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PubMedDate not supplied

Solid phase combinatorial synthesis of a library of macro-heterocycles and related acyclic compounds.

A solid phase synthesis of macrolactones from three building blocks and in eight steps is described. The synthesis which is carried out on the DHP resin includes Mitsunobu and DIC couplings. The macrocyclization occurs by SN2 displacement of an allylic chloride by a malonate anion. The synthetic methodology is suitable for the synthesis of arrays of macrocycles as well as linear compounds.

Journal Article↗
PubMed1981

Macrocyclic trichothecene toxins produced by a strain of Stachybotrys atra from Hungary.

A strain of Stachybotrys atra isolated from a field case of stachybotryotoxicosis in Hungary was cultured in Hungary. All of the compounds toxic to brine shrimp were separated from the culture extract by solvent partition, column chromatography, and preparative thin-layer chromatography. Two of the toxic compounds were identified as verrucarin J and satratoxin H by comparison with pure standards resolved by high-pressure liquid chromatography and characterized by mass spectrometry. Two other toxic components were identified as roriden E and satratoxin G on the basis of their mass spectra. The fifth toxic compound was identified as a macrocyclic trichothecene based on the following findings: a positive 4-(p-nitrobenzyl)pyridine color reaction, hydrolysis resulting in verrucarol verified by combined gas chromatography-mass spectrometry, and a characteristic trichothecene proton-nuclear magnetic resonance spectrum. This macrocyclic trichothecene has a molecular ion (528) identical to satratoxin H, and its mass spectrum is similar; however, its Rf value on Silica Gel G differs.

Chemical Phenomena↗
PubMed2005

Inherently chiral uranyl-salophen macrocycles: computer-aided design and resolution.

[structure: see text] A flipping motion rapidly inverts the bent structure of uranyl-salophen compounds and, consequently, causes fast enantiomerization of nonsymmetrically substituted derivatives. This process has been previously slowed by introducing bulky substituents in the imine bond region. Since the resulting complexes dissociate upon chromatographic treatment, an alternative approach to the design and synthesis of robust, nonflipping uranyl-salophen compounds is here described. Such an approach is based on the idea that the flipping motion would be blocked by connecting the para positions with respect to the phenoxide oxygens by means of polymethylene bridges of suitable length. Analysis of a number of uranyl-salophen compounds by molecular mechanics, while showing that bulky substituents in the imine bond region cause severe distortions of the ligand backbone, suggested that the best chain lengths are those that fit the gap between the phenoxide rings without altering the natural geometry of the parent uranyl-salophen compound. Calculations showed that such chains are those composed of 12 and 13 methylene units. Accordingly, chiral uranyl-salophen macrocycles bridged with 12- and 13-methylene chains were synthesized in fairly good yields and resolved by chiral HPLC.

Computer-Aided Design↗
PubMed1986

Genotoxicity and cytotoxicity of selected pyrrolizidine alkaloids, a possible alkenal metabolite of the alkaloids, and related alkenals.

Recently our laboratory isolated trans-4-OH-2-hexenal from the hepatic microsomal metabolism of the macrocyclic pyrrolizidine alkaloid (PA) senecionine and demonstrated in vivo that hepatic necrosis occurred following injection into the hepatic portal vein. To demonstrate similarities in the toxic effects of these compounds, as well as additional macrocyclic PAs and alkenals, genotoxicity and cytotoxicity were examined in primary cultures of rat hepatocytes. A positive cytotoxic response was exhibited by senecionine, retrorsine, seneciphylline, 19-OH-senecionine, trans-4-OH-2-hexenal, trans-4-OH-2-nonenal, and nonenal as measured by the release of LDH. A weaker response was elicited by hexenal. Dosages used of each of these compounds ranged from 30 to 600 nmol/10(6) cells, with each compound exhibiting a linear dose response within this range. All eight compounds exhibited a positive, dose-related genotoxic response as measured by autoradiographic detection of unscheduled DNA synthesis. These results would predict a carcinogenic role for both the PAs and the alkenals. This would suggest similarities in the mechanisms of action of the PAs and alkenals, lending support to the proposed role of trans-4-OH-2-hexenal as an important toxic metabolite of the PAs.

Aldehydes↗
PubMed1997

Compound I and Compound II Analogues from Porpholactones.

The tetraaza macrocycles 2-oxa-3-oxotetramesitylporphine (|H(2) 1|) and 2-oxa-3-oxotetrakis(2,6-dichlorophenyl)porphine (|H(2) 2|) and the corresponding iron complexes (|Fe(III)(X) 1| and |Fe(III)(X) 2|; X= Cl(-), OH(-), or SO(3)CF(3)(-)) have been synthesized. These macrocycles are derived from porphyrins by transformation of one pyrrole ring to an oxazolone ring. The resulting lactone functionality serves to restrict but not completely block pi-conjugation around the periphery. These complexes thus share properties with both porphyrins and chlorins. The ferric and high-valent iron complexes have been characterized by a variety of spectroscopic techniques. The molecular structure of |Fe(III)(Cl) 2| has been obtained by X-ray crystallography and shows that the structural changes at the macrocycle periphery do not perturb the coordination sphere of iron relative to the corresponding porphyrin complexes. This is illustrated by the observation that Fe-O frequencies in the resonance Raman spectra of the porpholactone analogues of compounds I and II are not substantially different from those of porphyrins and by the axial appearance of the EPR signals of the high-spin ferric complexes. This is consistent with reports that the Fe=O unit of oxidized porphyrins and chlorins is relatively insensitive to alteration of macrocycle symmetry. Nevertheless, probes of properties of the porpholactone macrocycle ((1)H NMR, resonance Raman skeletal modes) show effects of the asymmetry induced by the oxazolone ring. On the basis of (1)H NMR, EPR, Mössbauer, and resonance Raman data, the singly occupied molecular orbital of oxoferryl porpholactone pi-cation radicals correlates with the a(1u) molecular orbital of porphyrins under D(4)(h)() symmetry. Moreover, the paramagnetic properties and the intramolecular exchange interaction of ferryl iron and the porpholactone pi-radical have been characterized by EPR and magnetic Mössbauer measurements and spin-Hamiltonian analyses. The values J(0) = 17 cm(-)(1) and J(0) = 11 cm(-)(1) obtained for the exchange coupling constants of the oxoferryl porpholactone pi-cation radical complexes |Fe(IV)=O 1|(+) and |Fe(IV)=O 2|(+), respectively, are among the lowest found for synthetic compound I analogues.

Journal Article↗
PubMedDate not supplied

Chemical and metabolic transformations of selected bile acids.

This article surveys chemical transformations of selected bile acids. Chemical transformations were initially carried out with the aim of determining the structure of bile acids. More recently they have been concerned with bile acid interconversions as well as with the synthesis of steroid hormones, vitamins and therapeutc agents. Studies of similarities and differences in the biosynthesis of bile acids from cholesterol have occupied many researches. However, this article reviews only papers dealing with the synthesis of potential intermediates in the biosynthesis of bile acids. Steroid hormones such as pregnenolone, progesterone and testosterone are synthesized from methyl thiodeoxycholate whereas cortisone is synthesized from methyl deoxycholiate. Numerous papers and patents devoted to the synthesis of ursodeoxycholic acid from cholic or chenodeoxycholic acid testify to its effectiveness in the treatment of cholelithiasis. Chenodeoxycholic acid appears to be an excellent precursor in the synthesis of steroid plant growth regulators, as well as in the synthesis of metabolites and vitamin D analogues. Chirality of bile acids has been exploited in the synthesis of cyclic and acyclic receptors and solvents. Cholic and deoxycholic acids have been used to create new macrocyclic structures which show different capacities to bind and transport other compounds. Another important trend in the chemistry of bile acids is their application in combinatorial chemistry.

Acylation↗
PubMed2006

Synthesis and characterisation of bis-cyclen based dinuclear lanthanide complexes.

The design and synthesis of several bis-macrocyclic cyclen (1,4,7,10-tetraazacyclododecane) ligands and their corresponding lanthanum or europium complexes is described; these dinuclear lanthanide systems were made by connecting two macrocyclic cyclen moieties through a rigid, covalent, p-xylylenediamide bridge or a flexible aliphatic hexane bridge. These ligands were subsequently functionalised with six acetamide pendant arms (CONR1R2: R1 = R2 = H or CH3, or R1 = H, R2 = CH3). The corresponding lanthanide bis-complexes were then formed by reaction with La(III) and Eu(III) triflates, yielding overall cationic (+VI charged) complexes.

Cyclams↗
PubMed2005

The total synthesis of coleophomones B, C, and D.

Members of the coleophomone family of natural products all possess several intriguing and challenging architectural features, as well as exhibit unusual biological activity. They, therefore, constitute attractive targets for synthesis. In this Article, we describe the total synthesis of coleophomones B (2), C (3), and D (4). The highly strained and congested 11-membered macrocycle of coleophomones B (2) and C (3) was constructed using an impressive olefin metathesis reaction. Furthermore, both of the requisite geometric isomers of the Delta(16,17) within the macrocycle could be accessed from a common precursor, facilitating a divergence that lent the coleophomone B (2)/C (3) synthesis an unusually high degree of efficiency. The synthesis of coleophomone D (4) confirmed that it exists as a dynamic mixture of isomeric forms with a different aromatic substitution pattern from the other family members.

Alkylation↗
PubMed2003

Evaluation of generic chiral liquid chromatography screens for pharmaceutical analysis.

Two different automated generic liquid chromatography screens for the separation of chiral compounds of pharmaceutical interest have been evaluated. The test set comprised 53 chemically diverse chiral compounds involving 55 enantiomeric pairs from the pharmaceutical industry (i.e. starting materials, synthetic intermediates and drug substances). The first screen utilised four polysaccharide-based columns with five mobile phases and showed enantioselectivity for 87% of the test compounds. The second screen employed three macrocyclic glycopeptide columns with two mobile phases and showed enantioselectivity for 65% of the test compounds. Merging of the two screening procedures resulted in an enantioselectivity for 96% of the chiral compounds. It is anticipated that the systematic use of the automated chiral HPLC screens described in this report will substantially reduce the necessary time for method development of pharmaceutically related chiral analytical methods.

Chromatography, High Pressure Liquid↗
PubMed2005

Structure and photochemistry of 18-diazo-1,4,7,10,13,16-hexaoxacyclononadeca-17,19-dione and its sodium and potassium complexes. Control of the ground-state conformation of 2-diazo-1,3-dicarbonyl fragment via host-guest complexation.

[reaction: see text] The macrocyclic 18-diazo-1,4,7,10,13,16-hexaoxacyclononadeca-17,19-dione (3-diazo-2,4-dioxo-19-crown-6, 1) readily forms complexes with potassium (2, stability constant in methanol is K(K+) = 229 +/- 25 M(-1)) and sodium ions (3, K(Na+) = 84.2 +/- 7.9 M(-1) in methanol). According to B3LYP/6-31G+(d,p) calculations and temperature-dependent 1H NMR spectroscopy, the predominant conformation of 1 has a Z,Z arrangement of the diazo and carbonyl groups. The X-ray crystal structure analysis showed that the potassium complex (2) has the same Z,Z arrangement, while the sodium analogue (2) exists in conformation with Z,E geometry of the diazodicarbonyl moiety. Direct 254 nm photolysis of diazo compounds 1-3 in methanol results in the formation of 3-methoxy-2,4-dioxo-19-crown-6 (5), the product of the insertion of corresponding alpha,alpha'-dicarbonylcarbene into the O-H bond of the solvent. The triplet-sensitized photolysis of diazomalonates 1-3 produces 2,4-dioxo-19-crown-6 (6), which is apparently formed via the triplet state of the intervening carbene.

Azo Compounds↗
PubMed2005

Cucurbit[n]uril analogues: synthetic and mechanistic studies.

[reaction: see text] The synthesis of cucurbit[n]uril analogues (18, 19, (+/-)-20, 33, 34, 35, 36, and 37) is presented. These CB[5], CB[6], and CB[7] analogues all contain bis(phthalhydrazide) walls that are incorporated into the macrocycle. The tailor-made synthesis of these CB[n] analogues proceeds by the condensation of the appropriate bis(electrophile) (4, 7, or 9) with bis(phthalhydrazide) (17), which delivers the CB[6] and CB[7] analogues in good yield, whereas the CB[5] analogue is formed in low yield. To improve the solubility characteristics of the CB[n] analogues for recognition studies in water or organic solution, the CO2Et groups were transformed to CO2H and CO2(CH2)9CH3 groups. On the basis of the results of product resubmission experiments, we conclude that these macrocycles are kinetic products. To help rationalize the good yields obtained in the CB[6] and CB[7] analogue macrocyclization reactions, we performed mechanistic studies of model methylene bridged glycoluril dimers, which suggest an intramolecular isomerization during CB[n] analogue formation.

Bridged-Ring Compounds↗
PubMed2004

[Study on cucurbit[ 7] uril-mediated capillary electrophoresis].

The use of a novel macrocyclic molecule, cucurbit[7] uril (CB[7]), as an additive in capillary electrophoresis (CE) for the separation of several neutral nitrobenzenes is reported. Disodium hydrogen phosphate-hydrochloric acid was used as the buffer solvent with the UV detection at 254 nm. During the running process, CB [7] bore positive charge under the studied pH range (pH 2 - 6.5) and was adsorbed onto the inner wall of fused silica capillary, leading to a reversal of the electroosmotic flow (EOF). The effects of buffer pH and CB [7] concentration on the EOF behavior were investigated. The influences of the CB [7] concentration on electrophoretic behaviors of nitrobenzenes were also studied, and it was found that the selectivity increased with CB[7] concentration. The results showed that CB [7] provided good selectivity for nitrobenzenes and successful separation was obtained under optimum condition (10 mmol/L Na2HPO4 (pH 2.47, adjusted by HCl)-methanol (90 : 10, v/v), containing 5 mmol/L CB[7]). Possible explanation is also proposed.

Bridged-Ring Compounds↗
PubMed1988

Inhibition of human lymphocyte transformation by the macrocyclic trichothecenes roridin A and verrucarin A.

The effect of in vitro exposure to the macrocyclic trichothecenes roridin A and verrucarin A on human lymphocyte transformation was evaluated in the mitogen-induced blastogenesis assay. Both compounds were capable of inhibiting stimulation of B- and T-cell subsets by a mitogen panel that included leukoagglutinin, concanavalin A, and pokeweed mitogen. Doses of roridin A and verrucarin A which inhibited [3H]thymidine uptake by 50%, as averaged from this mitogen panel, were 20 and 9 pg/ml, respectively. Verrucarol, a compound which results from base hydrolysis of macrocyclic trichothecenes, had no effect on blastogenesis at levels up to 5 X 10(5) pg/ml, indicating that an intact macrocyclic ring was essential for the potent inhibitory activity of roridin A and verrucarin A. The toxicity of these two compounds was extraordinary relative to that reported for non-macrocyclic trichothecenes and could not be predicted quantitatively from previous structure-activity studies on the toxic and biochemical properties of the trichothecenes.

Humans↗
PubMed1986

Studies on macrocyclic lactone antibiotics. VIII. Absolute structures of rhizoxin and a related compound.

The absolute structure of rhizoxin, a potent antifungal and antitumor antibiotic, was determined by interrelation with compound 2 whose structure was established by X-ray analysis. Since a 18OH group was introduced at C-3 on a hydrolytic cleavage of C-2, C-3 epoxy group with alkaline H2(18)O, the original epoxy oxygen should be retained at C-2. The stereo-chemistry at C-2 and C-3 positions in rhizoxin was, therefore, determined as 2R,3S.

Chemical Phenomena↗
PubMed1997

A survey on resistance to anthelmintics in sheep stud farms of southern Brazil.

A survey to investigate the status of anthelmintic resistance in 29 sheep studs in southern Brazil was conducted from March 1992 to December 1993. Compounds from three drug families (macrocyclic lactone, levamisole and benzimidazole) were evaluated concurrently on 22 of the 29 studs. On seven of these properties, resistance to all three families was declared or suspected; at 15 of the 22 studs, ivermectin was the only compound found to be effective in reducing faecal egg counts. Resistance to levamisole was detected on 22 of the 23 studs where it was evaluated and was suspected in the remaining one. The position of benzimidazoles was similar, resistance being declared or suspected on all 28 studs where they were tested. Results of larval cultures indicated that Trichostrongylus, Ostertagia and Haemonchus were the most prevalent nematode genera in the survey, with Trichostrongylus and Haemonchus being the genera associated with anthelmintic resistance.

Albendazole↗
PubMed1997

Design and analysis of molecular motifs for specific recognition of RNA.

Selective targeting of RNA has become a recent priority in drug design strategies due to the emergence of retroviruses, the need for new antibiotics to counter drug resistance, and our increased awareness of the essential role RNA and RNA structures play in the progression of disease. Most organic compounds known to specifically target RNA are complex, naturally occurring antibiotics that are difficult to synthesize or derivatize and modification of these compounds to optimize interactions with structurally unique RNAs is difficult. The de novo design of synthetically accessible analogues is one possible alternative; however, little is known about the RNA recognition principles on which to design new compounds and limited information on RNA structure in general is available. To contribute to the growing body of knowledge on RNA recognition principles, we have prepared two series of polycationic RNA-binding agents, one with a linear scaffold, the other with a macrocyclic scaffold. We evaluated these compounds for their ability to bind to DNA and RNA, as well as to a specific RNA, the regulatory sequence, RRE, derived from HIV-1, by using thermal melting, circular dichroism, and electrophoresis gel shift methods. Out results suggest that cationic charge centers of high pKa that are displayed along a scaffold of limited flexibility bind preferentially to RNA, most likely within the major groove. Related derivatives that bind more strongly to DNA more closely mimic classical DNA minor-groove binding agents. Several of the macrocyclic polycations expand on a new binding motif where purine bases in duplex RNA are complexed within the macrocyclic cavity, enhancing base-pair opening processes and ultimately destabilizing the RNA duplex. The results in this report should prove a helpful addition to the growing information on molecular motifs that specifically bind to RNA.

Amino Acid Sequence↗
PubMed2004

Transforming chiral liquid chromatography methodologies into more sensitive liquid chromatography-electrospray ionization mass spectrometry without losing enantioselectivity.

LC-electrospray ionization (ESI) MS conditions were optimized for the individual chiral separation of 19 compounds of pharmaceutical interest using the macrocyclic glycopeptide-based chiral stationary phases in both polar organic and reversed-phase modes (RPM). The influence of mobile phase composition and MS additive type on sensitivity was investigated for all classes of compounds tested. Compounds with amine or amide groups were efficiently separated, ionized, and detected with the addition of 0.1% (w/w) ammonium trifluoroacetate to the solvent system in either the reversed-phase or polar organic mode (POM). Macrocyclic glycopeptide coupled column technology was initially used to screen all chiral compounds analyzed. Baseline resolution of enantiomers was then achieved with relatively short retention times and high efficiencies on Chirobiotic T, Chirobiotic V or Chirobiotic R narrow bore chiral stationary phases. The polar organic mode offered better limits of detection (as low as 100 pg/ml) and sensitivity over reversed-phase methods. An optimum flow-rate range of 200-400 microl/min was necessary for sensitive chiral LC-ESI-MS analysis.

Chromatography, Liquid↗