Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “macrocycles”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources
PubMed2002

Structure-activity relationships of methoctramine-related polyamines as muscular nicotinic receptor noncompetitive antagonists. 3. Effect of inserting the tetraamine backbone into a macrocyclic structure.

The present article expands on the study of another aspect of structure-activity relationships of the polymethylene tetraamines, namely, the effect of inserting the tetraamine backbone into a macrocyclic structure. To this end, compounds 8-12 were designed by linking the two terminal nitrogen atoms of prototype methoctramine 2 to an aryl moiety. Alternatively, 2 was first modified to achieve compounds 6 and 7, which in turn were cyclized by linking the two terminal primary amine functions to a polyphenyl spacer, affording 13-20. All the compounds were tested on muscle-type nAChRs and most of them as well on AChE. Furthermore, selected compounds were tested also on peripheral M(2) and M(3) mAChRs. All these cyclic derivatives, like prototypes, were potent noncompetitive antagonists at both frog and Torpedo nAChRs, suggesting that polyamines do not need to be linear or in extended conformation to optimally interact with the nicotinic channel; rather, they may bind in a U-shaped conformation. Relative to muscarinic activity, macrocyclic compounds 10, 13, 14, and 20, in contrast with the profile displayed by 2, were almost devoid of affinity. It is derived that an aryl spacer is detrimental to the interaction of polyamines with mAChRs. Finally, all the diamine diamides investigated in this study were much less potent in inhibiting AChE activity than prototype 3, suggesting that a macrocyclic structure may not be suitable for AChE inhibition.

Acetylcholinesterase↗
PubMed2003

Utilization of a beta-aminophosphotyrosyl mimetic in the design and synthesis of macrocyclic Grb2 SH2 domain-binding peptides.

Grb2 SH2 domains are protein-docking modules that exert important functions in both normal and pathogenic signal transduction processes. Development of synthetic Grb2 SH2 domain binding ligands is being pursued by several groups as potential new therapies for a variety of diseases, including certain cancers. In these efforts, macrocyclization has been successfully utilized to take advantage of preferential recognition by Grb2 SH2 domains of ligands in beta-bend conformations. Recent examples of this approach include olefin-metathesis-derived macrocycles that employ ring closure at the beta-position of key pTyr-mimicking residues. In the current study, a novel phosphatase-stable beta-amino-pTyr mimetic designated "Pmp(beta)" was utilized to prepare variants of previously reported olefin-metathesis-derived macrocycles. An initial set of simplified cyclic peptides lacking key naphthyl side chain functionality was first synthesized to determine optimum ring size, with results indicating that a four-unit ring-closing segment was appropriate. On the basis of these findings, macrolactamization was undertaken with a more highly functionalized, naphthyl-containing gamma-amino acid analogue. The resulting cyclic beta-amino peptide is the first of a new class of pTyr-mimetic-containing ligands that may have utility in the development of antagonists of both Grb2 SH2 domains and other pTyr-dependent signaling systems.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Cyclization strategies for the synthesis of macrocyclic bisindolylmaleimides.

Three new approaches to the synthesis of macrocyclic bisindolylmaleimides 1-4 have been identified. Two strategies afford 8, the penultimate intermediate for the synthesis of 1-4, in 73% and 32% yield by intramolecular cyclization of 31 and 40, respectively. The optimum synthesis of 1 was achieved in nine steps and 15% yield by intramolecular formation of the macrocycle and maleimide in one step by reaction of the sodium indolate of 12 with methyl indole-3-glyoxylate 47. The mechanism of this reaction has been elucidated, using the trityl-protected derivative, to involve initial formation of the tricarbonyl imide 48, followed by irreversible alkylation of the indole nitrogen to generate the 17-membered macrocycle 49. Cyclization of 49 to hydroxymaleimide 50 and subsequent dehydration afforded 8a. This approach eliminated the problem of dimerization observed in the intramolecular cyclization reactions.

Diabetic Retinopathy↗
PubMed2001

Ring-closing metathesis of olefinic peptides: design, synthesis, and structural characterization of macrocyclic helical peptides.

Heptapeptides containing residues with terminal olefin-derivatized side chains (3 and 4) have been treated with ruthenium alkylidene 1 and undergone facile ring-closing olefin metathesis (RCM) to give 21- and 23-membered macrocyclic peptides (5 and 6). The primary structures of peptides 3 and 4 were based upon a previously studied heptapeptide (2), which was shown to adopt a predominantly 3(10)-helical conformation in CDCl(3) solution and an alpha-helical conformation in the solid state. Circular dichroism, IR, and solution-phase (1)H NMR studies strongly suggested that acyclic precursors 3 and 4 and the fully saturated macrocyclic products 7 and 8 also adopted helical conformations in apolar organic solvents. Single-crystal X-ray diffraction of cyclic peptide 8 showed it to exist as a right-handed 3(10)-helix up to the fifth residue. Solution-phase NMR structures of both acyclic peptide 4 and cyclic peptide 8 in CD(2)Cl(2) indicated that the acyclic diene assumes a loosely 3(10)-helical conformation, which is considerably rigidified upon macrocyclization. The relative ease of introducing carbon-carbon bonds into peptide secondary structures by RCM and the predicted metabolic stability of these bonds renders olefin metathesis an exceptional methodology for the synthesis of rigidified peptide architectures.

Alkenes↗
PubMed2002

Conjugated macrocycles related to the porphyrins. 21. Synthesis, spectroscopy, electrochemistry, and structural characterization of carbaporphyrins.

The "3 + 1" variant of the MacDonald condensation has been shown to be an excellent methodology for synthesizing carbaporphyrins. In particular, 1,3-indenedicarbaldehyde condenses with tripyrranes in the presence of TFA to give, following oxidation with DDQ, a series of benzocarbaporphyrins in excellent yields. Triformylcyclopentadienes also afford carbaporphyrin products, albeit in low yields ranging from 5 to 8%. These hybrid bridged annulene structures have porphyrin-like electronic absorption spectra with strong Soret bands near 420 nm and a series of Q-bands through the visible region. The proton NMR spectrum confirms the presence of a strong diamagnetic ring current, and the meso-protons show up at 10 ppm, while the internal CH is shielded to approximately -7 ppm. Carbaporphyrins undergo reversible protonation with TFA. Initial addition of acid affords a monocation, although mixtures of protonated species are observed in the presence of moderate concentrations of TFA. However, in the presence of 50% TFA a C-protonated dication is generated. The dications relocate the pi-delocalization pathway through the benzo moiety of benzocarbaporphyrins, and these therefore represent bridged benzo[18]annulenes, although they nevertheless retain powerful macrocyclic ring currents. Carbaporphyrins with fused acenaphthylene and phenanthrene rings have been prepared, and the former demonstrated significantly larger bathochromic shifts in UV-vis spectroscopy that parallel previous observations for acenaphthoporphyrins. A diphenyl-substituted benzocarbaporphyrin 19b was also characterized by X-ray crystallography, and these data show that the macrocycle is reasonably planar although the indene subunit is tilted out of the mean macrocyclic plane by 15.5 degrees. The structural data indicates that the preferred tautomer in the solid state has the two NH's flanking the pyrrolene unit in agreement with previous spectroscopic and theoretical studies. Cyclic voltammetry for carbaporphyrin 19a was more complex than for true porphyrins, showing five anodic waves and two quasi-reversible reductive couples.

Journal Article↗
PubMed2002

Convergent synthesis of isomeric pairs of metallocene-containing polyether macrocycles.

A general method for rapid construction of metallocene-based hosts is described. Treatment of polyether bridged bis(diphenylacetylenes) with a source of cyclopentadienyl cobalt at high temperature leads, via macrocyclization and capture of the intermediate cyclobutadiene, to macrocyclic systems tethered to an integral metallocene platform. Equal yields of the two possible structural isomers, the products of parallel or antiparallel cycloaddition of the precursor, are obtained. A combination of X-ray crystallography and NMR is employed to assign structures to the individual isomers and to assess the strength of lithium ion binding by the individual macrocycles.

Journal Article↗
PubMed2003

Synthetic studies toward sarain A. Formation of the western macrocyclic ring.

Starting with the tricyclic core 2b, annulation to form the 13-membered western ring of sarain A has been achieved to afford the macrocycle 30a by initial construction of the sterically congested quaternary center at C-3, followed by elaboration of the C-3 side-chain and ring-closing olefin metathesis. Also included is a parallel conversion of tricycle 2c to macrocycle 30b containing a functionalized side-chain at N-1 suitable for attachment of the eastern macrocyclic ring.

Alkaloids↗
PubMed2003

A convergent solution-phase synthesis of the macrocycle Ac-Phe-[Orn-Pro-D-Cha-Trp-Arg], a potent new antiinflammatory drug.

Relatively few cyclic peptides have reached the pharmaceutical marketplace during the past decade, most produced through fermentation rather than made synthetically. Generally, this class of compounds is synthesized for research purposes on milligram scales by solid-phase methods, but if the potential of macrocyclic peptidomimetics is to be realized, low-cost larger scale solution-phase syntheses need to be devised and optimized to provide sufficient quantities for preclinical, clinical, and commercial uses. Here, we describe a cheap, medium-scale, solution-phase synthesis of the first reported highly potent, selective, and orally active antagonist of the human C5a receptor. This compound, Ac-Phe[Orn-Pro-d-Cha-Trp-Arg], known as 3D53, is a macrocyclic peptidomimetic of the human plasma protein C5a and displays excellent antiinflammatory activity in numerous animal models of human disease. In a convergent approach, two tripeptide fragments Ac-Phe-Orn(Boc)-Pro-OH and H-d-Cha-Trp(For)-Arg-OEt were first prepared by high-yielding solution-phase couplings using a mixed anhydride method before coupling them to give a linear hexapeptide which, after deprotection, was obtained in 38% overall yield from the commercially available amino acids. Cyclization in solution using BOP reagent gave the antagonist in 33% yield (13% overall) after HPLC purification. Significant features of the synthesis were that the Arg side chain was left unprotected throughout, the component Boc-d-Cha-OH was obtained very efficiently via hydrogenation of d-Phe with PtO(2) in TFA/water, the tripeptides were coupled at the Pro-Cha junction to minimize racemization via the oxazolone pathway, and the entire synthesis was carried out without purification of any intermediates. The target cyclic product was purified (>97%) by reversed-phase HPLC. This convergent synthesis with minimal use of protecting groups allowed batches of 50-100 g to be prepared efficiently in high yield using standard laboratory equipment. This type of procedure should be useful for making even larger quantities of this and other macrocyclic peptidomimetic drugs.

Anti-Inflammatory Agents↗
PubMed2004

Mild and selective reduction of imines: formation of an unsymmetrical macrocycle.

During investigations of 5, a [3 + 3] Schiff-base macrocycle with six imines, a partially reduced Schiff-base macrocycle, 6, possessing one CH(2)NH and five imine groups was obtained. Control experiments and deuterium labeling indicate that the macrocycle is reduced by a benzimidazoline generated during the reaction. Benzimidazolines may be convenient reagents for the mild and selective reduction of imines.

Cyclization↗
PubMed2005

Self-assembly, binding, and dynamic properties of heterodimeric porphyrin macrocycles.

A series of heterodimeric tetralactam macrocycles have been self-assembled using two kinetically labile zinc porphyrin-pyridine interactions. The stability constants have been determined by UV-vis titrations in CHCl3. The stability constants depend on the degree of preorganization of the linker units connecting the interacting groups. The ability of the self-assembled macrocycles to bind a terephthalamide guest was also investigated. One of the macrocycles was used for the construction of a [2]rotaxane. The dynamic properties of this system provide insight into the exchange mechanisms that operate in complex noncovalent assemblies.

Journal Article↗
PubMed2005

C2-symmetric macrocyclic carbohydrate/amino acid hybrids through copper(I)-catalyzed formation of 1,2,3-triazoles.

An efficient method was developed for the preparation of macrocyclic carbohydrate/amino acid hybrids by macrocyclization with copper(I)-catalyzed 1,2,3-triazole formation. Methyl 2-amino-6-azido-3,4-di-O-benzoyl-2,6-dideoxy-beta-D-glucopyranoside was prepared and coupled to two different N-propiolyl dipeptides (propiolyl-Tyr-Tyr-OH and propiolyl-Arg(Mtr)-Tyr-OH) to obtain bifunctional molecules carrying one azido group and one terminal alkyne. These bifunctional molecules were cyclodimerized using Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes to form macrocycles containing two 1,2,3-triazoles. Various cyclization methods were evaluated, and the most efficient conditions were found to be CuI and N,N-diisopropylethylamine in CH3CN.

Amino Acids↗
PubMed1996

Synthesis, Structure, and Reactivity of Enediyne Macrocycles.

The reaction of bis-propargyl bromide enediyne 4 with weakly basic nucleophiles allows the facile synthesis of acyclic and macrocyclic enediynes. Depending on the bis-nucleophile employed, 12- to 16-membered enediyne macrocycles were obtained. The thermal stability of the new cyclic enediynes was investigated by differential scanning calorimetry. Upon coordination of the macrocycle 5c with Hg(O(2)CCF(3))(2), a drop of the enediyne cyclization temperature of nearly 100 K was observed.

Journal Article↗
PubMed2006

Diphenyloligothiophene-based dichromophoric macrocycles and their ability to form donor/acceptor complexes.

A series of four dichromophoric rigid macrocycles 6a-6d, two with diphenyloligothiophene chromophores, the other two with more electron-rich diphenyl-EDOT or diphenyl-bis-EDOT chromophores, have been synthesized. The absorption spectrum of the diphenyl-bis-EDOT based macrocycle 6d displayed the most pronounced vibronic resolution with a well-resolved 0-0 transition, indicating a fully planarized geometry of the diphenyl-bis-EDOT chromophores. The (1)H NMR spectra of the macrocycles displayed weak to moderate chemical shifts of characteristic signals upon addition of pi-conjugated oligonitro-9-fluorenone acceptors. X-ray single-crystal analysis showed that columnar pi-stacked donor/acceptor complexes are formed with the stacks composed of alternating donor and acceptor molecules. The stoichiometry of the crystalline, dark-colored complexes was found to be 1:1 by elemental analysis and integration of the (1)H NMR peaks. The complex formation is accompanied by remarkably large Stern-Volmer constants of fluorescence quenching.

Journal Article↗
PubMed2000

The effect of varying substituents on the equilibrium distribution and conformation of macrocyclic steroidal N-acyl hydrazones

The equilibrium distribution of deoxycholate-based macrocyclic N-acyl hydrazones is dependent upon the nature of the substituents at the 3- and 12-position. These substituents can also influence the preferred conformation of the macrocycles. The conversion of pure cyclic dimer and trimer into a mixture of both components, in the presence of trifluoroacetic acid, has been demonstrated and an X-ray crystal structure obtained of a macrocyclic N-acyl hydrazone dimer.

Journal Article↗
PubMed2000

Transannular macrocyclization via intramolecular B-alkyl Suzuki reaction.

[reaction: see text]Transannular macrocyclizations via intramolecular B-alkyl Suzuki reactions are described. Regioselective terminal olefin hydroboration with 9-BBN followed by Pd(0)-catalyzed Suzuki reaction in the presence of a base such as TlOEt at high dilution generates macrocycles with a high degree of control over olefin geometry with isomerically pure E or Z vinyl iodide substrates. These reactions are complementary to ring closing metathesis (RCM) macrocyclizations and may prove superior in cases where control of olefin geometry is required.

Bridged-Ring Compounds↗
PubMed2001

Intramolecular O-arylation of phenols with phenylboronic acids: application to the synthesis of macrocyclic metalloproteinase inhibitors.

[reaction: see text]. The copper acetate mediated intramolecular O-arylation of phenols with phenylboronic acid pseudopeptides is the key step in the preparation of macrocyclic biphenyl ether hydroxamic acid inhibitors of collagenase 1 and gelatinases A and B. The intramolecular macrocyclization was found to be mild and tolerant of common chemical functionality. This methodology should provide a general route to macrocyclic biphenyl ethers.

Boronic Acids↗
PubMed2003

Novel antibiotics: macrocyclic peptides designed to trap Holliday junctions.

[reaction: see text] Described are the syntheses of eight macrocyclic peptides designed to trap Holliday junctions in bacteria, thereby inhibiting bacterial growth. These macrocycles were designed from linear dimerized hexapeptides that bind to the C-2 symmetrical Holliday junction. They were synthesized from three monomers using a combinatorial-like strategy that permits elucidation of the monomer role in accumulation of Holliday junctions and antibiotic activity. These macrocycles are an important step in designing and synthesizing a new class of antibiotics.

Anti-Bacterial Agents↗