Tetramethylpyridiniumporphyrazines--a new class of G-quadruplex inducing and stabilising ligands

3,4-Tetramethylpyridiniumporphyrazines bind strongly and selectively to human telomeric G-quadruplex DNA, inducing the formation of an antiparallel quadruplex in a process that mimics molecular chaperones.     

Elite new anion ligands: polythioamide macrocycles

Prototypes for a new class of polythioamide-based macrocycles have been synthesized and anion-binding capabilities assessed. Results indicate higher anion binding for H(2)PO(4)(-), HSO(4)(-), and F(-) for monocycles, but somewhat lessened binding capabilities for bicycles compared with amide corollaries.     

Enantiomerically pure phenanthroline or bipyridine containing macrocycles: a new class of ligands for asymmetric catalysis

New enantiomerically pure phenanthroline- and bipyridine-containing macrocycles have been synthesized by combination of the coordinating unit to inexpensive and readily available chiral templates. The catalytic properties of their Cu(I) complexes have been studied in the cyclopropanation of alkenes as test reaction. A simple structural modification of the chiral cavity allowed us to successfully control the trans or cis diastereoselectivity of the reaction.     

Bridged peptide macrocycles as ligands for PDZ domain proteins

[reaction: see text] Conformationally constrained side chain-bridged cyclic peptides were prepared using bis-carboxylic acid ring spacers. These macrocyles were designed to inhibit protein-protein interactions mediated by the third PDZ domain (PDZ3) of a mammalian neuronal protein, PSD-95. Isothermal titration calorimetry (ITC) experiments measured dissociation constants in the low micromolar range. For each compound, the change in entropy (TdeltaS) of binding either is comparable in magnitude to the enthalpy change (deltaH) or is the predominant driving force for association.     

Natural products and their derivatives as G-quadruplex binding ligands

G-quadruplexes comprise a class of secondary structures that are formed in guanine-rich sequences in eukaryotic genomes and play a crucial role in the regulation of many biological events. G-quadruplexes have become targets for anticancer drugs with high selectivity vs. duplex DNA and low cytotoxicity against normal cells. Natural products and their derivatives display polymorphism, structural complexity, and potent activity. It is, therefore, reasonable to seek ligands targeting G-quadruplexes from natural products. Recently, many successful examples have been reported, showing ligands with excellent anticancer activities. In this review, we summarized the development of research on natural products and derivatives that target G-quadruplex structures in an effort to guide future studies.     

Cationic corrole derivatives: a new family of G-quadruplex inducing and stabilizing ligands

Water-soluble cationic corrole derivatives were designed and synthesized, and the first observation of their interactions with the telomeric G-quadruplex was made.     

Encoded peptide libraries and the discovery of new cell binding ligands

Cells over-expressing integrins or CCR6 were incubated on a DNA microarray, pre-hybridized with a 10,000 member PNA-encoded peptide library allowing novel cell specific ligands for integrins and CCR6 to be identified.     

A new method for the study of G-quadruplex ligands

A new method for the study of G-quadruplex ligands was developed, in which the interaction of G-quadruplexes with ligands can be judged by the naked eye, eliminating the need for any expensive machines.     

A new class of non-racemic chiral macrocycles: a conformational and synthetic study

Amino alcohols have been used to introduce non-racemic chirality into macrocycles using a modular approach that relies on a Heck macrocyclisation reaction. A wide variety of macrocycles have been synthesised, and their structures studied using X-ray crystallography and molecular modelling. A fragmentation reaction encountered during the use of (S)-1,1-dimethylvalinol revealed that carboxylic acids generate acylals under reaction conditions often used for Heck reactions.     

Synthesis and cytotoxicity of a new class of potent decapeptide macrocycles

Described are the syntheses of five decapeptides that are C-2-symmetrical derivatives of the natural product pentapeptide sansalvamide A. Derivatives were made using a succinct convergent synthesis. These analogues share no structural homology to current cancer drugs, are cytotoxic at levels on par with existing drugs treating cancers, and demonstrate selectivity for drug-resistant pancreatic cancer cell lines over noncancerous cell lines. These molecules are excellent chemotherapeutic leads in the search for new anticancer agents.     

Enolphosphato-phosphines: a new class of P,O ligands

The new bifunctional ligands Ph(2)PCH[double bond]CPh[OP(O)(OR)(2)] (1) (1a, R = Et; 1b, R = Ph) represent the first examples of P,O derivatives resulting from the association of a phosphine moiety and an enolphosphate group. The Z stereochemistry about the double bond provides a favorable situation for these ligands to act as P,O-chelates. Neutral and cationic Pd(II) complexes have been synthesized and characterized, in which 1a or 1b acts either as a P-monodentate ligand or a P,O-chelate, via coordination of the oxygen atom of the P[double bond]O group. In the latter case, it has been observed that phosphines 1a and 1b can display a hemilabile behavior, owing to successive dissociation and recoordination of the O atom. Competition experiments revealed that phosphine 1a presents a higher chelating ability than 1b, a feature ascribed to the more electrodonating properties of the ethoxy groups in 1a compared to the phenoxy groups in 1b. P,O-Chelation affords seven-membered metallocycles, which is unusual for P,O-chelates. Complexes trans-[PdCl(2)[Ph(2)PCH[double bond]C(Ph)OP(O)(OPh)(2)](2)] (2b), [PdCl[Ph(2)PCHdouble bond]C(Ph)OP(O)(OEt)(2)](mu-Cl)](2) (3a), [complex--see text] (8a'), and [complex--see text] (10a) have been structurally characterized. Interestingly, the seven-membered rings in 8a' and 10a adopt a sofa conformation with the double bond lying almost perpendicular to the plane containing the Pd, the two P, and the two O atoms.     

Pyrazolin-4-ylidenes: a new class of intriguing ligands

The immense success of N-heterocyclic carbenes in recent years has initiated the search for even stronger ligands leading to the discovery of abnormal and remote NHCs. This article reflects our particular interest in the coordination chemistry of pyrazolin-4-ylidenes as a contribution to this field. A modular approach to 4-iodopyrazolium salts with different substitution patterns is described, which upon oxidative addition to Pd(0) gave rise to a library of new Pd(ii) pyrazolin-4-ylidene complexes. A preliminary study showed that selected complexes are active precatalysts in Suzuki-Miyaura and Mizoroki-Heck coupling reactions. The 3,5-substituents of pyrazolin-4-ylidenes are found to have significant effects on complexation and catalytic activities. Finally, the nature of this new class of ligands is discussed, and a future direction for further explorations in this exciting field is envisioned.     

Convenient synthesis of 6,6-bicyclic malonamides: a new class of conformationally preorganized ligands for f-block ion binding

A general synthetic approach was developed for the preparation of a series of 6,6-bicyclic malonamides, a class of ligands that provide a preorganized binding site for f-block ions (particularly trivalent lanthanides). The approach described is convenient to introduce a variety of functional groups at the amide nitrogens to tune the properties of the ligand without altering the preorganized binding. Each of the ten derivatives (that represent a range of functionality, including R = alkyl, hydroxy, phenyl, ester, perfluorocarbon) reported here derives from a single, readily prepared dialdehyde intermediate. This intermediate is converted to the final products via reductive amination with an appropriately functionalized benzylamine, followed by hydrogenolysis and lactam formation. Because derivatization occurs late in the synthesis, the approach is general, requiring only modification of the purification procedures for each new derivative. To aid in the purification of the bicyclic malonamides, we report a novel complexation-based purification method that takes advantage of the high affinity of the ligand for f-block metals.     

Unraveling the relationship between structure and stabilization of triarylpyridines as G-quadruplex binding ligands

A series of novel 2,4,6-triarylpyridines have been synthesized and their interactions with intramolecular G-quadruplexes have been measured by F?rster Resonance Energy Transfer (FRET) melting and Fluorescent Intercalator Displacement (FID) assays. A few of these compounds exhibit stabilization of G4-DNA that is comparable to other benchmark G4-DNA ligands with fair to excellent G4-DNA vs. duplex selectivity and significant cytotoxicity towards HeLa cells. The nature of the 4-aryl substituents along with side chain length governs the G4-DNA stabilization ability of the compounds. In addition, we demonstrate that there is a strong correlation between the ability of the compounds to stabilize the same G4-DNA sequence in K(+) and Na(+) conditions and a strong correlation between the ability of the compounds to stabilize different G4-DNA sequences in K(+) or Na(+) buffer.     

Synthesis, structural characterization and anion binding studies of palladium macrocycles with hydrogen-bonding ligands

The reactions between [Pd(P-P)(OTf)2] (where P-P=dppp or dppf) and two different bipyridyl ligands (=1,3-bis(4-pyridylmethyl)urea and=1,3- bis(pyridinylmethyl)benzenedicarboxamide) containing hydrogen-bonding units have been studied. The X-ray crystal structures of three of these assemblies have been solved showing them to be the [2+2] metallo-macrocycles [Pd(P-P)(n)]2(OTf)4 [P-P=dppp, n=1, (); P-P=dppp, n=2, (); P-P=dppf, n=1, ()]. To confirm whether the dimeric assembly of one of these species () is retained in solution, several investigations have been carried out. 1H NMR studies in DMSO and high resolution ESI mass spectrometry have shown that is in equilibrium with a larger [3+3] metallo-macrocycle. The equilibrium between these two species can be modified by changing the temperature, concentration or solvent. Also, addition of certain anions (e.g. [H2PO4]-) to the mixture shifts the equilibrium favoring the formation of the [2+2] metallo-macrocycle over the [3+3] (initially present in a larger proportion).     

Anion receptors: a new class of amide/quaternized amine macrocycles and the chelate effect

A new class of tetraamide macrocyclic receptors for anions with two quaternized amine functionalities exhibited higher affinities for anions compared with the corresponding neutral amides. In two crystal structures of halide complexes of the prototypes with phenyl and pyridine spacers, the anions are held by hydrogen bonding with the amide hydrogens. The pyridine analogues display higher affinities in general than the phenyl systems, a phenomenon which is attributed to the anion version of the chelate effect.     

Chiral phosphite-oxazolines: a new class of ligands for asymmetric Heck reactions

[chemical reaction: see text]. A series of phosphite-oxazoline ligands, derived from readily available D-glucosamine, have been used for the first time in the palladium-catalyzed Heck reaction of several substrates with high regio- and enantioselectivities (ee's up to 99%) and improved activities in standard conditions.