather than kinetically controlled. The metathesis byproduct, 3-hexyne, is shown to inhibit the catalyst. It is suggested that the relative metathesis rates of dialkylalkynes versus diarylalkynes trap the catalyst in a nonproductive manifold, rendering it unavailable for the productive metathesis of aryl alkylalkyne substrates. This finding indicates that dialkyl-substituted alkyne byproducts should be avoided (or efficiently removed) if the metatheses of aryl substrates, especially those with electron-withdrawing groups, are to proceed to high conversion.

Alkynes↗
PubMed2006

[6 + 6] Schiff-base macrocycles with 12 imines: giant analogues of cyclohexane.

Hexagon-shaped [6 + 6] Schiff-base macrocycles with 12 imine bonds are reported. These giant macrocycles possess 6 N2O2 coordination environments and mass spectrometry evidence for hexametallation of one macrocycle is provided. Semi-empirical calculations reveal two stable conformations with boat and chair geometries for the macrocycles metallated with Ni(II), analogous to the conformations observed for cyclohexane.

Cyclohexanes↗
PubMed2006

Synthesis of macrocyclic analogues of the neuroprotective agent glycyl-L-prolyl-L-glutamic acid (GPE).

The syntheses of seven macrocyclic analogues of the neuroprotective tripeptide glycyl-L-prolyl-L-glutamic acid (GPE) are described. Macrocycles 6 and 7 mimic the cis conformer of GPE whereas macrocycles 2-5, 8, and 9 mimic the trans conformer of GPE. The macrocyclic peptides of well-defined geometry were prepared via Grubbs ring closing metathesis of an appropriate diene precursor. In turn each of the diene precursors were prepared from the readily available allyl-substituted amino acid building blocks 12, 13, 14, 27, 36 and 51.

Macrocyclic Compounds↗
PubMed2002

Zirconocene-mediated, high-yielding macrocyclizations of silyl-terminated diynes.

A series of silyl-terminated diynes of varying lengths and substitution patterns have been prepared. These diynes undergo zirconocene coupling with selective formation of trimeric macrocycles from linear alkynes, while nonlinear diynes give cyclodimeric products. The length of the linear diynes can be increased for the preparation of macrocycles with large nanoscale cavities. Reaction of the zirconium-containing macrocycles with acid results in the synthesis of metal-free cyclophanes. All of these macrocycles were prepared in multigram quantities, in the absence of high-dilution conditions, to give products in > 75% yield that are easily purified as crystalline solids.

Journal Article↗
PubMed2002

Phenylacetylene macrocycles with two opposing bipyridine donor sites: syntheses, X-ray structure determinations, and Ru complexation.

Reaction of the known macrocycle 1a, which contains two bipyridine units in opposing sides, with two equivalents of [Ru(bipy)2Cl2] furnishes the doubly exocyclically complexed macrocycle 8a in 55% yield. Synthesis of the shape-persistent macrocycle 1c by Hagihara-Sonogashira cross-coupling chemistry of suitably functionalized building blocks is reported. This macrocycle was also converted into a Ru complex (8c). X-ray analysis of single crystals of 1b and 1c shows a layered structure that contains "channels" filled with solvent molecules and parts of the flexible chains, with which the cycle is decorated for solubility reasons.

Journal Article↗
PubMed2003

Formation and chemical reactivities of a new type of double-butterfly [[Fe2(mu-CO)(CO)6]2(mu-SZS-mu)]2-: synthetic and structural studies on novel linear and macrocyclic butterfly Fe/E (E=S, Se) cluster complexes.

A new type of double-butterfly [[Fe(2)(mu-CO)(CO)(6)](2)(mu-SZS-mu)](2-) (3), a dianion that has two mu-CO ligands, has been synthesized from dithiol HSZSH (Z=(CH(2))(4), CH(2)(CH(2)OCH(2))(1-3)CH(2)), [Fe(3)(CO)(12)], and Et(3)N in a molar ratio of 1:2:2 at room temperature. Interestingly, the in situ reactions of dianions 3 with various electrophiles affords a series of novel linear and macrocyclic butterfly Fe/E (E=S, Se) cluster complexes. For instance, while reactions of 3 with PhC(O)Cl and Ph(2)PCl give linear clusters [[Fe(2)(mu-PhCO)(CO)(6)](2)(mu-SZS-mu)] (4 a,b: Z=CH(2)(CH(2)OCH(2))(2,3)CH(2)) and [[Fe(2)(mu-Ph(2)P)(CO)(6)](2)(mu-SZS-mu)] (5 a,b: Z=CH(2)(CH(2)OCH(2))(2,3)CH(2)), reactions with CS(2) followed by treatment with monohalides RX or dihalides X-Y-X give both linear clusters [[Fe(2)(mu-RCS(2))(CO)(6)](2)(mu-SZS-mu)] (6 a-e: Z=CH(2)(CH(2)OCH(2))(1,2)CH(2); R=Me, PhCH(2), FeCp(CO)(2)) and macrocyclic clusters [[Fe(2)(CO)(6)](2)(mu-SZS-mu)(mu-CS(2)YCS(2)-mu)] (7 a-e: Z=(CH(2))(4), CH(2)(CH(2)OCH(2))(1-3)CH(2); Y=(CH(2))(2-4), 1,3,5-Me(CH(2))(2)C(6)H(3), 1,4-(CH(2))(2)C(6)H(4)). In addition, reactions of dianions 3 with [Fe(2)(mu-S(2))(CO)(6)] followed by treatment with RX or X-Y-X give linear clusters [[[Fe(2)(CO)(6)](2)(mu-RS)(mu(4)-S)](2)(mu-SZS-mu)] (8 a-c: Z=CH(2)(CH(2)OCH(2))(1,2)CH(2); R=Me, PhCH(2)) and macrocyclic clusters [[[Fe(2)(CO)(6)](2)(mu(4)-S)](2)(mu-SYS-mu)(mu-SZS-mu)] (9 a,b: Z=CH(2)(CH(2)OCH(2))(2,3)CH(2); Y=(CH(2))(4)), and reactions with SeCl(2) afford macrocycles [[Fe(2)(CO)(6)](2)(mu(4)-Se)(mu-SZS-mu)] (10 d: Z=CH(2)(CH(2)OCH(2))(3)CH(2)) and [[[Fe(2)(CO)(6)](2)(mu(4)-Se)](2)(mu-SZS-mu)(2)] (11 a-d: Z=(CH(2))(4), CH(2)(CH(2)OCH(2))(1-3)CH(2)). Production pathways have been suggested; these involve initial nucleophilic attacks by the Fe-centered dianions 3 at the corresponding electrophiles. All the products are new and have been characterized by combustion analysis and spectroscopy, and by X-ray diffraction techniques for 6 c, 7 d, 9 b, 10 d, and 11 c in particular. X-ray diffraction analyses revealed that the double-butterfly cluster core Fe(4)S(2)Se in 10 d is severely distorted in comparison to that in 11 c. In view of the Z chains in 10 a-c being shorter than the chain in 10 d, the double cluster core Fe(4)S(2)Se in 10 a-c would be expected to be even more severely distorted, a possible reason for why 10 a-c could not be formed.

Journal Article↗
PubMed2003

Complexation behavior of a highly preorganized 7,7-diphenylnorbornane-derived macrocycle: towards the design of molecular clocks.

The syntheses of two new cyclophane hosts, 4 and 6, are described. The main difference between them is the higher degree of preorganization of 4 as a consequence of the inclusion of the 7,7-diphenylnorbornane (DPN) subunit. The inner cavity of 4 adopts a belt-shaped structure, while 6 has a twisted geometry. In the solid state, the molecules of macrocycle 6 are stacked along an axis to form nanotubular structures. Compounds 4 and 6 form two of the strongest complexes between arene cyclophanes and Ag(+) reported up to date. The silver cation is located inside the cavity of the macrocycles. The stability of 4.Ag(+) is considerably higher than that of 6.Ag(+). The additional stabilization of 4.Ag(+) is attributed to higher preorganization of macrocycle 4. DNMR experiments as well as theoretical calculations carried out with 4.Ag(+) show evidence of Ag(+)-hopping between two different binding sites inside the macrocycle. This phenomenon could be the basis for the design of molecular clocks.

Journal Article↗
PubMed2006

Helicate, macrocycle, or catenate: Dynamic topological control over subcomponent self-assembly.

The aqueous reaction between equimolar amounts of 2-(2-(2-aminoethoxy)ethoxy)ethanamine, 1,10-phenanthroline-2,9-dialdehyde and copper(I) produced a dimeric helical macrocycle in quantitative yield. This ring could also be generated by the addition of two equivalents of the diamine to an acyclic helicate containing four mono-imine residues: A transimination occurred, the chelate effect being implicated as a driving force. In the case of a helicate containing mono-imines derived from anilines, the substitution of diamine for monoamine was reversible upon lowering the pH. The aliphatic diamine was protonated at a higher pH than the arylamine, which left the arylamine free for incorporation instead of the alkyl diamine. This reaction thus opened the possibility of switching between closed macrocyclic and open helicate topologies by changing the pH. An additional closed topology became accessible through the use of a diamine that incorporates two rigid phenylene spacer groups between a flexible chain and the imine-forming nitrogen atoms. The resulting catenate consists of a pair of topologically interlinked macrocycles. The presence of the phenylene groups appeared to dictate the topology of the final product, making the formation of a single macrocycle energetically disfavoured.

Journal Article↗
PubMed2007

A combined computational and experimental approach for the analysis of the enantioselective potential of a new macrocyclic receptor for N-protected alpha-amino acids.

A new macrocyclic receptor incorporating a thiourea moiety has been synthesised. Crystal structures of the macrocycle showed that the receptor has a rigid backbone but the thiourea moiety can orientate itself to bind to a DMSO solvent molecule. Force-field (MMFFs) calculations were performed to model the macrocycle and its binding properties with respect to N-protected amino acids, which were measured experimentally by NMR titration. Binding free energies were calculated by using the mode integration algorithm (MINTA) or free-energy perturbation (FEP). Excellent qualitative agreement with experiment was obtained. To further exploit the accuracy of the free-energy predictions for this system, the faster free-energy algorithm MINTA was used as a prediction tool to test the binding affinity of the macrocycle towards a series of several other amino acid derivatives, which speeded up considerably the screening process and reduced laboratory costs.

Journal Article↗
PubMed2004

Enantiomeric separation of dansyl amino acids using macrocyclic antibiotics as chiral mobile phase additives by narrow-bore high-performance liquid chromatography.

Seven macrocyclic antibiotics were evaluated as chiral selectors for the enantiomeric separation of 11 dansyl amino acids using narrow-bore high-performance liquid chromatography (HPLC). The macrocyclic antibiotics were incorporated as mobile phase additives to determine the enantioselective effects on the chiral analytes. The resolution and capacity factor (k') of each analyte were assessed while varying the structure of macrocyclic antibiotic and the mobile phase buffer pH. The selectivity of the chiral selectors was measured as a function of changes in these parameters. All 11 dansyl amino acids were separated by at least one of the chiral selectors. Three-dimensional computer modeling of the more effective chiral selectors illustrated the importance of macrocyclic antibiotic structure concerning stereospecific analyte interaction.

Journal Article↗
PubMed2007

Macrocyclic aminopyrimidines as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activities.

X-ray structures from CDK2-aminopyrimidine inhibitor complexes led to the idea to stabilize the active conformation of aminopyrimidine inhibitors by incorporating the recognition site into a macrocyclic framework. A modular synthesis approach that relies on a new late-stage macrocyclization protocol that enables fast and efficient synthesis of macrocyclic aminopyrimidines was developed. A set of structurally diverse derivatives was prepared. Macrocyclic aminopyrimidines were shown to be multitarget inhibitors of CDK1/2 and VEGF-RTKs. In addition, potent antiproliferative activities toward various human tumor cells and a human tumor xenograft model were demonstrated.

Amines↗