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PubMed1998

Aminotriazines as Locking Fragments in Macrocyclic Synthesis.

The macrocyclic compounds (6-(4',6'-diamino-1',3',5'-triazinyl)-1,4,6,8,11-pentaazacyclotetradecane)copper(II) triperchlorate dihydrate, [Cu(HL(2))](ClO(4))(3).2H(2)O, (6-(6'-amino-4'-oxo-1'H-1',3',5'-triazinyl)-1,4,6,8,11-pentaazacyclotetradecane)copper(II) diperchlorate hydrate, [CuL(3)](ClO(4))(2).H(2)O, and [(6-(4',6'-dioxo-1'H-1',3',5'-triazinyl)-1,4,6,8,11-pentaazacyclotetradecane)copper(II)] diperchlorate, [CuL(4)](ClO(4))(2), have been synthesized. The macrocycles synthesized contain respectively pendant melamine, ammeline, and ammelide rings. The X-ray cyrstallographic analyses of [Cu(HL(2))](ClO(4))(3).2H(2)O, triclinic, space group P&onemacr;, a = 9.489(10) Å, b = 12.340(2) Å, c = 24.496(4) Å, alpha = 87.74(10) degrees, beta = 85.51(10) degrees, gamma = 70.95(10) degrees, and Z = 4, and {[CuL(3)](ClO(4))(2).H(2)O}(2), monoclinic, space group C2/c, a = 18.624(8) Å, b = 17.160(2) Å, c = 15.998(6) Å, beta = 117.82(2) degrees, and Z = 4, are reported. The structure of [Cu(HL(2))](ClO(4))(3).2H(2)O shows the formation of linear tapes, formed by a combination of hydrogen bonds and pi-pi stacking interactions. The structure of [CuL(3)](ClO(4))(2).H(2)O displays formation of dimers, formed by a coordinate bond from the oxygen in one molecule to the copper atom of another. The tautomeric forms of the ammeline and ammelide moieties have been determined. The potential of these compounds as subunits for cocrystallization has been investigated.

Journal Article↗

PubMed1991

Tumour localisation with a radioactively labelled reshaped human monoclonal antibody.

A genetically reshaped human IgG1 monoclonal antibody (Hu2PLAP) with anti-tumour specificity, was radiolabelled with Indium-111 by chelation with a new macrocyclic compound (DOTA) which allows the production of stable radioimmunoconjugates for in vivo application. This was used to image seven patients with malignant disease, of whom two had been previously exposed to mouse monoclonal antibodies and had developed human anti-mouse antibodies (HAMA). Successful tumour localisation was seen in the four patients with active disease and antigen positive tumours. No patient showed any antibody responses against Hu2PLAP, but three out of six patients tested showed an immune response against the macrocycle DOTA. Reshaped human monoclonal antibodies with anti-tumour specificity may facilitate repeated administrations of radioactive antibodies, thus allowing new possibilities, both in the diagnosis and treatment of cancer.

Adult↗

PubMed1991

The asymmetric hydroformylation in the synthesis of pharmaceuticals.

The asymmetric hydroformylation reaction represents a potential powerful synthetic tool for the preparation of large number of different chiral products to be used as precursors of several organic compounds endowed with therapeutic activity. Essential and nonessential amino acids, 2-arylpropanoic acids, aryloxypropyl- and beta-phenylpropylamines, modified beta-phenylethylamines, pheniramines, and other classes of pharmaceuticals are available through enantioselective oxo-reaction of appropriate functionalized olefins; this process is catalyzed by rhodium or platinum complexes with chiral ligands, mainly chelating phosphines, and sometimes affords very high enantiomeric excesses. Furthermore, the application of many simple optically active aldehydes arising from asymmetric hydroformylation as chiral building blocks for the synthesis of complex pharmacologically active molecules such as antibiotics, peptides, antitumor macrocycle compounds, and prostaglandins is conveniently emphasized. The possibility of a future application of this asymmetric process for the production of many synthons to obtain other valuable pharmaceuticals is widely discussed too.

Amines↗

PubMed2002

Current progress on farnesyl protein transferase inhibitors.

The hypothesis that the inhibition of farnesyl protein transferase (FPTase) may be beneficial in the treatment of certain cancers is finally being clinically tested. The efforts of almost a decade of preclinical research have resulted in several new chemical entities that are currently undergoing phase I, II or III clinical trials. The number of compounds being tested is small and disproportionate given the amount of effort by a large number of organizations in targeting FPTase. The three compounds, BMS-214662 (Bristol-Myers Squibb), R-115777 (Janssen Pharmaceutica BV) and Sch-66336 (Schering-Plough Research Institute) are the most advanced. While initial results with these three candidate drugs are encouraging, it is disappointing that the clinical efficacy of many other candidates has been less successful. In this review, we summarize the clinical and preclinical data published in 2001, and discuss the natural product inhibitors reported between 1998 to 2001. In addition, a comprehensive history of the FPTase inhibitory discovery effort at Merck, from CAAX tetrapeptides to peptidomimetics to macrocyclic compounds, is summarized for the first time.

Alkyl and Aryl Transferases↗

PubMed2003

Functionalizing inorganic solids: towards organic-inorganic nanostructured materials for intelligent and bioinspired systems.

The design, preparation, and properties of organic-inorganic hybrid compounds are described and discussed with respect to their potential uses as intelligent and bioinspired materials. Several synthesis strategies based on intercalation in 2D solids, the grafting of organic groups onto silica and silicates, and the self-assembly of organo-silica materials are presented, focusing on the soft procedures that are used to modify the functionality of the inorganic substrates. The combination of both organic and inorganic moieties at the nanometer level forms the basis for preparing multifunctional solids that are provided with specific functions in response to different types of stimuli. In some cases these resemble materials that are found in biological systems. Examples include organic-inorganic membranes that are based on intercalated macrocyclic compounds and bi-layer vesicles that consist of alkyl long-chains arranged either in the confined region of layered silicates or as self-organized organo-silica micelles. The role of certain hybrid materials such as membranes provides a different approach to the development of artificial liposomes and other mimetic systems that have an organic-inorganic composition and nanostructural organization. Their potential uses for DDS or DNA-dense phases are also discussed and novel alternatives to bioinspired systems development are proposed.

Biomedical Engineering↗

PubMed2000

1H-NMR determination of the solution structure and absolute configuration of FR134043, a novel inhibitor of human leukocyte elastase.

FR134043 is a semisynthetic disulfonated derivative of the natural product FR901277, is isolated from the culture filtrate of Streptomyces resistomicificus and has potent inhibitory activity against human leukocyte elastase. Although the chemical structure of FR134043 was determined to be a unique bicyclic peptide-like compound consisting of seven amino acids by using several spectroscopic analytical methods, the chiralities of three centers were unknown. A simple simulated annealing protocol to determine the structure was applied to the eight possible stereoisomers, and the one that best satisfied the NOE distance constraints was determined to be the true stereoconfiguration of FR134043. The solution structure showed that all Calpha atoms existed in the L configuration and six of the seven side chains were located towards the outside of the bicyclic framework, even though most of them are highly hydrophobic moieties. The simulated annealing calculation described here is a frequently used method for the determination of the solution structure of peptides or small proteins. We show here that it is also applicable to the determination of the absolute configuration of macrocyclic compounds produced from natural sources.

Heterocyclic Compounds↗

PubMed1999

Application of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to the structure determination of medium and large macrocycles formed by palladium(0)-catalyzed allylation of arenesulfonamides, sulfamide, and cyanamide.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry allowed the direct determination of the extent of macrocyclic and linear oligomer formation in the palladium(0)-catalyzed allylation of highly acidic and non-nucleophilic arenesulfonamides, sulfamide, and cyanamide. Palladium-containing 15-membered-ring macrocyclic compounds gave unusual [M - H](+) ions besides [M + Na](+) and [M + K](+) adducts. Copyright 1999 John Wiley & Sons, Ltd.

Journal Article↗

PubMed2000

Physical, chemical, and biological evaluations of P760: a new gadolinium complex characterized by a low rate of interstitial diffusion.

An original gadolinium chelate, termed P760, which diffuses through the vascular endothelium but at a much lower rate than nonspecific agents (NSA), is described. P760 is a gadolinium macrocyclic compound based on a DOTA structure that is substituted by hydrophilic bulky groups branched on the amino-carboxylic residues. The molecular weight is 5293, and the molecular volume, measured by light scattering, is 30 times higher (11.5 nm3) than that of gadolinium (Gd)-DOTA (0.38 nm3). The increase in molecular volume and weight has two consequences: a) higher relaxivity (r1; 24.7 mM-1.s-1 compared with 3.4 mM-1.s-1 for Gd-DOTA at 20 Mhz, 37 degrees C); and b) a lengthening of its transport rate through the endothelium. P760 presents a peculiar pharmacokinetic profile: at early times post injection, the blood concentrations are higher than those of Gd-DOTA, but after 20 minutes, the blood concentrations are equal for the two compounds. The body clearances of the products are identical (i.e., glomerular filtration rate). P760 molecules are large enough to have a restricted diffusion through the endothelium but, conversely, small enough to pass freely through the glomerular membrane. This limited extravasation has been observed in rabbits by magnetic resonance angiography or in investigations of tumor permeability. Further experimental imaging studies are needed to define the clinical interest of such properties.

Animals↗

PubMed2003

Synthetic expanded porphyrin chemistry.

Expanded porphyrins are synthetic analogues of the porphyrins, and differ from these and other naturally occurring tetrapyrrolic macrocycles by containing a larger central core with a minimum of 17 atoms, while retaining the extended conjugation features that are a hallmark of these quintessential biological pigments. The result of core expansion is to produce systems with novel spectral and electronic features, interesting and, often unprecedented, cation-coordination properties, and, in many cases, an ability to bind anions in certain protonation states. Also adding to the appeal of expanded porphyrins is their central role in addressing issues of aromaticity. In many cases, they also display structural features, such as decidedly nonplanar "figure-eight" motifs, that have no antecedents in the chemistry of porphyrins or related macrocyclic compounds. In this Review, the various synthetic approaches now being employed to produce expanded porphyrins as well as their various applications-related aspects are discussed.

Journal Article↗

PubMed2006

New macrocycles with planar chirality-synthesis and determination of absolute configurations.

A versatile system for preparing macrocyclic compounds with planar chirality is presented. In this system chiral diazacoronands are synthesized readily from lariat-type diesters 13 and 14 and unsymmetrical diamines 7, 8, 12, 15, and 16 under non-high-dilution conditions. The title compounds were subjected to structural analysis by X-ray crystallography and circular dichroism spectroscopy, and absolute configurations for two representative examples (compounds 2 and 3) were assigned by molecular modeling. The correctness of the theoretical approach was verified by the crystallographic results obtained experimentally.

Journal Article↗

PubMedDate not supplied

Clearance of liposomal gadolinium: in vivo decomplexation.

The contrast agents gadolinium-DTPA (diethylenetriaminepentaacetic acid), Gd-DOTA (tetraazacyclododecanetetraacetic acid), and Gd-HP-DO3A (1,4,7-tris[carboxymethyl]-10-[2' hydroxypropyl]-1,4,7,10-tetraazacyclododecane) are used in humans as extracellular contrast agents. Although free Gd+ ion is toxic, the intact Gd3+ complexes are rapidly excreted and are relatively nontoxic. Decomplexation with release of free gadolinium is a relevant clinical concern in patients with altered renal clearance. Blood pool contrast agents currently under development may have longer clearance half-lives and be more prone to decomplexation. The present study was designed to evaluate the clearance of liposomally encapsulated Gd3+ complexes (DTPA, DOTA, and HP-DO3A). The macrocyclic compounds had more rapid and complete clearance than DTPA (P less than .05). Parallel studies with carbon-14 and Gd-153-labeled complexes showed significant differences (P less than .05) in the amount of these isotopes retained in the heart, kidney, lungs, and spleen, providing strong supportive evidence for in vivo decomplexation.

Animals↗

PubMed2003

Electrospray mass spectrometry determination of poly(oxazolidine acetal).

The polycondensation of terephthalaldehyde with 2-amino-2-hydroxymethyl-1,3-propanediol (TRIS), or of terephthaldehyde with 2,2'-(1,4-phenylene)-bis-1,3-(4,4-dihydroxymethyl)oxazolidine (bis-oxazolidine), using acidic catalysts, leads to the formation of linear polymers and macrocyclic compounds. The structure of the polymer was determined by (1)H-, (13)C-NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS) analysis. ESI-MS measurements were used to study the details of the polymer structure and support the alternating nature of equimolar amounts of oxazolidine and the cyclic acetal of terephthaldehyde in these macromolecules.

Acetals↗

PubMed2004

Electrospray mass spectrometry studies of macromolecules containing 1,3-oxazolidine moieties.

The polycondensation of terephthalaldehyde with 2-amino-2-methyl-1,3-propanediol using acidic catalysts leads to the formation of linear polymers and macrocyclic compounds with 2-(1',4'-phenylene)-5-methyl-1-aza-3,7-dioxabicyclo[3.3.0]octane as the repeating unit in all compounds. The structure of the polymer was determined by 1H- and 13C-NMR spectroscopy, and electrospray ionization mass spectrometric (ESI-MS) analysis. ESI-MS measurements were used to study the details of the polymer structure and support the equimolar alternating nature of bicyclo-O,N-acetals of terephthaldehyde in these macromolecules.

Magnetic Resonance Spectroscopy↗

PubMed1982

Bioorganic modelling stereoselective reactions with chiral neutral ligand complexes as model systems for enzyme catalysis.

In terms of the reporting of accomplished chemistry this review can do no more than give an indication of the rapid progress in the branch of bioorganic modelling based on the use of macrocyclic compounds that (usually) act as complexing agents. What remains to be done, however, is to point out problems that have not been satisfactorily solved and to suggest other profitable areas of investigation. From the material accumulated in this review one can draw the conclusion that especially crown (or cryptate) systems offer special advantages in bioorganic modelling because such compounds can - enzyme like - complex a potential substrate. On the basis of quite simple binding considerations, coupled with an analysis of steric interactions, accurate predictions of the stereochemistry of the complex can be made. The inclusion of catalytic groups in the crown (or cryptate) system and reactive functional groups in the substrate is then done in such a fashion that the stereoelectronic arrangement is compatible with the predicted geometry of the complex. However, the good complexing ability of the ligand is paradoxically often its greatest failing in terms of developing a system in which the functionalized ligand acts truly as a catalyst. As seen from much of the chemistry discussed in this review the ligand is incapable of the double task of complexing substrate but releasing product in an enzymic fashion, i.e. that turnover occurs. How is this problem to be solved? Induced conformational changes are an obvious approach although the design of proper systems remains a challenge for which few suggestions outside of unlimited ingenuity can be given. Much of the solution to such problems will lie also in a much better understanding than we now have of non-covalent interactions and the stereochemistry of such interactions. The assembly and disassembly of large molecular aggregates by the making and dissolution of non-covalent bonds is an art at which chemists are still relative amateurs. A better understanding of non-covalent interactions may also provide the key to achieving also the twin goals of both speed and selectivity in bioorganic modelling. As far as enantioselectivity is concerned it is clear that this can be achieved fairly effectively by the use of relatively small, but appropriately placed, groups that force the substrate to complex in an enantioselective step with the ligand. In other words, the problem of enantioselectivity can be solved at the stage of complex forming, which is kinetically rapid. The p]roblem of rate enhancement lies in the mentarity with the transition state of the reaction being catalyzed. Again the achievement of this goal lies in ingenuity of design. Potential areas of applications of chiral crown ether (or cryptate) ligand systems in bioorganic modelling lie in, for example, the formation of carbon-carbon bonds, development of oxidative processes (i.e...

Chemical Phenomena↗

PubMed2001

P792: a rapid clearance blood pool agent for magnetic resonance imaging: preliminary results.

An original MRI contrast agent, called P792, is described. P792 is a gadolinium macrocyclic compound based on a Gd-DOTA structure substituted by hydrophilic arms. The chemical structure of P792 has been optimized in order to provide (1) a high r(1) relaxivity in the clinical field for MRI: 29 mM(-1)xs(-1) at 60 MHz, (2) a high biocompatibility profile and (3) a high molecular volume: the apparent hydrodynamic volume of P792 is 125 times greater than that of Gd-DOTA. As a result of this high molecular volume, P792 presents an unusual pharmacokinetic profile, as it is a Rapid Clearance Blood Pool Agent (RCBPA) characterized by limited diffusion across the normal endothelium. The original pharmacokinetic properties of this RCBPA are expected to be well suited to MR coronary angiography, angiography, perfusion imaging (stress and rest), and permeability imaging (detection of ischemia and tumor grading). Further experimental imaging studies are ongoing to define the clinical value of this compound.

Animals↗

PubMed2003

Structural study of spirolide marine toxins by mass spectrometry. Part I. Fragmentation pathways of 13-desmethyl spirolide C by collision-induced dissociation and infrared multiphoton dissociation mass spectrometry.

A novel group of toxins, the spirolides, has been investigated by several mass spectrometric (MS) methods to enable structure elucidation and metabolite identification. These macrocyclic compounds, produced by the dinoflagellate Alexandrium ostenfeldii, are a new class of marine phycotoxin with characteristic spiro-linked tricyclic ether and imine moieties. A crude phytoplankton extract has been shown to contain known spirolides and several unknown compounds, present at low yet significant levels. This study has focused on mass spectrometric characterization of the main component of this extract, 13-desmethyl spirolide C. Collision-induced dissociation (CID) spectra were collected on triple-quadrupole and quadrupole linear ion-trap instruments. High-resolution Fourier-transform ion cyclotron resonance MS data revealed the accurate masses of the protonated molecule and the product ions formed by infrared multiphoton dissociation. A fragmentation scheme for this toxin has been proposed to explain the formation of the collision-induced fragments. Charge-remote fragmentations dominate the CID spectra, because there is only one predominantly basic site in this molecule, and prove to be structurally informative. Extensive MS characterization of 13-desmethyl spirolide C will undoubtedly be useful in the characterization of known and unknown spirolides and other related compounds.

Animals↗

PubMed1996

Functional crown ether derivatives as sorbents for ligand exchange chromatography.

Two kinds of macrocyclic compounds, S-TAROH18C6 and S-TAROEt12C4 derived from tartaric acid have been synthesized. The structure and conversion of functional groups on this silica gel based resin have been confirmed by IR spectral and elemental analysis. The coordination behaviour of these materials has been investigated by means of IR, EPR, potentiometry and the modification of Langmuir isotherm equation. The metal complexes have been investigated as stationary phases for the separation of amino acid mixtures. Factors affecting the retention and the sample selectivity have been examined. S-TAROEt12C4 possesses good chromatographic characteristics and a unique selectivity in separating underivatized amino acid mixtures and can be used as well for enantiomeric separations.

Journal Article↗

PubMed2006

Population pharmacokinetics and bioavailability of motexafin gadolinium (Xcytrin) in CD1 mice following intravenous and intraperitoneal injection.

Motexafin gadolinium (Xcytrin) is an expanded porphyrin macrocyclic compound under development for the treatment of several types of cancer. Currently clinical trials and non-clinical pharmacology and toxicology studies are ongoing. The goals of this open label, four arm, non-crossover bioavailability study were to explore motexafin gadolinium pharmacokinetics, determine the i.p. bioavailability, and define a pharmacokinetic model suitable for descriptive and predictive use. Mice received one or seven daily i.v. or i.p. injections (40 mg/kg) then blood samples were collected and analyzed. Plasma concentration data were modelled using population pharmacokinetic methods and a two compartment model was the most appropriate model. The stability and predictive performance of the model were evaluated using bootstrap procedures. The accuracy of the predicted concentrations was 8.3%. Motexafin gadolinium was rapidly cleared from the plasma and although T(1/2beta) was 12.9 h there was no accumulation following seven doses. The i.p. bioavailability was 87.4% and higher plasma concentrations were sustainable for a longer period with i.p. dosing. V(c) was larger than the blood volume and the tissue compartment volume was 38% of V(c), suggesting motexafin gadolinium was not widely distributed into less well perfused tissues. The pharmacokinetic profile in this study was similar to that in oncology patients administered multiple doses of motexafin gadolinium. The unbiased model yields reliable parameter estimates and insight into the pharmacokinetics of motexafin gadolinium in mice, is suitable for both descriptive and predictive purposes, and is a valuable tool in the planning, analysis, and interpretation of pharmacology and toxicology studies in mice.

Animals↗