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PubMed1976

Synthesis of corrins and related macrocycles based on pyrrolic intermediates.

Intermediate in structure between porphyrins and corrins are the corroles and 1-methyltetradehydrocorrins. These ring systems, like the porphyrins, can be obtained by cyclization of linear tetrapyrrolic compounds, reactions which have been shown to proceed by orbital symmetry-allowed electrocyclic processes, and examples will be quoted. Thermolysis of nickel 1-methyltetradehydrocorrins causes a migration of the methyl group whereas similar treatment of nickel 1,19-dimethyltetradehydrocorrin salts yields porphyrin derivatives; the mechanisms of these transformations have been elucidated. Stepwise hydrogenation of metal tetradehydrocorrin salts (10 double bonds) yields a series of macrocycles containing 9, 8, 7, 6 and 5 double bonds and conditions necessary to obtain corrins have been established.

Chemical Phenomena↗

PubMed1986

Biosynthesis of the Macrocyclic Diterpene Casbene in Castor Bean (Ricinus communis L.) Seedlings : Changes in Enzyme Levels Induced by Fungal Infection and Intracellular Localization of the Pathway.

Casbene is a macrocyclic diterpene hydrocarbon that is produced in young castor bean (Ricinus communis L.) seedlings after they are exposed to Rhizopus stolonifer or other fungi. The activities of enzymes that participate in casbene biosynthesis were measured in cell-free extracts of 67-hour castor bean seedlings (a) that had been exposed to R. stolonifer spores 18 hours prior to the preparation of extracts, and (b) that were maintained under aseptic conditions throughout. Activity for the conversion of mevalonate to isopentenyl pyrophosphate does not change significantly after infection. On the other hand, the activities of farnesyl pyrophosphate synthetase (geranyl transferase), geranylgeranyl pyrophosphate synthetase (farnesyl transferase), and casbene synthetase are all substantially greater in infected tissues in comparison with control seedlings maintained under sterile conditions. The subcellular localization of these enzymes of casbene biosynthesis was investigated in preparations of microsomes, mitochondria, glyoxysomes, and proplastids that were resolved by centrifugation in linear and step sucrose density gradients of homogenates of castor bean endosperm tissue from both infected and sterile castor bean seedlings. Isopentenyl pyrophosphate isomerase and geranyl transferase activities are associated with proplastids from both infected and sterile seedlings. Significant levels of farnesyl transferase and casbene synthetase are found only in association with the proplastids of infected tissues and not in the proplastids of sterile tissues. From these results, it appears that at least the last two steps of casbene biosynthesis, geranylgeranyl pyrophosphate synthetase and casbene synthetase, are induced during the process of infection, and that the enzymes responsible for the conversion of isopentenyl pyrophosphate to casbene are localized in proplastids.

Journal Article↗

PubMed2003

AgI and CuI binuclear macrocyclic complexes with 1-(3-pyridyl)ethanone oxime.

Bis[micro-1-(3-pyridyl)ethanone oxime-kappa(2)N:N']bis[nitratosilver(I)], [Ag(2)(NO(3))(2)(C(7)H(8)N(2)O)(2)], crystallizes as a centrosymmetric binuclear macrocylic complex containing silver(I) ions bridged by the organic 1-(3-pyridyl)ethanone oxime ligand. The ligand coordinates via the pyridine and the oxime N atoms. A similar metal-ligand arrangement was found in the copper(I) complex catena-poly[[bis[micro-1-(3-pyridyl)ethanone oxime-kappa(2)N:N']dicopper(I)]-di-micro-iodo], [Cu(2)I(2)(C(7)H(8)N(2)O)(2)](n), but here the centrosymmetric macrocycles are connected by double anion bridges, resulting in the formation of a one-dimensional coordination polymer.

Journal Article↗

PubMed2005

Cyanocobalt(III) complexes of penta- and tetradentate-coordinated macrocyclic hexaamines.

The pendent-arm macrocyclic hexaamine trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine (L) may coordinate in tetra-, penta- or hexadentate modes, depending on the metal ion and the synthetic procedure. We report here the crystal structures of two pseudo-octahedral cobalt(III) complexes of L, namely sodium trans-cyano(trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine)cobalt(III) triperchlorate, Na[Co(CN)(C13H30N6)](ClO4)3 or Na{trans-[CoL(CN)]}(ClO4)3, (I), where L is coordinated as a pentadentate ligand, and trans-dicyano(trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine)cobalt(III) trans-dicyano(trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diaminium)cobalt(III) tetraperchlorate tetrahydrate, [Co(CN)2(C14H32N6)][Co(CN)2(C14H30N6)](ClO4)4.4H2O or trans-[CoL(CN)2]trans-[Co(H2L)(CN)2](ClO4)4.4H2O, (II), where the ligand binds in a tetradentate mode, with the remaining coordination sites being filled by C-bound cyano ligands. In (I), the secondary amine Co-N bond lengths lie within the range 1.944 (3)-1.969 (3) A, while the trans influence of the cyano ligand lengthens the Co-N bond length of the coordinated primary amine [Co-N = 1.986 (3) A]. The Co-CN bond length is 1.899 (3) A. The complex cations in (II) are each located on centres of symmetry. The Co-N bond lengths in both cations are somewhat longer than in (I) and span a narrow range [1.972 (3)-1.982 (3) A]. The two independent Co-CN bond lengths are similar [1.918 (4) and 1.926 (4) A] but significantly longer than in the structure of (I), again a consequence of the trans influence of each cyano ligand.

Journal Article↗

PubMed1995

Design, synthesis and structure of non-macrocyclic inhibitors of FKBP12, the major binding protein for the immunosuppressant FK506.

We have synthesized a series of non-macrocyclic ligands to FKBP12 that are comparable in binding potency and peptidyl prolyl isomerase (PPIase) inhibition to FK506 itself. We have also solved the structure of one of these ligands in complex with FKBP12, and have compared that structure to the FK506-FKBP12 complex. Consistent with the observed inhibitory equipotency of these compounds, we observe a strong similarity in the conformation of the two ligands in the region of the protein that mediates PPIase activity. Our compounds, however, are not immunosuppressive. In the FKBP12-FK506 complex, a significant portion of the FK506 ligand, its 'effector domain', projects beyond the envelope of the binding protein in a manner that is suggestive of a potential interaction with a second protein, the calcium-dependent phosphatase, calcineurin, whose inhibition by the FKBP 12-FK506 complex interrupts the T-cell activation events leading to immunosuppression. In contrast, our compounds bind within the surface envelope of FKBP12, and induce significant changes in the structure of the FKBP12 protein which may also affect calcineurin binding indirectly.

Journal Article↗

PubMed1993

Antitumor activity of oenothein B, a unique macrocyclic ellagitannin.

The antitumor effect of oenothein B, a macrocyclic ellagitannin from Oenothera erythrosepala Bordas, on rodent tumors was studied. Oenothein B exhibited a strong antitumor activity against MM2 ascites tumors upon intraperitoneal administration to the mice before or after the tumor inoculation. The tannin also inhibited the growth of Meth-A solid type tumor in mice. This antitumor effect of the tannin could not be attributed to its direct cytotoxic action on tumor cells, because the cytotoxicity was very weak in the presence of serum protein. When oenothein B was injected into the peritoneal cavity of mice, peritoneal exudate cells, including cytostatic macrophages, were induced. Furthermore, in the in vitro treatment of macrophages from mice and humans, the tannin stimulated release of an interleukin 1 (IL-1)-like activity and IL-1 beta from the cells. These results suggest that oenothein B exerts its antitumor effect through potentiation of the host-immune defense via activation of macrophages.

Animals↗

PubMed1998

Lanthionine macrocyclization by in situ activation of serine.

The present report details a straightforward, solid-phase approach to cyclolanthionine peptides. After stepwise assembly of the linear sequence and transformation of a single exposed serine to bromoalanine using P(Ph)3/CBr4, the detritilation of a cysteine side-chain sets the stage for a base-promoted macrocyclization. The entire procedure can be carried out in a solid-phase vessel using conventional 9-fluorenylmethyloxycarbonyl/tert-butyl-based chemistry and is amenable to automated format. The utility of this novel procedure is demonstrated by the synthesis of two previously reported lanthionine-containing cyclic peptides.

Alanine↗

PubMed1991

Fluorescence study of the conformational properties of myoglobin structure. 3. pH-dependent changes in porphyrin and tryptophan fluorescence of the complex of sperm whale apomyoglobin with protoporphyrin IX; the role of the porphyrin macrocycle and iron in formation of native myoglobin structure.

The porphyrin and tryptophan fluorescence of sperm whale apomyoglobin complexed with protoporphyrin IX has been studied in the pH range 2-13. It has been shown that the fluorescence and absorption spectra of protoporphyrin incorporated into the heme crevice remain constant in the pH range 5.5-10.8 but change significantly at pH less than 5.5 and pH greater than 10.8, due to the acid and alkaline denaturation, respectively, of the complex accompanied by dissociation of protoporphyrin IX. At the same pH ranges, the quantum yield of tryptophanyl fluorescence increases sharply as a result of removal of protoporphyrin, acting as a quencher, from the complex. Other parameters of tryptophanyl fluorescence (maximum position, halfwidth and spectrum shape) change in the alkaline region as well. In the acidic pH range, these parameters change only at pH less than 4.3, indicating that the Trp surroundings are more stable to denaturation than the heme crevice region. Between pH 5.5 and 10.9, where the complex of apomyoglobin with protoporphyrin IX is in its native state, the main parameters of tryptophan fluorescence remain unchanged except for the ratio I325/I350 which diminishes at pH greater than 9.5. Its alteration precedes the alkaline denaturation of the complex and can be explained by a local conformational change induced by the break of the 'salt bridges' essential for the maintenance of the native Mb structure in the N-terminal region. The fluorescence data obtained for apomyoglobin, myoglobin and the complex between protoporphyrin IX and apomyoglobin enable one to compare their structures and to evaluate the role of the porphyrin macrocycle and the iron atom in the formation of the native myoglobin structure and its functioning.

Animals↗

PubMed2001

Efficacy of macrocyclic lactones for the control of larvae of the Old World screw-worm fly (Chrysomya bezziana).

OBJECTIVE: To assess the efficacy of four macrocyclic lactones for the control of larvae of the Old World Screw-worm Fly (OWS), Chrysomya bezziana, and to examine the effects of excreted residues on the dung fauna. ANIMALS: 100 heifers were divided into five groups of 20 animals. One group remained untreated, whereas the other groups were treated respectively with pour-on formulations of moxidectin, eprinomectin or doramectin, or a sustained-release bolus of ivermectin. PROCEDURES: At intervals of 1 to 15 weeks after treatment, five cattle from each group were challenged with newly-laid eggs of OWS. The efficacy of each treatment was determined 48 h later by comparing the number of myiases in the treated and untreated groups. Abundance of fly larvae in naturally-voided dung pads and the survival of a species of dung beetle, Onthophagus sagittarius, were used to assess the effects of drug residues on the dung fauna. RESULTS AND CONCLUSIONS: Moxidectin showed no activity against larvae of OWS during the first 14 days after treatment. Eprinomectin provided protection for 3 days after dosing, but failed at days 7 and 14, whereas doramectin was effective at day 7, but not at days 14 or 21. In contrast, no myiases were established on bolus-treated cattle from 14 to 102 days after treatment. Faecal residues of moxidectin had no effect on the survival of larvae of dung-feeding flies, whereas those of eprinomectin and doramectin reduced survival for 1 to 2 weeks. Dung voided by bolus-treated cattle inhibited fly breeding and had adverse effects on the development and survival of O sagittarius for up to 15 weeks after treatment.

Animals↗

PubMed2001

Principles for the use of macrocyclic lactones to minimise selection for resistance.

OBJECTIVE: To provide principles for the appropriate use of avermectin/milbemycin or macrocyclic lactone (ML) anthelmintics in sheep, to ensure effective worm control and to minimise selection for ML resistance. STRATEGY: The principles were based on an assessment of the information currently available. The MLs were categorised into three groups (ivermectin [IVM], abamectin [ABA] and moxidectin [MOX]) based on structural differences, persistence and efficacy against ML resistant strains. The reported order of activity or efficacy against ML resistant worm strains was IVM<ABA<MOX. General treatment schemes were considered for Australian conditions and were divided into the following situations: 1. quarantine treatment, 2. treatment on/to clean pasture, 3. treatment on/to safe pasture, 4. treatment on/to moderate/heavily contaminated pasture. For each of these situations a strategy was considered for farms where ML resistance was present or absent. It was assumed that resistance commonly occurs in some or all other broad spectrum anthelmintics, and even where ML resistance has been detected, the ML group remains the most effective. The guidelines provided are general and it is expected that state agencies and sheep/veterinary advisers would give specific advice to suit their environments and drug resistance/worm problems. CONCLUSIONS: The primary recommendation is to use a mixture of effective drugs when treating sheep. However, unless the combination treatment is highly effective it is unlikely to delay selection for ML resistance if sheep are being treated and moved to a clean or safe pasture. Where possible, reliance on the ML anthelmintics should be reduced by not using them every year, not using them in low risk stock or by using narrow spectrum and low efficacy drugs such as naphthalophos when appropriate. Anthelmintic treatment should be given as part of a strategic worm control program. It is suggested that IVM-oral and IVM-capsules should not be used when ML resistance is present. In this situation MOX or ABA should be used in combination with other drugs, provided that the chosen ML is effective against the resistant parasite. It is essential to monitor the efficacy of ML and drug combinations by post-treatment worm egg counts, particularly when ML resistance has been detected.

Animals↗

PubMed1991

In vitro photodynamic inactivation of herpes simplex virus with sapphyrins: 22 pi-electron porphyrin-like macrocycles.

The photodynamic inactivation of HSV-1, a virus having a membranous envelope, with both a decaalkyl sapphyrin and its dicarboxy-substituted analog was studied. The decaalkyl sapphyrin was as efficient in the inactivation of HSV-1 on a per macrocycle basis as DHE, whereas the efficiency of the dicarboxy-substituted sapphyrin was approximately two orders of magnitude less. Fluorescence studies of sapphyrin's binding to liposomes and VSV suggested that the decaalkylsapphyrin bound monomerically to cholesterol-rich regions of the viral envelope, whereas its charged analog localized in a more polar environment.

Animals↗

PubMed1998

Anti-HIV activity and mechanism of action of macrocyclic diamide SRR-SB3.

The importance of cyclic compounds as anti-cancer and anti-viral agents has been recognized for some time. We have studied a series of macrocyclic amide derivatives for activity against HIV infection of T lymphocytes in-vitro. Compounds containing aromatic rings and sulphur atoms were generally active, however the selectivity was greatly enhanced when two benzene rings were bridged by a disulphide linkage to produce 7-methyl-6,7,8,9-tetrahydrodibenzo[c,k][1,2,6,9]-dithiadiazacyc lododecine-5,10-dione (SRR-SB3). This compound was studied in detail with different cell and virus infections including macrophages and chronically infected H9 cells. It was active with an EC50 (the dose affording 50% inhibition of infection) of 0.05-01 microg mL(-1) and a TC50 (concentration reducing uninfected cell growth by 50%) of 50 microg mL(-1). The compound did not inhibit protease, but seemed to act by inhibiting maturation of progeny virus, by interfering with precursor protein processing. It was synergistic with AZT (3'-azido-3'-deoxythymidine; zidovudine) when tested in-vitro. The unusual mode of action and potent anti-HIV activity in T lymphocytes and macrophages makes this compound a potential candidate for clinical trials.

Anti-HIV Agents↗

PubMed1988

Enzyme immunoassay for the macrocyclic trichothecene roridin A: production, properties, and use of rabbit antibodies.

Antisera against roridin A were prepared by using a roridin A-hemisuccinate derivative coupled to human serum albumin as the immunogen. Antibodies could be detected in the sera of the immunized rabbits as early as 4 weeks after the initial exposure. After one booster injection at week 14, high antibody titers were measured over a period of 21 weeks. The specificity and sensitivity of the antibodies were tested by using roridin A-hemisuccinate coupled to horseradish peroxidase as an enzyme-linked toxin in a competitive assay with a double-antibody solid phase. The assay was most specific for the tested macrocyclic trichothecenes, and the relative cross-reactivities with roridin A, roridin J, verrucarin A, satratoxin H, and satratoxin G were 1, 0.41, 0.15, 0.15, and 0.07, respectively. When 16 nonmacrocyclic trichothecenes were tested, only diacetylverrucarol (0.0015) and verrucarol (0.0005) showed minor cross-reactivity. The sensitivity of the enzyme immunoassay for the detection of roridin A was in the range of 5 to 50 ng/ml (0.16 to 1.6 ng per assay).

Animals↗

PubMed2000

The macrocyclic peptide antibiotic micrococcin P(1) is secreted by the food-borne bacterium Staphylococcus equorum WS 2733 and inhibits Listeria monocytogenes on soft cheese.

Staphylococcus equorum WS 2733 was found to produce a substance exhibiting a bacteriostatic effect on a variety of gram-positive bacteria. The metabolite was purified to homogeneity by ammonium sulfate precipitation and semipreparative reversed-phase high-performance liquid chromatography. Electrospray mass spectrometry confirmed the high purity of the compound and revealed a molecular mass of 1,143 Da. By two-dimensional nuclear magnetic resonance spectroscopy the substance was identified as micrococcin P(1) which is a macrocyclic peptide antibiotic that has not yet been reported for the genus Staphylococcus. A total of 95 out of 95 Listeria strains and 130 out of 135 other gram-positive bacteria were inhibited by this substance, while none of 37 gram-negative bacteria were affected. The antilisterial potential of this food-grade strain as a protective starter culture was evaluated by its in situ application in cheese-ripening experiments under laboratory conditions. A remarkable growth reduction of Listeria monocytogenes could be achieved compared to control cheese ripened with a nonbacteriocinogenic type strain of Staphylococcus equorum. In order to prove that inhibition was due to micrococcin P(1), a micrococcin-deficient mutant was constructed which did not inhibit L. monocytogenes in cheese-ripening experiments.

Anti-Bacterial Agents↗

PubMed1991

Proportions of diether, macrocyclic diether, and tetraether lipids in Methanococcus jannaschii grown at different temperatures.

Growth of Methanococcus jannaschii over a wide temperature range (47 to 75 degrees C) is correlated with an ability to alter dramatically the proportions of three ether lipid cores. These lipids shifted from predominantly diether (2,3-di-O-phytanyl-sn-glycerol) at the lower growth temperatures to macrocyclic diether and tetraether at near optimal growth temperatures. Lipid head groups varied as well, especially with respect to an increase in phosphate at the higher temperatures.

Autoradiography↗

PubMed1989

Continuous-flow quantitation of Na+ and K+ in nanoliter samples using chromogenic macrocyclic ionophores.

Continuous-flow colorimetric methods for measurement of sodium and potassium contents in 1- to 30-nl aqueous samples are described. The methods employ macrocyclic ionophores (cryptahemispherands) that selectively bind sodium or potassium, altering the absorbance spectra of covalently attached chromophores. The potassium method is linear in the range 0-350 pmol and exhibits a high degree of precision (coefficient of variation of approximately 2% in the 150- to 350-pmol range). It can detect as little as 8 pmol of K+. The sodium method is linear in the range 0-2,700 pmol and also exhibits a high degree of precision (coefficient of variation of approximately 3% in the 1,700- to 2,700-pmol range). It can detect as little as 57 pmol of Na+. The instrumentation and reagents are available from commercial sources. These methods are proposed for measurement of K+ and Na+ fluxes in isolated perfused tubules.

Colorimetry↗

PubMed2004

Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389.

E7389, a macrocyclic ketone analog of the marine natural product halichondrin B, currently is undergoing clinical trials for cancer. This fully synthetic agent exerts its highly potent in vitro and in vivo anticancer effects via tubulin-based antimitotic mechanisms, which are similar or identical to those of parental halichondrin B. In an attempt to understand the impressive potency of E7389 in animal models of human cancer, its ability to induce apoptosis following prolonged mitotic blockage was evaluated. Treatment of U937 human histiocytic lymphoma cells with E7389 led to time-dependent collection of cells in the G2-M phase of the cell cycle, beginning as early as 2 h and becoming maximal by 12 h. Increased numbers of hypodiploid events were seen beginning at 12 h, suggesting initiation of apoptosis after prolonged E7389-induced mitotic blockage. The identity of hypodiploid events as apoptotic cells under these conditions was confirmed by two additional morphologic criteria: green to orange/yellow shifts on acridine orange/ethidium bromide staining, and cell surface annexin V binding as assessed by flow cytometry. Several biochemical correlates of apoptosis also were seen following E7389 treatment, including phosphorylation of the antiapoptotic protein Bcl-2, cytochrome c release from mitochondria, proteolytic activation of caspase-3 and -9, and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP). In LNCaP human prostate cancer cells, treatment with E7389 also led to generation of hypodiploid cells, activation of caspase-3 and -9, and appearance of cleaved PARP, indicating that E7389 can activate cellular apoptosis pathways under anchorage-independent and -dependent cell culture conditions. These results show that prolonged mitotic blockage by E7389 can lead to apoptotic cell death of human cancer cells in vitro and can provide a mechanistic basis for the significant in vivo anticancer efficacy of E7389.

Apoptosis↗

PubMed1992

The effects of the macrocyclic lactone bryostatin-1 on leukemic cells in vitro.

The macrocyclic lactone bryostatin-1 was found to exert in vitro antineoplastic activity against several leukemic cell lines, including human K562 erythroleukemia, HL60 promyelocytic leukemia, REH and MOLT-4 lymphoblastic leukemias, CCRF-CEM lymphoma, KG-1 myeloid leukemia, and murine P388 lymphocytic leukemia. No statistically significant difference in sensitivity to bryostatin-1 was found between adriamycin-resistant P388 and K526 subclones and their sensitive counterparts. Freshly explanted clonogenic leukemic cells showed a variable sensitivity to bryostatin-1 in 10/12 tested samples. The IC50 of clonogenic leukemic cells was 4 x 10(-3) M bryostatin-1, and that of normal marrow CFU-GM was 10(-5) M. Leukemic cells exposed to bryostatin-1 showed a variable degree of monocytic differentiation as evaluated by ANAE staining and morphology. Bryostatin-1 is also able to inhibit the growth of CFU-GM from myelodysplastic marrow and to shorten the duration of dysplastic hematopoiesis in liquid culture. In conclusion, these data suggest that bryostatin-1 is a potent antileukemic agent in vitro that may be potentially useful for clinical studies.

Antineoplastic Agents↗