Exploration of structure--activity relationships among foldamer ligands for a specific protein binding site via parallel and split-and-mix library synthesis

We describe the use of parallel and split-and-mix library synthesis strategies for exploration of structure-activity relationships among peptidic foldamer ligands for the BH3-recognition cleft of the anti-apoptotic protein Bcl-xL. This effort began with a chimeric (alpha/beta+alpha)-peptide oligomer (composed of an alpha/beta-peptide segment and an alpha-peptide segment) that we previously identified to bind tightly to the target cleft on Bcl-xL. The side chains that interact with Bcl-xL were varied in a 1000-member one-bead-one-compound library. Fluorescence polarization (FP) screening identified four new analogues with binding affinities similar to that of the lead compound but no analogues with enhanced affinity. These results suggested that significant improvements in affinity were unlikely in this series. We then used library synthesis to examine backbone variations in the C-terminal alpha-peptide segment of the lead compound. These studies provided an opportunity for direct comparison of parallel and split-and-mix synthesis formats for foldamer libraries with respect to synthetic variability and assay sensitivity. We found that compounds from both the parallel and one-bead-one-compound libraries could be reliably screened in a competition FP assay without purification of library members. Our findings should facilitate the use of combinatorial library synthesis for exploration of foldamers as inhibitors of protein-protein interactions.     

Synthesis and thermotropic properties of new polyacrylates containing alkanoyl-substituted azobenzene mesogens

The synthesis and characterization of a series of new polyacrylates 1, containing the azobenzene mesogen spaced from the backbone by a hexamethylene segment and substituted in the 4-position by an alkanoyl chain of variable length, together with those of the relevant precursors are reported. Optical and X-ray analyses provided evidence for the presence of a smectic A mesophase in a fairly broad range of temperature in both polymers and low molar mass compounds. In polyacrylates 1, the side-chain substituents were fully interdigitated in a smectic A₁ structure. The comparison of the transition parameters of polymers 1 with those of another series of polyacrylates 7 containing the azobenzene unit substituted in the 4-position by an alkyloxy chain of variable length revealed that the replacement of an oxygen atom by a carbonyl group strongly enhanced the smectogenic character of the azobenzene group.     

Synthesis of linear tripeptides for right-hand segments of complestatin

This paper concerns a synthetic study of the right-hand segment of complestatin, an inhibitor of gp120-CD4 receptor. The effective synthesis of four important precursors for the right-hand segment of complestatin is described. Two of them are the precursor tripeptides for macrolactamization to the right-hand segment of complestatin at the last step and the other two are the precursor tripeptides for ring-closing reaction using Suzuki and Stille coupling, respectively, to the right-hand segment of complestatin at the last step. These compounds and the synthetic procedure will serve for both the synthesis of the right-hand segment and total synthesis of complestatin in the near future. In addition, consideration of the smooth acidic isomerization of complestatin to chloropeptin was carried out by density functional theory (DFT) calculation.     

Preparation of planar chiral amino phenols based on the [2.2]paracyclophane backbone

The synthesis of various planar and central chiral secondary and tertiary amino phenols based on the [2.2]paracyclophane backbone is described. Planar chiral tertiary amino phenols are prepared by reductive amination of 5-formyl-4-hydroxy[2.2]paracyclophane (FHPC) with secondary amines. The reduction of imine and ketimine precursors, as well as the 1,2-addition to these compounds is also described.     

pH-independent triple-helix formation with 6-oxocytidine as cytidine analogue

The syntheses of six different phosphoramidite building blocks of 6-oxocytosine and 5-allyl-6-oxocytosine as analogues of N(3)-protonated cytosine are described. These compounds have been incorporated into oligonucleotides by standard solid-phase synthesis. Hybridization of 15-mer Hoogsteen strands with target 21-mer duplexes was investigated. Comparison of the triplex-forming abilities of the different building blocks revealed that: i) 5-allyl substitution has a negative influence on triplex stability, ii) a uniform backbone of the Hoogsteen strand stabilizes triplexes relative to mixed backbones; iii) RNA strands with 6-oxocytidine or 5-allyl-6-oxocytidine do not form a triple helix with the DNA target duplex, probably due to backbone torsional constraints; and (iv) a 15-mer DNA sequence with three isolated 2'-deoxy-6-oxocytidines has the highest T(m) of all cytidine analogues investigated in this study. CD experiments provided further evidence for the presence or absence of triplex structures. In the course of these temperature-dependent CD measurements we were able to detect duplex and triplex melting independent from each other at selected wavelengths. This methodology is especially interesting in cases where UV melting curves show only one transition owing to spectral overlap.     

Synthesis and properties of electrophosphorescent chelating polymers with iridium complexes in the conjugated backbone

The synthesis of electrophosphorescent chelating polymers by Suzuki polycondensation of A-A- and B-B-type monomers is described, in which the fluorene-alt-carbazole (PFCz) segment is used as polymer backbone. By using alkyl-substituted ligands of iridium complex monomers, chelating copolymers with higher contents of iridium complex can be synthesized. Chemical and photophysical characterization confirm that the Ir complex is incorporated into the polymer backbone as one of the monomer repeat units by means of two 5-bromotolylpyridine ligands. Chelating polymers with Ir complexes in the conjugated polymer backbone show highly efficient energy transfer of excitons from the PFCz host segment to the Ir complex by an intramolecular trapping mechanism. The external quantum and luminous efficiencies of a device made with PFCzMppyIrhm4 copolymer reach 4.1 % ph/el (photons/electron) and 5.4 cd A(-1), respectively, at a current density of 32.2 mA cm(-2), an emission peak of 577 nm, and a luminance of 1730 cd cm(-2). Most important, the devices made from the chelating copolymers show no notable efficiency decay with increasing current density due to reduced concentration quenching and triplet-triplet (T-T) annihilation. This indicates that incorporation of the phosphorescent complex into the rigid conjugated polymer main chain is a new way to simultaneously realize high efficiency, long-term stability, and simple processing of phosphorescent polymer light-emitting diodes.     

Anti-Melanogenic Properties of Velutin and Its Analogs

Velutin, one of the flavones contained in natural plants, has various beneficial activities, such as skin whitening, as well as anti-inflammatory, anti-allergic, antioxidant, and antimicrobial activities. However, the relationship between the structure of velutin and its anti-melanogenesis activity is not yet investigated. In this study, we obtained 12 velutin derivatives substituted at C5, C7, C3′, and C4′ of the flavone backbone with hydrogen, hydroxyl, and methoxy functionalities by chemical synthesis, to perform SAR analysis of velutin structural analogues. The SAR study revealed that the substitution of functional groups at C5, C7, C3′, and C4′ of the flavone backbone affects biological activities related to melanin synthesis. The coexistence of hydroxyl and methoxy at the C5 and C7 position is essential for inhibiting tyrosinase activity. However, 1,2-diol compounds substituted at C3′ and C4′ of flavone backbone induce apoptosis of melanoma cells. Further, substitution at C3′ and C4′ with methoxy or hydrogen is essential for inhibiting melanogenesis. Thus, this study would be helpful for the development of natural-derived functional materials to regulate melanin synthesis.     

Incorporation of a conjugated side‐chain in regioregular polythiophenes: Chiroptical properties and selective oxidation

The synthesis, aggregation, and optical properties of a chiral, regioregular polythiophene, substituted with a conjugated substituent, are described. The polymer was prepared using a Stille coupling reaction. The fact that the side‐chain contributes to the absorption (UV‐vis), emission (fluorescence), and redox behavior (cyclic voltammetry) of the material demonstrates that the substituent contributes to the electronic properties. It was shown that the conjugated side‐chain chirally stacks in conditions in which the polymer backbone aggregates, which demonstrates the ability of conjugated polymers to induce a (chiral) lamellar organization of conjugated moieties, present in their side‐chain. The aggregation of both the side‐chain and the backbone was monitored using UV‐vis and CD spectroscopy. Finally, it is shown that the conjugated side‐chain can selectively be oxidized, without oxidizing the polythiophene backbone. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1891–1900, 2009     

Transpositions spinales in vitro en milieu acide—VI : Synthese partielle et transposition d'un homologue octacyclique de steroide

The partial synthesis of an A-seco-nor and of a D-homo steroid carried out in connection with the synthesis of steroid-like octacyclic compounds is described. The backbone rearrangement of these octacyclic compound is controlled by the intracyclic strain resulting from the methyl hydrinadol or hydrindanone moiety; the double bond of these quasi-symmetric octacyclic structures is displaced only towards the pentacyclic cycle.     

Synthesis of thiophene/phenylene co‐oligomers. V. Functionalization at molecular terminals toward optoelectronic device applications

We report the synthesis of various thiophene/phenylene co‐oligomers with a total number of thiophene and benzene (phenylene) rings of 5 and 6 with various terminal groups. Those terminal groups have been chosen from among alkyl groups, methoxy groups, trifluoromethyl groups, and cyano groups. The molecular backbone of these compounds comprises phenyl‐ or biphenylyl‐capped thiophene (or oligothiophene) or an alternating co‐oligomer. The synthesis is based on either the Suzuki coupling reaction or the Negishi coupling reaction. These reaction schemes enabled us to obtain the target compounds in high quality. In particular, the latter coupling method turned out to produce the compounds at a high yield. The terminal groups are expected to produce various functionalities based upon their electron donating character (alkyl groups and methoxy groups) or electron withdrawing character (trifluoromethyl groups and cyano groups). Additionally some of these groups bring about enhanced solubility. This will lead to the production of a diversity of modified compounds of thiophene/phenylene co‐oligomers. To give an example that demonstrates usefulness of the target compounds, we present optoelectronic data that are associated with their device applications.     

Macromonomers as well-defined building blocks in macromolecular engineering

The present work compares the efficiency of different polymerization methods to design well-defined comb-shaped structures based on macro monomers. Anionic polymerization remains the method of choice and allows the control of polymerization degree of the main chain and the length of the grafts. The presence of an active chain end on the backbone enabled the synthesis of a new type of hyperbranched polymers by reaction with appropriate low molar multifunctional compounds. Free radical polymerization is less efficient for the controlled homopolymerization of macromonomers but less sensitive to the presence of impurities. It requires in most cases long fractionation procedures to access well defined comb-shaped fractions characterized by high molar masses. The controlled free radical polymerization constitutes an interesting alternative. The homopolymerization of macromonomers with late transition metal catalysts was also examined and comb-shaped polymers characterized by a syndiotactic backbone and atactic grafts could be obtained.     

β‐Cyclodextrin as an Efficient and Recyclable Supramolecular Catalyst for the Synthesis of Heterocyclic Compounds

β‐Cyclodextrin (β‐CD ), a naturally occurring supramolecular structure, is an effective catalyst for the synthesis of heterocyclic compounds. Its ubiquity, high performance, nontoxicity, ease of separation, and reusability have drawn the attention of green chemists. Here we present the synthetic procedures of heterocyclic compounds catalyzed by β‐CD in water and compare them with those using organic solvents. In many cases, using water as the solvent shows better efficiency than conventional organic solvents with regard to catalytic activity and simplicity of recycling procedures. This review highlights the applications of β‐CD in catalysis covering the years 2004–2016.     

On resin synthesis of sulfated oligosaccharides

Sulfated glycans are involved in many biological processes, making well-defined sulfated oligosaccharides highly sought molecular probes. These compounds are a considerable synthetic challenge, with each oligosaccharide target requiring specific synthetic protocols and extensive purifications steps. Here, we describe a general on resin approach that simplifies the synthesis of sulfated glycans. The oligosaccharide backbone, obtained by Automated Glycan Assembly (AGA), is subjected to regioselective sulfation and hydrolysis of protecting groups. The protocol is compatible with several monosaccharides and allows for multi-sulfation of linear and branched glycans. Seven diverse, biologically relevant sulfated glycans were prepared in good to excellent overall yield.

Well-defined sulfated oligosaccharides are important synthetic targets. We present an on resin approach for the synthesis of sulfated glycans with a broad reaction scope that overcomes previous limitations associated with on resin synthesis.     

An efficient, scalable synthesis of the molecular transporter octaarginine via a segment doubling strategy

[reaction: see text]. Short oligomers of arginine function as remarkably efficient molecular transporters of drugs and probe molecules into cells and tissue. Currently, these compounds are prepared on resin through a unidirectional solid-phase synthesis. To extend the utility of these compounds for therapeutic and research applications, a scalable solution-phase synthesis of Arg8 (1) has been developed on the basis of a segment doubling strategy that proceeds in 13 steps and 28% overall yield from 4, including a novel one-step perdeprotection-perguanidinylation reaction.     

Design, synthesis and biological characterization of novel inhibitors of CD38

Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca(2+) messenger molecule, cyclic ADP-ribose, from NAD(+). It is well established that this novel Ca(2+) signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD(+) complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound 1-14). A number of these compounds exhibited moderate inhibition of the NAD(+) utilizing activity of CD38, with Compound 4 showing the highest potency. The crystal structure of CD38/Compound 4 complex and computer simulation of Compound 7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds 4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development.     

N,N'-linked oligoureas as foldamers: chain length requirements for helix formation in protic solvent investigated by circular dichroism, NMR spectroscopy, and molecular dynamics

N,N'-linked oligoureas with proteinogenic side chains are peptide backbone mimetics belonging to the gamma-peptide lineage. In pyridine, heptamer 4 adopts a stable helical fold reminiscent of the 2.6(14) helical structure proposed for gamma-peptide foldamers. In the present study, we have used a combination of CD and NMR spectroscopies to correlate far-UV chiroptical properties and conformational preferences of oligoureas as a function of chain length from tetramer to nonamer. Both the intensity of the CD spectra and NMR chemical shift differences between alphaCH2 diastereotopic protons experienced a marked increase for oligomers between four and seven residues. No major change in CD spectra occurred between seven and nine residues, thus suggesting that seven residues could be the minimum length required for stabilizing a dominant conformation. Unexpectedly, in-depth NMR conformational investigation of heptamer 4 in CD3OH revealed that the 2.5 helix probably coexists with partially (un)folded conformations and that Z-E urea isomerization occurs, to some degree, along the backbone. Removing unfavorable electrostatic interactions at the amino terminal end of 4 and adding one H-bond acceptor by acylation with alkyl isocyanate (4 --> 7) was found to reinforce the 2.5 helical population. The stability of the 2.5 helical fold in MeOH is further discussed in light of unrestrained molecular dynamics (MD) simulation. Taken together, these new data provide additional insight into the folding propensity of oligoureas in protic solvent and should be of practical value for the design of helical bioactive oligoureas.     

Porphyrin binding to DNA investigated by cyclodextrin supramolecular system

The interactive mode of meso-tetrakis- (4- N-trimethylaminobenzyl) porphyrin (TAPP) with DNA has been investigated by the cyclodextrin (CD)-porphyrin supramolecular system. The binding of TAPP with DNA is inhibited by the anion CD derivative, sulfurbutyl-beta-cyclodextrin (SB-beta-CD); however, the neutral CD cannot influence the binding. As for the inclusion procedure of the CDs-TAPP system, the (1)H-NMR data suggests that the hydrophobic segment of TAPP enters into the cavity of CD, which means that the hydrophobic part of TAPP is not the binding site in the TAPP-DNA interaction. Therefore, the binding model cannot be the intercalation and is not related to the grooves of DNA. In addition, experimental data show that the charge attraction, which exists in the inclusion procedure of SB-beta-CD and TAPP hampers the binding of TAPP with DNA. The negative groups of SB-beta-CD compete with the phosphate groups of the DNA backbone, and have an attraction to the positive groups of TAPP. This competitive attraction supports the theory that the binding mode of TAPP with DNA is "electrostatic binding". Furthermore, there are two binding sites between one TAPP molecule and one DNA standard. We produce a possible binding structure (a suprahelical structure of DNA) for this TAPP-DNA complex. This structure is in good agreement with the literature.     

Cationic polymerization of α-methylstyrene from polydienes. I. Synthesis and characterization of poly(butadiene-g-α-methylstyrene) copolymers

The preparation of poly(butadiene-g-α-methylstyrene) copolymers was investigated with three different alkylaluminum coinitiators. The alkylaluminum compounds in conjunction with polybutadiene which contained a low concentration of labile chlorine atoms initiated the polymerization of α-methylstyrene to produce graft copolymers. Trimethylaluminum gave higher grafting efficiencies than diethylaluminum chloride at comparable monomer conversions. Triethylaluminum produced only very low monomer conversions (<5%), even at long reaction times, and for this reason was not studied extensively. The number of grafts per polybutadiene backbone was determined for a number of copolymers and found to increase slightly as the allylic chlorine concentration in the polybutadiene backbone was increased. In all cases, however, only a low percentage of the available labile chlorine sites along the polybutadiene backbone resulted in grafted α-methylstyrene side chains. The addition of small quantities of water to the polymerization solvent greatly enhanced the grafting rate and ultimate monomer conversion during the synthesis of these poly(butadiene-g-α-methylstyrene) copolymers. The mechanistic role of water during these grafting reactions is unknown at the present time.     

The Formazanate Ligand as an Electron Reservoir: Bis(Formazanate) Zinc Complexes Isolated in Three Redox States

The synthesis of bis(formazanate) zinc complexes is described. These complexes have well‐behaved redox‐chemistry, with the ligands functioning as a reversible electron reservoir. This allows the synthesis of bis(formazanate) zinc compounds in three redox states in which the formazanate ligands are reduced to “metallaverdazyl” radicals. The stability of these ligand‐based radicals is a result of the delocalization of the unpaired electron over four nitrogen atoms in the ligand backbone. The neutral, anionic, and dianionic compounds (L₂Zn^0/?1/?2) were fully characterized by single‐crystal X‐ray crystallography, spectroscopic methods, and DFT calculations. In these complexes, the structural features of the formazanate ligands are very similar to well‐known β‐diketiminates, but the nitrogen‐rich (NNCNN) backbone of formazanates opens the door to redox‐chemistry that is otherwise not easily accessible.     

Organic Chemistry on Solid Supports

Until recently, repetitive solid-phase synthesis procedures were used predominantly for the preparation of oligomers such as peptides, oligosaccharides, peptoids, oligocarbamates, peptide vinylogues, oligomers of pyrrolin-4-one, peptide phosphates, and peptide nucleic acids. However, the oligomers thus produced have a limited range of possible backbone structures due to the restricted number of building blocks and synthetic techniques available. Biologically active compounds of this type are generally not suitable as therapeutic agents but can serve as lead structures for optimization. “Combinatorial organic synthesis” has been developed with the aim of obtaining low molecular weight compounds by pathways other than those of oligomer synthesis. This concept was first described in 1971 by Ugi.^[56f,g,59c] Combinatorial synthesis offers new strategies for preparing diverse molecules, which can then be screened to provide lead structures. Combinatorial chemistry is compatible with both solution-phase and solid-phase synthesis. Moreover, this approach is conducive to automation, as proven by recent successes in the synthesis of peptide libraries. These developments have led to a renaissance in solid-phase organic synthesis (SPOS), which has been in use since the 1970s. Fully automated combinatorial chemistry relies not only on the testing and optimization of known chemical reactions on solid supports, but also on the development of highly efficient techniques for simultaneous multiple syntheses. Almost all of the standard reactions in organic chemistry can be carried out using suitable supports, anchors, and protecting groups with all the advantages of solid-phase synthesis, which until now have been exploited only sporadically by synthetic organic chemists. Among the reported organic reactions developed on solid supports are Diels–Alder reactions, 1,3-dipolar cycloadditions, Wittig and Wittig–Horner reactions, Michael additions, oxidations, reductions, and Pd-catalyzed C? C bond formation. In this article we present a comprehensive review of the previously published solid-phase syntheses of nonpeptidic organic compounds.