Allostery-Mimicking Self-assembly of Helical Poly(phenylacetylene) Block Copolymers and the Chirality Transfer.

Allostery can regulate protein self-assembly which further affects biological activities, and achieving precise control over the chiral suprastructures during self-assembly remains challenging. Herein, to mimic the allosterical nature of proteins, the poly(phenylacetylene) block copolymers PPA-b-PsmNap with the dynamic helical backbone were synthesized to investigate their conformational-transition-induced self-assembly. As the helical conformation of the block PsmNap spontaneously transforms from cis-transiod to cis-cisoid, the decreasing solubility of PsmNap blocks in THF induced self-assembly of PPA-b-PsmNap. The self-assembly structures of copolymers can sequentially evolve from vesicles to nanobelts to helical strands during the process of conformation transformation. The screw sense of final helical strands was strictly correlated to the helicity of the block PsmNap. This is helpful to understand the mechanism of allostery-modulated self-assembly.

An atom efficient synthesis of tamoxifen.

The direct carbolithiation of diphenylacetylenes and their cross-coupling procedure taking advantage of the intermediate alkenyllithium reagents are presented. By employing our recently discovered highly active palladium nanoparticle based catalyst, we were able to couple an alkenyllithium reagent with a high (Z/E) selectivity (10 : 1) and good yield to give the breast cancer drug tamoxifen in just 2 steps from commercially available starting materials and with excellent atom economy and reaction mass efficiency.

Synthesis and Magnetic Properties of Stable Radical Derivatives Carrying a Phenylacetylene Unit.

A nitronyl nitroxide derivative, 2-phenylethynyl-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-oxyl-3-oxide (1), and two verdazyl derivatives carrying a phenylacetylene unit, 1,5-diphenyl-3-phenylethynyl-6-oxo-1,2,4,5-tetrazin-2-yl (2) and 1,5-diisopropyl-3-phenylethynyl-6-oxo-1,2,4,5-tetrazin-2-yl (3), were synthesized and their packing structures were studied by X-ray crystallographic analysis and magnetically characterized in the solid state. While 1 and 3 had an isolated doublet spin state, 2 formed an antiferromagnetically coupled pair (2J/kB = -118 K). Density functional theory (DFT) calculations reveal that the spin density polarized in the phenyl group decreases as the dihedral angle between the phenyl ring and radical plane increases.

Unprecedented Double aza-Michael Addition within a Sapphyrin Core.

A novel sapphyrin derivative was obtained from the reaction between a free-base sapphyrin and dimethyl acetylenedicarboxylate (DMAD). The formation of the new compound involved a double aza-Michael addition of two pyrrolic NH groups to a DMAD molecule, with the formation of a disubstituted ethano bridge. The NMR spectral data reveal a product with an unsymmetrical structure; DFT calculations provided support for a structure in which the ethano bridge links two adjacent pyrrole units. The present study provides a seemingly unprecedented example of an N,N'-dinucleophile reacting with DMAD to form a heterocyclic compound in which the two N-atoms are linked to the two sp(3) carbon atoms derived from a substituted acetylene.

Ultrasonic Synthesis, Molecular Structure and Mechanistic Study of 1,3-Dipolar Cycloaddition Reaction of 1-Alkynylpyridinium-3-olate and Acetylene Derivatives.

Regioselectively, ethyl propiolate reacted with 1-(propergyl)-pyridinium-3-olate to give two regioisomers; ethyl 4-oxo-8-(prop-2-ynyl)-8-aza-bicyclo(3.2.1)octa-2,6-diene-6-carboxylate 4, ethyl 2-oxo-8-(prop-2-ynyl)-8-aza-bicyclo(3.2.1)octa-3,6-diene-6-carboxylate 5 as well as ethyl 2,6-dihydro-6-(prop-2-ynyl)furo(2,3-c)pyridine-3-carboxylate 6. The obtained compounds were identified by their spectral (IR, mass and NMR) data. Moreover, DFT quantum chemical calculations were used to study the mechanism of the cycloaddition reaction. The regioselectivity was explained using transition state calculations, where the calculations agreed with the formation of products 4 and 5 in almost the same ratio. The reaction was also extended for diphenylaceylene as dipolarophile to give only two products instead of three.

Temperature-Triggered Switchable Helix-Helix Inversion of Poly(phenylacetylene) Bearing l-Valine Ethyl Ester Pendants and Its Chiral Recognition Ability.

A phenylacetylene containing the l-valine ethyl ester pendant (PAA-Val) was synthesized and polymerized by an organorhodium catalyst (Rh(nbd)BPh4) to produce the corresponding one-handed helical cis-poly(phenylacetylene) (PPAA-Val). PPAA-Val showed a unique temperature-triggered switchable helix-sense in chloroform, while it was not observed in highly polar solvents, such as N,N'-dimethylformamide (DMF). By heating the solution of PPAA-Val in chloroform, the sign of the CD absorption became reversed, but recovered after cooling the solution to room temperature. Even after six cycles of the heating-cooling treatment, the helix sense of the PPAA-Val's backbone was still switchable without loss of the CD intensity. The PPAA-Val was then coated on silica gel particles to produce novel chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC). These novel PPAA-Val based CSPs showed a high chiral recognition ability for racemic mandelonitrile (α = 2.18) and racemic trans-N,N'-diphenylcyclohexane-1,2-dicarboxamide (α = 2.60). Additionally, the one-handed helical cis-polyene backbone of PPAA-Val was irreversibly destroyed to afford PPAA-Val-H by heating in dimethyl sulfoxide (DMSO) accompanied by the complete disappearance of the Cotton effect. Although PPAA-Val-H had the same l-valine ethyl ester pendants as its cis-isomer PPAA-Val, it showed no chiral recognition. It was concluded that the one-handed helical cis-polyene backbone of PPAA-Val plays an important role in the chiral recognition ability.

Identification of dialkyl diacetylene diols with potent cancer chemopreventive activity.

An increasing importance of chemoprevention for controlling cancer risks prompted the discovery of new active cancer chemopreventive agents. In this study, we designed and synthesized substituted hexa-2,4-diyne-1,6-diols, more structurally simplified, tunable, and easily preparable than natural gymnasterkoreaynes, and evaluated their cancer chemopreventive activities by measuring concentration of doubling quinone reductase activity (CD), cell viability, and chemopreventive index (CI). Most of the diols exhibited good CD activity and low cytotoxicity. In particular, tetradeca-5,7-diyne-4,9-diol and 2-methyltetradeca-5,7-diyne-4,9-diol showed the best cancer chemopreventive activity, approximately equipotent to that of sulforaphane. And, by synthesizing optically active stereoisomers of selected active compounds, the effect of stereochemistry was also studied. Eventually, we produced a chemopreventive compound for in vivo study.

Dithiafulvenyl-substituted phenylacetylene derivatives: synthesis and structure-property-reactivity relationships.

A series of regioisomers for dithiafulvenyl-substituted phenylacetylene derivatives was synthesized and characterized to show structure-dependent electronic properties and different reactivities in their oxidized states.

Radiosynthesis and 'click' conjugation of ethynyl-4-[(18)F]fluorobenzene--an improved [(18)F]synthon for indirect radiolabeling.

Reproducible methods for [(18)F]radiolabeling of biological vectors are essential for the development of new [(18)F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi-step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [(18)F]radiolabeling of such molecules, our group has synthesized ethynyl-4-[(18)F]fluorobenzene ([(18)F]2, [(18)F]EYFB) in a single step (14 ± 2% non-decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne-functionalized synthon [(18)F]2 was then conjugated to two azido-functionalized vector molecules via CuAAC reactions. The first 'proof of principle' conjugation of [(18)F]2 to 1-azido-1-deoxy-ß-D-glucopyranoside (3) gave the desired radiolabeled product [(18)F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [(18)F]2 to matrix-metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [(18)F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [(18)F]4 and [(18)F]6 including [(18)F]F(-) drying, two-step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [(18)F]2 and the conjugated products, [(18)F]4 and [(18)F]6, were all greater than 98%. The specific activities of [(18)F]2 and [(18)F]6 were low, 5.97 and 0.17 MBq nmol(-1), respectively.

Redox-dependent conformational switching of diphenylacetylenes.

Herein we describe the design and synthesis of a redox-dependent single-molecule switch. Appending a ferrocene unit to a diphenylacetylene scaffold gives a redox-sensitive handle, which undergoes reversible one-electron oxidation, as demonstrated by cyclic voltammetry analysis. (1)H-NMR spectroscopy of the partially oxidized switch and control compounds suggests that oxidation to the ferrocenium cation induces a change in hydrogen bonding interactions that results in a conformational switch.

Topochemical polymerization of phenylacetylene macrocycles: a new strategy for the preparation of organic nanorods.

Soluble organic nanorods were prepared from phenylacetylene macrocycles using the topochemical polymerization of butadiyne moieties placed both inside and outside the macrocycles' skeletons. Macrocycles containing amide groups were self-assembled in a columnar fashion through the formation of an organogel in ethyl acetate. Upon irradiation with UV light, the Raman signals associated with butadiyne units completely vanished, indicating the creation of covalently linked nanorods.

Exploring the potential of diarylacetylenediols as hydrogen bonding catalysts.

In the course of a search for new classes of hydrogen bonding catalysts, we have examined diarylacetylenediols as potential catalysts for the Diels-Alder reaction. General and efficient methods have been developed for the preparation of these diols. Their structures were systematically modified, and increased activity was observed for those possessing an electron-withdrawing group on the aryl groups. The electron-deficient diarylacetylenediol catalysts, while more active, undergo spontaneous cyclization to the corresponding benzo[b]furans. A mechanism is postulated to explain this facile transformation. Computational studies performed on 2-ethynylphenol help to explain the effect of the alkyne on the conformation and hydrogen bond donating ability of the adjacent OH group. Finally, the crystal structure of one of the diols is reported, and it displays an intricate network of intermolecular hydrogen bonds.

Single molecular conductance of tolanes: experimental and theoretical study on the junction evolution dependent on the anchoring group.

Employing a scanning tunneling microscopy based beak junction technique and mechanically controlled break junction experiments, we investigated tolane (diphenylacetylene)-type single molecular junctions having four different anchoring groups (SH, pyridyl (PY), NH(2), and CN) at a solid/liquid interface. The combination of current-distance and current-voltage measurements and their quantitative statistical analysis revealed the following sequence for junction formation probability and stability: PY > SH > NH(2) > CN. For all single molecular junctions investigated, we observed the evolution through multiple junction configurations, with a particularly well-defined binding geometry for PY. The comparison of density functional theory type model calculations and molecular dynamics simulations with the experimental results revealed structure and mechanistic details of the evolution of the different types of (single) molecular junctions upon stretching quantitatively.

Silyl-based alkyne-modifying linker for the preparation of C-terminal acetylene-derivatized protected peptides.

A novel linker for the synthesis of C-terminal acetylene-functionalized protected peptides is described. This SAM1 linker is applied in the manual Fmoc-based solid-phase peptide synthesis of Leu-enkephalin and in microwave-assisted automated synthesis of Maculatin 2.1, an antibacterial peptide that contains 18 amino acid residues. For the cleavage, treatment with tetramethylammonium fluoride results in protected acetylene-derivatized peptides. Alternatively, a one-pot cleavage-click procedure affords the protected 1,2,3-triazole conjugate in high yields after purification.

Design of switchable wettability sensor for paraquat based on clicking calix[4]arene.

A calix[4]arene acetylene (C4AE)-modified gold surface is successfully constructed in situ via click chemistry. The functionalized surface is used for selective recognition of paraquat by a wettability switch. Impedance measurements showed that the surface also expresses recognition for paraquat with a high sensitivity of 10 pM. The recognition mode, based on host-guest inclusion, is studied by computational calculations and the possible mechanism is analyzed.

Synthesis of stable and soluble one-handed helical homopoly(substituted acetylene)s without the coexistence of any other chiral moieties via two-step polymer reactions in membrane state: molecular design of the starting monomer.

A soluble and stable one-handed helical poly(substituted phenylacetylene) without the coexistence of any other chiral moieties was successfully synthesized by asymmetric-induced polymerization of a chiral monomer followed by two-step polymer reactions in membrane state: (1) removing the chiral groups (desubstitution); and (2) introduction of achiral long alkyl groups at the same position as the desubstitution to enhance the solubility of the resulting one-handed helical polymer (resubstitution). The starting chiral monomer should have four characteristic substituents: (i) a chiral group bonded to an easily hydrolyzed spacer group; (ii) two hydroxyl groups; (iii) a long rigid hydrophobic spacer between the chiral group and the polymerizing group; (iv) a long achiral group near the chiral group. As spacer group a carbonate ester was selected. The two hydroxyl groups formed intramolecular hydrogen bonds stabilizing a one-handed helical structure in solution before and after the two-step polymer reactions in membrane state. The rigid long hydrophobic spacer, a phenylethynylphenyl group, enhanced the solubility of the starting polymer, and realized effective chiral induction from the chiral side groups to the main chain in the asymmetric-induced polymerization. The long alkyl group near the chiral group avoided shrinkage of the membrane and kept the reactivity of resubstitution in membrane state after removing the chiral groups. The g value (g = ([θ]/3,300)/ε) for the CD signal assigned to the main chain in the obtained final polymer was almost the same as that of the starting polymer in spite of the absence of any other chiral moieties. Moreover, since the one-handed helical structure was maintained by the intramolecular hydrogen bonds in a solution, direct observation of the one-handed helicity of the final homopolymer has been realized in CD for the solution for the first time.

Synthesis and binding studies of novel diethynyl-pyridine amides with genomic promoter DNA G-quadruplexes.

Herein, we report the design, synthesis and biophysical evaluation of novel 1,2,3-triazole-linked diethynyl-pyridine amides and trisubstituted diethynyl-pyridine amides as promising G-quadruplex binding ligands. We have used a Cu(I)-catalysed azide-alkyne cycloaddition click reaction to prepare the 1,2,3-triazole-linked diethynyl-pyridine amides. The G-quadruplex DNA binding properties of the ligands have been examined by using a Förster resonance energy transfer (FRET) melting assay and surface plasmon resonance (SPR) experiments. The investigated compounds are conformationally flexible, having free rotation around the triple bond, and exhibit enhanced G-quadruplex binding stabilisation and specificity between intramolecular promoter G-quadruplex DNA motifs compared to the first generation of diaryl-ethynyl amides (J. Am. Chem. Soc. 2008, 130, 15950-15956). The ligands show versatility in molecular recognition and promising G-quadruplex discrimination with 2-50-fold selectivity exhibited between different intramolecular promoter G-quadruplexes. Circular dichroism (CD) spectroscopic analysis suggested that at higher concentration these ligands disrupt the c-kit2 G-quadruplex structure. The studies validate the design concept of the 1,3-diethynyl-pyridine-based scaffold and demonstrate that these ligands exhibit not only significant selectivity over duplex DNA but also variation in G-quadruplex interaction properties based on small chemical changes in the scaffold, leading to unprecedented differential recognition of different DNA G-quadruplex sequences.

pH-dependent conformational switching in 2,6-benzamidodiphenylacetylenes.

The conformational equilibrium of a pH-dependent switch based on an intramolecularly H-bonded diphenylacetylene can be predictably biased by using electron-donating or -withdrawing groups. Furthermore, protonation of the electron-donating dimethylamino group converts it into an electron-withdrawing dimethylammonium cation with a concomitant switch in conformation.

Rational Design of Diphenyldiacetylene-Based Fluorescent Materials Enabling a 365-nm Light-Initiated Topochemical Polymerization.

Photopolymerization of diacetylenes usually requires stringent reaction conditions like high energy irradiation of 254-nm light or even γ-rays, which are generally harmful to the human body and thus mild conditions with lower energy irradiation are required. In this study, different diphenyldiacetylene (DPDA) derivatives were rationally designed followed by the investigation of their photopolymerization behavior. It was found that the para-substituted amino groups could render the absorption band of DPDA bathochromically shifted, ensuring a 365-nm light wavelength coverage. On this basis, an organogel system was constructed by chemically modifying cholesteryl and lipoic acid onto the DPDA moiety in aromatic solvents. Such uniform self-assemblies further facilitated to a rather high degree of polymerization by 365-nm irradiation. As a kind of fluorescent materials, the whole polymerization process of this system can be visualized by a photoluminescent signal.

Identity of the active site in gold nanoparticle-catalyzed Sonogashira coupling of phenylacetylene and iodobenzene.

XPS, TEM, and reaction studies were used to examine the catalytic behavior of gold species deposited on lanthana toward the cross-coupling of phenylacetylene and iodobenzene. Atomically dispersed Au(I) and Au(III) were catalytically inert, whereas metallic Au(0) nanoparticles were both active and very selective. Thus it is metallic gold and not ionic gold that provides the catalytically active sites. Au(0) nanoparticles supported on silica, gamma-alumina, and BaO were active but relatively unselective; however, as with lanthana, ceria-supported Au(0) nanoparticles showed high selectivity. This strong promoting effect of the lanthanide oxide supports on Sonogashira selectivity cannot be accounted for in terms of acid/base, redox, or SMSI effects; it may be tentatively ascribed to metal --> support hydrogen spillover.