Neomycin-capped aromatic platforms: quadruplex DNA recognition and telomerase inhibition

A series of aminoglycoside-capped macrocyclic structures has been prepared using intramolecular bis-tethering of neomycin on three aromatic platforms (phenanthroline, acridine, quinacridine). Based on NMR and calculations studies, it was found that the cyclic compounds adopt a highly flexible structure without conformational restriction of the aminoglycoside moiety. FRET-melting stabilization measurements showed that the series displays moderate to high affinity for the G4-conformation of human telomeric repeats, this effect being correlated with the size of the aromatic moiety. In addition, a FRET competition assay evidenced the poor binding ability of all macrocycles for duplex DNA and a clear binding preference for loop-containing intramolecular G4 structures compared to tetramolecular parallel G4 DNA. Finally, TRAP experiments demonstrated that the best G4-binder (quinacridine ) is also a potent and selective telomerase inhibitor with an IC(50) in the submicromolar range (200 nM).     

Bis-diazeniumdiolates of dialkyldiamines: enhanced nitric oxide loading of parent diamines

[reaction: see text] The synthesis and characterization of a series of symmetric bis-dialkyldiamine-based diazeniumdiolates, RN[N(O)NO(-)Na(+)](CH(2))(x)()N[N(O)NO(-)Na(+)]R', are reported. Preparation of corresponding intramolecular diazeniumdiolates of the form RN[N(O)NO](-)(CH(2))(x)()NH(2)(+)R' with alkyl groups > (CH(2))(4)CH(3) have been shown previously to lack stability. In contrast, sodium-stabilized bis-diazeniumdiolates of such lipophilic species can be readily formed when these same diamines are reacted with NO in basic media. The resulting compounds release 4 mol of NO per mole of original diamine. This approach enables the synthesis of more lipophilic NO donors than previously possible.     

A convenient and efficient route for the synthesis of amidecrownophanes via 1:1 macrocyclization of di(acid chloride) with diamine derivatives

Four amidecrownophanes 3a-d, including three new compounds 3a, 3c and 3d, were readily prepared through amidation of dicarbonyl dichloride with diamine derivatives without using high-dilution or template conditions and then the tandem Claisen rearrangement. At the macrocyclization step the intramolecular hydrogen bonding of the intermediate might play an important role to give high yields of 1:1 macrocycles.     

Effect of peracylation of beta-cyclodextrin on the molecular structure and on the formation of inclusion complexes: an X-ray study.

The molecular structures of peracylated beta-cyclodextrins (CDs)--heptakis(2,3,6-tri-O-acetyl)-beta-CD (TA), heptakis(2,3,6-tri-O-propanoyl)-beta-CD (TP), and heptakis(2,3,6-tri-O-butanoyl)-beta-CD (TB)--have been determined by single crystal X-ray structure analysis. Due to the lack of O2...O3' hydrogen bonds between adjacent glucose units of the peracylated CDs, the macrocycles are elliptically distorted into nonplanar boat-shaped structures. The glucose units are tilted with respect to the O4 plane to relieve steric hindrance between adjacent acyl chains. In TB, all glucose units adopt the common (4)C(1)-chair conformation and one butanoyl chain intramolecularly penetrates the cavity, whereas, in TA and TP, one glucose unit each occurs in (O)S(2)-skew-boat conformation and one acyl chain closes the O6 side like a lid. In each of the three homologous molecules the intramolecular self-inclusion and lidlike orientation of acyl chains forces the associated O5-C5-C6-O6 torsion angle into a trans-conformation never observed before for unsubstituted CD; the inclusion behavior of TA, TP, and TB in solution has been studied by circular dichroism spectroscopy with the drug molsidomine and several organic compounds. No inclusion complexes are formed, which is attributed to the intramolecular closure of the molecular cavity by one of the acyl chains.     

Systematic evaluation of the conformational properties of aliphatic omega-methoxy methyl esters

[structure: see text] A systematic conformational study of omega-methoxy methyl esters, CH(3)O-(CH2)n-COO-CH3 with n = 3 and 4, has been performed using quantum mechanical calculations at the MP2 level. Calculations have been carried out in both gas phase and chloroform solution, a polarizable continuum solvation model being used to represent the latter. Results have been compared with those recently obtained for the analogues omega-hydroxy acids, HO-(CH2)n-COOH with n = 3 and 4. The compounds with n = 3 clearly favor coiled conformations, the population expected for extended and semiextended conformations being very low. However, for compounds with n = 4 the minimum energy extended and semiextended structures become considerably more stable. The overall results indicate that the conformational preferences of the central aliphatic segment of omega-methoxy methyl esters and omega-hydroxy acids are not influenced by the formation of intramolecular O-H...O hydrogen bonds.     

Polymerization,Stimuli-induced Depolymerization,and Precipitation-driven Macrocyclization in a Nitroaldol Reaction System**

Dynamic covalent polymers of different topology have been synthesized from an aromatic dialdehyde and α,ω-dinitroalkanes via the nitroaldol reaction. All dinitroalkanes yielded dynamers with the dialdehyde, where the length of the dinitroalkane chain played a vital role in determining the structure of the final products. For longer dinitroalkanes, linear dynamers were produced, where the degree of polymerization reached a plateau at higher feed concentrations. In the reactions involving 1,4-dinitrobutane and 1,5-dinitropentane, specific macrocycles were formed through depolymerization of the linear chains, further driven by precipitation. At lower temperature, the same systemic self-sorting effect was also observed for the 1,6-dinitrohexane-based dynamers. Moreover, the dynamers showed a clear adaptive behavior, displaying depolymerization and rearrangement of the dynamer chains in response to alternative building blocks as external stimuli.     

Intercalation of diamines into zirconium phosphate-phosphite: A layered compound with asymmetric layers

Many primary diamines H₂N(CH₂)_nNH₂ (all the members withn ranging from 0 to 12 with the exception ofn =I 1) have been intercalated within the phosphate regions of layered zirconium phosphate-phosphite. As a general rule, intercalation occurs in two steps that are not well differentiated. The first one leads to intercalation compounds in which the diamines are arranged with their alkyl chain oriented parallel to the layers; the second one to the fully intercalated compounds. These latter compounds have composition Zr(HPO₄)_0.7(HPO₃)1,3-yNH₂(CHn2)·NH₂, withy ranging from 0.36 to 0.49 depending on the nature of the diamine. Not all the diamine molecules are thus diprotonated and they show a tendency to reach a y value of 0.5, corresponding to the total occupancy of the crystal sites available for intercalation. Diamines are arranged as a monolayer of extended molecules and an evident even-odd alternation of the interplanar spacing has been observed.A comparison with the intercalation of-zirconium phosphate for the same diamines is also made.     

Can a Proton be Encapsulated in Tetraamido/Diamino Quaternized Macrocycles in Aqueous Solution and Electric Field?

The proton‐binding behavior of solvated tetraamido/diamino quaternized macrocyclic compounds with rigid phenyl and flexible phenyl bridges in the absence or presence of an external electric field is investigated by molecular dynamics simulation. The proton can be held through H‐bonding interactions with the two carbonyl oxygen atoms in macrocycles containing rigid (phenyl) and flexible (propyl) bridges. The solute–solvent H‐bonding interactions cause the macrocyclic backbones to twist to different extents, depending on the different bridges. The macrocycle with the rigid phenyl linkages folds into a cuplike shape due to π–π interaction, while the propyl analogue still maintains the ellipsoidal ringlike shape with just a slight distortion. The potential energy required for proton transfer is larger in the phenyl‐containing macrocycle than in the compound with propyl units. When an external electric field with a strength of 2.5 V nm^?1 is exerted along the carbonyl oxygen atoms, a difference in proton encircling is exhibited for macrocycles with rigid and flexible bridges. In contrast to encapsulation of a proton in the propyl analogue, the intermolecular solute–solvent H‐bonding and intramolecular π–π stacking between the two rigid phenyl spacers leads to loss of the proton from the highly distorted cuplike macrocycle with phenyl bridges. The competition between intra‐ and intermolecular interactions governs the behavior of proton encircling in macrocycles.     

Conformational Bias in Macrocyclic Ethers and Observation of High Solvolytic Reactivity at a Masked Furfuryl (=2‐Furylmethyl) C‐Atom

New polyhalogenated, twelve‐membered, O‐bridged cyclic C₁₅‐ethers, having in common oxygenation at C(6) and a bromoallene side chain at C(4) (where C(1) is the bromoallene‐chain terminus), were isolated from the red seaweed Laurencia obtusa from the Turkish Mediterranean Sea, i.e., the 9,12‐O‐bridged obtusallene VII ( 5 ), the 6,9 : 9,12‐bis‐O‐bridged obtusallene V ( 3 ) and obtusallene VI ( 4 ), as well as the 6,9‐O‐bridged obtusallene VIII ( 8 ) and obtusallene IX ( 9 ). The behavior of portions of the macrocycle involved in fast motions and their equilibrium position depend on the particular compound, revealing a subtle conformational behavior of these macrocycles, while 8 and 9 show an unprecedented solvolytic reactivity at the masked furfuryl (=2‐furylmethyl) C‐atom.     

Clays as a host matrix in the synthesis of organic macrocycles

A new approach for the synthesis of amide macrocycles, based on the use of organo-clay derivatives as controlling template, is proposed as an alternative to the rotaxane method. Dications of p-xylylene diamine inserted in the clay interlayer space act as molding pillars around which neutral diamine molecules are erected via hydrogen bonding and pi-pi interactions to form supramolecular arrays. Condensation of diamines in the supramolecular arrays with diacetyl dichlorides yields various tetramide macrocycles in good yields. Shape, aromaticity and dimensions of the reactants are factors affecting the condensation reaction.     

Synthesis of novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles

A total of twelve novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles have been synthesised in quantitative yields by reacting chiral (4R,5R)- and (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazides with aromatic bis-aldehydes in a [2 + 2]-cyclocondensation reaction. The compounds show a dynamic behaviour in solution, which has been rationalized in terms of an unprecedented conformational interconversion between two conformers one stabilised by intramolecular hydrogen bonding and π-π stacking interactions.     

Poly-p-phenylene phosphine/polyaniline alternating copolymers: electronic delocalization through phosphorus

Phosphorus-containing poly(N-arylaniline)s and related polymer model compounds have been prepared. The spectroscopic and electronic properties of the materials were investigated via UV-vis-NIR spectroscopy and cyclic voltammetry. PPPP-PANI copolymers containing p-phenylene diamine units in the polymer backbone have electronic and spectroscopic properties characteristic of aromatic substituted p-phenylene diamines. Copolymers containing -(-C(6)H(4)-P-C(6)H(4)-P-C(6)H(4)-)- linkages between nitrogen centers show evidence for weak electronic delocalization along the polymer chain. The electrochemical and spectroscopic properties support strong electronic delocalization in copolymers containing -(-P-C(6)H(4)-N-C(6)H(4)-)- repeat units. The presence of a single diphenylphosphine bridge between nitrogen centers provides an efficient mode of electronic delocalization between nitrogen centers. PPPP oxide-PANI copolymers and related polymer model compounds were also prepared and investigated. The resemblance of PPPP oxide-PANI copolymers to isolated p-phenylene diamines or triarylamines suggests electronic isolation of the amine fragments in the polymer. The conversion of phosphorus(III) phosphines to phosphorus(V) phosphine oxides inhibits electronic delocalization through phosphorus, further supporting delocalization of the lone pair of electrons on phosphorus in PPPP-PANI copolymers. PPPP-PANI copolymers are a new type of pi-conjugated polymer with low oxidation potentials and electronic delocalization through phosphorus along the polymer chain.     

带内取向柔性多醚链苯炔大环合成

采用分子间Glaser半环闭环法合成了带内取向柔性多醚链的苯炔大环.用1H NMR,13C NMR,HRMS,UV及PL(photduminescence)确证了目标大环结构,凝胶色谱测定了目标大环纯度.经偏光显微镜(POM)和差热分析仪(DSC)测试表明大环没有呈现预期的液晶性质,可能是由于环内柔性链过于拥挤,不能形成与环平面共面结构,以至于难于进行有序堆积的缘故.     

Synthesis of orthogonally protected cyclic homooligomers from sugar amino acids

Two new families of orthogonally protected cyclic homooligomers with two to four sugar units were synthesized from pyranoid sugar amino acids. Cyclic oligomers composed of amide-linked sugar amino acids (1-3) were prepared by cyclization of linear oligomers of the novel orthogonally protected pyranoid sugar amino acid 12 using a solution-phase coupling method. These orthogonally protected cyclic molecules can be selectively or fully deprotected, affording the macrocycles ready to further functionalization. The straightforward reduction of the amide bonds in the cyclic oligomers 1-3 gave the corresponding amine-linked macrocycles 4-6. This kind of amine-linked carbohydrate-based cyclic oligomer has never been reported before. These flexible molecular receptors could be studied as molecular hosts for molecular, cationic, and anionic recognition. Conformational analysis by molecular modeling (AM1) showed that all of the deprotected cyclic trimers and tetramers preferred a (4)C(1) chair conformation with oxygen atoms of the sugar ring located on the interior of the cavity and the secondary hydroxyl groups outward. In the amide-linked macrocycles, all of the amide bonds are in s-trans conformation. The estimated size of the internal cavity is about 4.5 A for the cyclic trimer and 6.9 A for the cyclic tetramer. The amine-linked macrocycles displayed similar conformational behavior with a slight decrease in internal cavity.     

Conformational control of flexible molecules: design and synthesis of novel chiral 1,5-diaza-cis-decalins

Control of the conformational equilibria of 1,5-diaza-cis-decalins, a new class of chiral diamine ligands, has been investigated. Chiral 2,6- and 3,7-substituted derivatives of 1,5-diaza-cis-decalins were designed to stabilize the conformational form needed to chelate a lithium. These derivatives were synthesized in optically pure form starting from 1,5-diaza-cis-decalin. Due to the rigid and conformationally well-defined nature of these compounds, the potential of these compounds as chiral diamine ligands was investigated. Asymmetric lithiation-substitution reactions of N-Boc-pyrrolidine and N,N-diisopropyl-o-ethylbenzamide were performed using these ligands and up to 60% ee was obtained. For the latter substrate, results spanning a range from 32% ee (R) to 60% ee (S) were obtained (Delta ee = 92%) with 1,5-diaza-cis-decalin ligands differing only in the location of two methyl substituents. Unlike many other diamines that have been employed in asymmetric lithiation-substitution reactions, the limited conformational flexibility of the 1,5-diaza-cis-decalins is analogous to (-)-sparteine such that these results may permit the construction of structure-activity relationships.     

Synthesis and Characterization of Complex Mixtures Consisting of Cyclic and Linear Polyamides from Ethyl Bis-Ketal Galactarates

Bis-ketal-protected diethyl galactarate was condensed with different diamines to prepare sugar-based polyamides. Ketal-protected polyamides, which are soluble in organic solvents, were deprotected with 90% trifluoroacetic acid to yield water insoluble materials. FTIR, NMR, GPC, MALDI-TOF, ESI and TGA techniques were used to characterize the structure and the properties of these biodegradable materials.

D-galactaric acid-based polyamides are complex mixtures of cyclic and linear structures. High molecular weight linear polymer formation was limited by competitive cyclization reactions. The percentage of cyclization was highly dependent on the nature of the diamine used. Polycondensation with linear aliphatic diamines favored the formation of macrocycles, identified by MALDI-TOF and ESI.     

Novel aromatic polyamides bearing pendent diphenylamino or carbazolyl groups

Two new diamines, 2,4‐diaminotriphenylamine ( 3 ) and N‐(2,4‐diaminophenyl)carbazole ( 4 ), were synthesized via the cesium fluoride‐mediated aromatic substitution reactions of 1‐fluoro‐2,4‐dinitrobenzene with diphenylamine and carbazole, followed by palladium‐catalyzed hydrazine reduction. Amorphous and soluble aramids having pendent diphenylamino and carbazolyl groups were prepared by the phosphorylation polycondensation of aromatic dicarboxylic acids with diamines 3 and 4 , respectively. The aramids derived from diamine 3 had sufficiently high molecular weights to permit the casting of flexible and tough films. They exhibited excellent mechanical properties and moderately high softening temperatures in the 221–298 °C range. However, the reactions of diamine 4 with aromatic diacids gave relatively lower molecular weights products that could not afford flexible films. For a comparative purpose, the parent aramids derived from m‐phenylenediamine and aromatic diacids were also prepared and characterized. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 3302–3313, 2004     

苯丙氨酸桥联手性锌双卟啉受体对胺的分子识别

金属卟啉的分子识别研究是当今卟啉仿生化学的重要课题.手性金属卟啉作为光学活性分子的对映选择识别受体和手性核磁共振试剂^[1]尤为引人注目.     

Predicting bioactive conformations and binding modes of macrocycles

Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein–protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.     

Kinetics and thermodynamics of amine and diamine signaling by a trifluoroacetyl azobenzene reporter group

[reaction: see text] (Trifluoroacetyl)azobenzene dyes were previously employed as amine reporter groups (chemosensors) in a dendrimer-based monomolecular imprinting system. Kinetic and binding studies with a range of amines and diamines show that the highly selective signaling observed for alkane diamines by these imprinted dendrimers arises from a kinetic effect due to intramolecular general base-catalyzed carbinolamine formation with the dye itself. The relationship between diamine structure and carbinolamine stability and rate of formation is described.