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PubMed2002

How to synthesize macrocycles efficiently by using virtual combinatorial libraries.

The selection of different diimines 4 a-c by alkaline earth ions from a virtual combinatorial library (VCL) is described. The products were stabilized by reduction to the diamines 6 a-c; this allowed easy analysis. The library can be directed toward different target molecules 6 a-c upon addition of alkaline earth ions with different radii. Competition experiments show the possibility of synthesizing the macrocycles 6 a, 6 b, and 6 c simultaneously when using Mg(2+), Ca(2+), and Ba(2+) as template ions. The scope of this thermodynamically controlled, reversible approach for macrocycle syntheses is illustrated.

Combinatorial Chemistry Techniques↗
PubMed1994

The modification of acetate and propionate side chains during the biosynthesis of haem and chlorophylls: mechanistic and stereochemical studies.

In the conversion of uroporphyrinogen III into protoporphyrin IX and thence into chlorophylls, all eight carboxylic side chains, as well as the four meso positions, are modified, and four enzymes are involved. In the uroporphyrinogen decarboxylase-catalysed reaction all four acetate side chains are converted into methyl groups by the same mechanism, to produce coproporphyrinogen III. Both methylene hydrogen atoms remain undisturbed and the reaction occurs with the retention of stereochemistry. Several questions regarding the enzymology of the decarboxylase are posed. Do all the decarboxylations occur at the same active site and, if so, are the four acetate chains handled in a particular sequence? Is the decarboxylation reaction aided by the transient formation of an electron-withdrawing functionality in the pyrrole ring? Coproporphyrinogen oxidase converts the two propionate side chains of rings A and B into vinyl groups, with an overall anti-periplanar removal of the carboxyl group and the Hsi from the neighbouring position. Evidence is examined to evaluate whether a hydroxylated compound acts as an intermediate in the oxidative decarboxylation reaction. Protoporphyrinogen oxidase then converts the methylene-interrupted macrocycle of protoporphyrinogen IX into a conjugated system. The conversion has been suggested to involve three consecutive dehydrogenation reactions followed by an isomerization step. The face of the macrocycle from which the three meso hydrogen atoms are removed in the dehydrogenation reaction is thought to be opposite to that from which the fourth meso hydrogen is lost during the prototropic rearrangement. In an investigation of the in vivo mechanism for the esterification of the ring D propionic acid group with a C20 isoprenyl group 5-aminolaevulinic acid was labelled with 13C and 18O at C-1 and incorporated into bacteriochlorophyll a. The 18O-induced shift of the 13C resonance in the NMR spectrum showed that both oxygen atoms of the carboxyl group are retained in the ester bond. This and other results suggest that the reaction occurs by the nucleophilic attack of the ring D carboxylate anion on the activated form of an isoprenyl alcohol.

Acetates↗
PubMed2005

The cucurbit[n]uril family.

In 1981, the macrocyclic methylene-bridged glycoluril hexamer (CB[6]) was dubbed "cucurbituril" by Mock and co-workers because of its resemblance to the most prominent member of the cucurbitaceae family of plants--the pumpkin. In the intervening years, the fundamental binding properties of CB[6]-high affinity, highly selective, and constrictive binding interactions--have been delineated by the pioneering work of the research groups of Mock, Kim, and Buschmann, and has led to their applications in waste-water remediation, as artificial enzymes, and as molecular switches. More recently, the cucurbit[n]uril family has grown to include homologues (CB[5]-CB[10]), derivatives, congeners, and analogues whose sizes span and exceed the range available with the alpha-, beta-, and gamma-cyclodextrins. Their shapes, solubility, and chemical functionality may now be tailored by synthetic chemistry to play a central role in molecular recognition, self-assembly, and nanotechnology. This Review focuses on the synthesis, recognition properties, and applications of these unique macrocycles.

Bridged-Ring Compounds↗
PubMed2006

Squaraine-derived rotaxanes: highly stable, fluorescent near-IR dyes.

Squaraines are fluorescent, near-IR dyes with promising photophysical properties for biomedical applications. A limitation with these dyes is their inherent reactivity with nucleophiles, which leads to loss of the chromophore. Another drawback is their tendency to form nonfluorescent aggregates in water. Both problems can be greatly attenuated by encapsulating the dye inside an amide-containing macrocycle. In other words, the squaraine becomes the thread component in a Leigh-type rotaxane, a permanently interlocked molecule. Two new rotaxanes are described: an analogue with four tri(ethyleneoxy) chains on the squaraine to enhance water solubility, and a rotaxane that has an encapsulating macrocycle with transposed carbonyl groups. An X-ray crystal structure of the latter rotaxane shows that the macrocycle provides only partial protection of the electrophilic cyclobutene core of the squaraine thread. The stabilities of each compound in various solvents, including serum, were compared with a commercially available cyanine dye. The squaraine rotaxane architecture is remarkably resistant to chemical and photochemical degradation, and likely to be very useful as a versatile fluorescent scaffold for constructing various types of highly stable, near-IR imaging probes.

Animals↗
PubMed1996

Biological activity of 26-succinylbryostatin 1.

Bryostatin 1, a macrocyclic lactone, has undergone phase I trials as an anticancer agent. Because of the lipid solubility of this compound it must be delivered either in ethanol or in a PET formulation. During the trial, these vehicles caused a large number of treatment-related side effects. We have synthesized the triethanolamine salt of 26-succinylbryostatin 1 and find that this compound is approx. 100-fold more water soluble than bryostatin 1. Because of the potential for clinical use, we have evaluated the biologic activity of this compound. We find that in a concentration-dependent manner 26-succinylbryostatin 1 is capable of activating protein kinase C (PKC) in vitro and displacing [3H]PDBu from PKC. However, at all concentrations tested the activity was less than the parent compound bryostatin 1. Addition of bryostatin 1 but not 26-succinylbryostatin 1 to U937 leukemic cells in culture stimulated a drop in cytosolic PKC, secondary to translocation of PKC to the membrane. Although 26-succinylbryostatin 1 did not stimulate a drop in the cytosolic levels of PKC, addition to U937 cells activated transcription from an AP-1 enhancer construct and c-Jun protein phosphorylation in a similar fashion to bryostatin 1 and differentiation of U937 cells. Unlike bryostatin 1, 26-succinylbryostatin 1 was unable to cause aggregation of human platelets. Although injection of bryostatin-1 into mice carrying B16 melanoma inhibits tumor growth, there was no significant inhibition of melanoma growth when identical doses of 26-succinylbryostatin 1 were injected. Therefore, 26-succinylbryostatin 1 shares some but not all of the pharmacologic properities of bryostatin 1. This compound can activate protein phosphorylation without lowering cytosolic levels of PKC.

Animals↗
PubMed2004

A convergent synthesis of the macrocyclic core of cytotrienins: application of RCM for macrocyclization.

[reaction: see text] The asymmetric synthesis of the fully elaborated macrocyclic core of cytotrienins A-D, potent apoptosis-inducing agents, is described. Synthetic highlights include the construction of the aniline bond using a copper-mediated amidation and the use of a ring-closing metathesis (RCM) reaction to efficiently install the (E,E,E)-triene and simultaneously construct the macrocyclic lactam.

Alkenes↗
PubMed2005

Total synthesis of (+)-dactylolide.

[reaction: see text] The development of an approach leading to the total synthesis of dactylolide is described. The key features of this route include a catalytic asymmetric allylation, a diastereoselective pyran annulation, and a Horner-Wadsworth-Emmons macrocyclization.

Animals↗
PubMed2006

Reaction of geldanamycin and C17-substituted analogues with glutathione: product identifications and pharmacological implications.

17-Dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and 17-allylamino-17-demethoxygeldanamycin (17-AAG) are two derivatives of geldanamycin (GA) that are currently undergoing clinical evaluation as anticancer agents. These agents bind to heat shock protein 90 (hsp90), resulting in the destabilization of client proteins and inhibition of tumor growth. In a search for the mechanism of hepatotoxicity, which is a dose-limiting toxicity for these agents, we found that GA and its derivatives, 17-AAG and 17-DMAG, react chemically (i.e., nonenzymatically) with glutathione (GSH). A combination of liquid chromatography/electrospray ionization/mass spectrometry and nuclear magnetic resonance analyses were used to identify the product of this reaction as a GSH adduct in which the thiol group of GSH is substituted in the 19-position of the benzoquinone ring. The reaction proceeds rapidly with GA and 17-DMAG (half-lives of approximately 1.5 and 36 min, respectively) and less rapidly with 17-AAG and its major metabolite, 17-AG (half-lives of approximately 9.8 and 16.7 h). The reaction occurs at pH 7.0, 37 degrees C, and a physiological concentration of GSH, indicating that cellular GSH could play a role in modulating the cellular toxicity of these agents and therefore be a factor in their mechanism of differential toxicity. Moreover, reactions with thiol groups of critical cellular proteins could be important to the mechanism of toxicity with this class of anticancer agents.

Antibiotics, Antineoplastic↗
PubMed2004

Stereoselective dialkylation of the proximal hydroxy groups of calix- and thiacalix[4]arenes.

Treatment of p-tert-butylcalix[4]arene (C1) and its sulfur-bridged analog T1 with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in the presence of imidazole gives proximally O,O'-disiloxane-1,3-diyl-bridged calixarenes C2 and T2 in excellent yields, respectively. Subsequent base-catalyzed etherification of the remaining hydroxy groups with alkyl halides gives syn- and anti-O'',O'''-dialkylated products, the stereoselectivity of which varies depending on the nature of the macrocycle, as well as the metal cation of the base employed. Thus, conventional calixarene C2 preferentially affords syn compounds of 1,2-alternate conformation (C3) with the aid of tert-BuOK and K(2)CO(3) and anti counterparts of partial-cone conformation (C4) with Cs(2)CO(3). On the other hand, thiacalixarene T2 affords syn compounds of 1,2-alternate conformation (T3) with any of the bases. The disiloxanediyl bridge of the resulting products can readily be removed by treatment with tetrabutylammonium fluoride. Thus, the net process provides an efficient method for the regio- and stereoselective synthesis of proximally dialkylated calix[4]arenes.

Journal Article↗
PubMed2006

Dichloro(4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane)iron(III) hexafluorophosphate.

The title compound, [FeCl2(C12H26N4)]PF6, is the first mononuclear Fe3+ complex of an ethylene cross-bridged tetraaza-macrocycle to be structurally characterized. Comparison with the mononuclear Fe2+ complex of the same ligand shows that the smaller Fe3+ ion is more fully encapsulated by the cavity of the bicyclic ligand. Comparison with the mu-oxo dinuclear complex of an unsubstituted ligand of the same size demonstrates that the methyl groups of 4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane prevent dimerization upon oxidation of the metal centre. Nax -Fe3+ -Nax bond angles (ax is axial), and thus the degree of encapsulation by the ligand, are quite different between the mononuclear and dinuclear mu-oxo species, which is probably the consequence of steric considerations.

Journal Article↗
PubMed1985

A model for the origin of photosynthesis--III. The ultraviolet photochemistry of uroporphyrinogen.

The photochemical ramifications of the high ultraviolet flux on the primordial earth prior to the formation of the ozone layer have been considered in a study of the ultraviolet photochemistry of uroporphyrinogen (urohexahydroporphyrin), a colorless compound which absorbs strongly at wavelengths less than 220 nanometers. Urohexahydroporphyrin was investigated since it is the first macrocycle formed on the biosynthetic pathway of chlorophyll and can be used to test the hypothesis that the biosynthetic pathway to chlorophyll recapitulates the evolutionary history of photosynthesis. When urohexahydroporphyrin is illuminated in aqueous anaerobic solution, hydrogen gas is produced. More hydrogen gas is produced in the presence of a colloidal platinum catalyst. The products of the photooxidation of urohexahydroporphyrin are urotetrahydroporphyrin (uroporphomethene) and uroporphyrin. This research shows how the oxidation of uroporphyrinogen to uroporphyrin, the first biogenetic porphyrin, could have occurred anaerobically and abiotically on the primordial earth.

Atmosphere↗
PubMed2002

Oxidative stress-induced cell death of human oral neutrophils.

Polymorphonuclear leukocytes (PMN) play crucial roles in protecting hosts against invading microbes and in the pathogenesis of inflammatory tissue injury. Although PMN migrate into mucosal layers of digestive and respiratory tracts, only limited information is available of their fate and function in situ. We previously reported that, unlike circulating PMN (CPMN), PMN in the oral cavity spontaneously generate superoxide radical and nitric oxide (NO) in the absence of any stimuli. When cultured for 12 h under physiological conditions, oral PMN (OPMN) showed morphological changes that are characteristic of those of apoptosis. Upon agarose gel electrophoresis, nuclear DNA samples isolated from OPMN revealed ladder-like profiles characteristic of nucleosomal fragmentation. l-cysteine, reduced glutathione (GSH), and herbimycin A, a protein tyrosine kinase inhibitor, suppressed the activation of caspase-3 and apoptosis of OPMN. Neither thiourea, superoxide dismutase (SOD), nor catalase inhibited the activation of caspase-3 and apoptosis. Moreover, N-acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), inhibitor for caspase-3, inhibited the fragmentation of DNA. These results suggested that oxidative stress and/or tyrosine-kinase-dependent pathway(s) activated caspase-3 in OPMN, thereby inducing their apoptosis.

Antioxidants↗
PubMedDate not supplied

Multiresidue determination of abamectin, doramectin, ivermectin, and moxidectin in milk using liquid chromatography and fluorescence detection.

Abamectin, doramectin, ivermectin, and moxidectin are macrocyclic lactones derived from soil dwelling actinomycetes, and are very effective against nematode, insect, and arthropod infestations. These compounds, known as endectocides, have been approved for use in beef cattle in the United States; however, they are currently not approved for use in dairy cattle. Abamectin, doramectin, ivermectin, and moxidectin residues were isolated from milk by a series of liquid-liquid extraction steps, derivatized with trifluoroacetic anhydride, and determined by liquid chromatography with fluorescence detection. Recovery studies were performed in 2 laboratories. Recoveries of > 80% (1-30 ng/mL) were achieved for all 4 compounds.

Animals↗
PubMed2004

Synthesis of novel 11-desmethyl analogues of laulimalide by Nozaki-Kishi coupling.

As a first entry into structurally simplified analogues of the anticancer agent laulimalide, 11-desmethyl compounds 2 and 3 were selected by molecular modeling. The unfavorable diastereoselectivity in the key synthetic step, a Nozaki-Kishi coupling between macrocyclic aldehyde 4 and vinyl iodide 5, was overcome either by use of catalytic amounts of DIANANE-type ligands or L-Selectride reduction of the derived enone. This methodology should allow modular introduction of other, unnatural, side chains. [reaction: see text]

Aldehydes↗
PubMed2004

Total synthesis of macroviracin D (BA-2836-4).

The first total synthesis of the complex glycolipid macroviracin D (BA-2836-4) (1) is described. This antivirally active metabolite isolated from the mycelium extracts of Streptomyces sp. BA-2836 incorporates a unique 46-membered macrodilactone motif decorated with glycosylated fatty acid appendices. Compound 1 consists of three identical subunits which are closely related to one of the segments found in cycloviracin B(1) (2), another antiviral glycoconjugate previously synthesized in our laboratory. Key steps of the synthesis route to 1 involve the stereoselective, ligand-controlled addition of the functionalized diorganozinc derivative 9 to aldehydes 8 a, b, a series of beta-selective glycosidation reactions using appropriately protected trichloroacetimidate donors, and three esterifications via the Yamaguchi method; one of them is performed intramolecularly to forge the macrocyclic lactone ring of the target in 89 % isolated yield. This total synthesis also firmly establishes the absolute configuration of the subunits of compound 1 as 3R,17S,23R.

Antiviral Agents↗
PubMed1982

Studies on macrocyclic lactone antibiotics. VI. Skeletal structure of copiamycin.

Skeletal structure of copiamycin (1) (C54H95N3O17), a potent antifungal antibiotic, was determined from the physicochemical properties of this compound and of its degradation products. This compound consists of 32-membered polyhydroxy lactone ring, an alpha, beta-unsaturated ester group, as well as a side chain with a disubstituted guanidine moiety as its terminal. One of the hydroxyl groups (presumably at C-19) forms a hemiketal ring with the keto group at C-15, and another (at either C-21 or C-23) forms a hemiester with a malonic acid moiety.

Anti-Bacterial Agents↗