Limited Conformational Flexibility Research Articles

Testing the Simplified Molecular Dynamics Approach to Improve the Reproduction of ECD Spectra and Monitor Aggregation.

A simplified molecular-dynamics-based electronic circular dichroism (ECD) approach was tested on three condensed derivatives with limited conformational flexibility and an isochroman-2H-chromene hybrid, the ECD spectra of which could not be precisely reproduced by the conventional ECD calculation protocol. Application of explicit solvent molecules at the molecular mechanics (MD) level in the dynamics simulations and subsequent TDDFT-ECD calculation for the unoptimized MD structures was able to improve the agreements between experimental and computed spectra. Since enhancements were achieved even for molecules with limited conformational flexibility, deformations caused by the solvent molecules and multitudes of conformers produced with unoptimized geometries seem to be key factors for better agreement. The MD approach could confirm that aggregation of the phenanthrene natural product luzulin A had a significant contribution to a specific wavelength range of the experimental ECD. The MD approach has proved that dimer formation occurred in solution and this was responsible for the anomalous ECD spectrum. The scope and limitations of the method have also been discussed.

Characterization of Deformational Isomerization Potential and Interconversion Dynamics with Ultrafast X-ray Solution Scattering.

Dimeric complexes composed of d8 square planar metal centers and rigid bridging ligands provide model systems to understand the interplay between attractive dispersion forces and steric strain in order to assist the development of reliable methods to model metal dimer complexes more broadly. [Ir2 (dimen)4]2+ (dimen = para-diisocyanomenthane) presents a unique case study for such phenomena, as distortions of the optimal structure of a ligand with limited conformational flexibility counteract the attractive dispersive forces from the metal and ligand to yield a complex with two ground state deformational isomers. Here, we use ultrafast X-ray solution scattering (XSS) and optical transient absorption spectroscopy (OTAS) to reveal the nature of the equilibrium distribution and the exchange rate between the deformational isomers. The two ground state isomers have spectrally distinct electronic excitations that enable the selective excitation of one isomer or the other using a femtosecond duration pulse of visible light. We then track the dynamics of the nonequilibrium depletion of the electronic ground state population─often termed the ground state hole─with ultrafast XSS and OTAS, revealing a restoration of the ground state equilibrium in 2.3 ps. This combined experimental and theoretical study provides a critical test of various density functional approximations in the description of bridged d8-d8 metal complexes. The results show that density functional theory calculations can reproduce the primary experimental observations if dispersion interactions are added, and a hybrid functional, which includes exact exchange, is used.

Pathogen-specific structural features of Candida albicans Ras1 activation complex: uncovering new antifungal drug targets.

An important feature associated with Candida albicans pathogenicity is its ability to switch between yeast and hyphal forms, a process in which CaRas1 plays a key role. CaRas1 is activated by the guanine nucleotide exchange factor (GEF) CaCdc25, triggering hyphal growth-related signaling pathways through its conserved GTP-binding (G)-domain. An important function in hyphal growth has also been proposed for the long hypervariable region downstream the G-domain, whose unusual content of polyglutamine stretches and Q/N repeats make CaRas1 unique within Ras proteins. Despite its biological importance, both the structure of CaRas1 and the molecular basis of its activation by CaCdc25 remain unexplored. Here, we show that CaRas1 has an elongated shape and limited conformational flexibility and that its hypervariable region contains helical structural elements, likely forming an intramolecular coiled-coil. Functional assays disclosed that CaRas1-activation by CaCdc25 is highly efficient, with activities up to 2,000-fold higher than reported for human GEFs. The crystal structure of the CaCdc25 catalytic region revealed an active conformation for the α-helical hairpin, critical for CaRas1-activation, unveiling a specific region exclusive to CTG-clade species. Structural studies on CaRas1/CaCdc25 complexes also revealed an interaction surface clearly distinct from that of homologous human complexes. Furthermore, we identified an inhibitory synthetic peptide, prompting the proposal of a key regulatory mechanism for CaCdc25. To our knowledge, this is the first report of specific inhibition of the CaRas1-activation via targeting its GEF. This, together with their unique pathogen-structural features, disclose a set of novel strategies to specifically block this important virulence-related mechanism. IMPORTANCE Candida albicans is the main causative agent of candidiasis, the commonest fungal infection in humans. The eukaryotic nature of C. albicans and the rapid emergence of antifungal resistance raise the challenge of identifying novel drug targets to battle this prevalent and life-threatening disease. CaRas1 and CaCdc25 are key players in the activation of signaling pathways triggering multiple virulence traits, including the yeast-to-hypha interconversion. The structural similarity of the conserved G-domain of CaRas1 to those of human homologs and the lack of structural information on CaCdc25 has impeded progress in targeting these proteins. The unique structural and functional features for CaRas1 and CaCdc25 presented here, together with the identification of a synthetic peptide capable of specifically inhibiting the GEF activity of CaCdc25, open new possibilities to uncover new antifungal drug targets against C. albicans virulence.

Atomistic Pictures of Self-Assembled Helical Peptide Nanofibers.

Spontaneous self-assembly of peptides has been at the forefront of supramolecular chemistry and materials science research over the last two decades. Despite the wealth of information on the morphology of the assembled objects, atomic resolution details of molecular arrangements inside them are largely unknown. In this paper, we investigated non-covalent assemblies of zwitterionic l-phenylalanine tripeptides in water using all-atom explicit-solvent molecular dynamics computer simulations. Our studies produced atomistic pictures of spontaneously assembled nanofibers composed of hundreds of peptide molecules. The dimensions of the nanofibers varied from 10 to 18 nm, with irregular helical twists along the long axes. Previously published experimental data, acquired under similar conditions, provided direct validation of the fibrous morphology and indirect support for the non-trivial helicity observed in our simulations. Quantitative analyses of peptide-water and peptide-peptide interactions revealed heterogeneous local environments of molecules across the nanometer length scales. The combination of electrostatic, hydrogen bonding, van der Waals, and hydrophobic interactions, adopted by a single molecule, was dependent on its relative position inside the fiber. Despite the presence of three hydrophobic phenyl groups, very few molecules were found to be completely shielded from the surrounding water, indicating a subtle role of the hydrophobic effect. Limited conformational flexibility of the tripeptide, along with bare electrostatic interactions, appeared to play a crucial role in the emergence of fibrous morphology of the nanostructures. Our analyses led us to formulate plausible qualitative explanations of the assembly behavior in terms of thermodynamic driving forces and kinetic considerations. We established a clear relationship between details of chemical interactions operating within few molecules and characteristics of the self-assembled states at much longer length scales.

A memetic algorithm enables efficient local and global all-atom protein-protein docking with backbone and side-chain flexibility

Protein complex formation is encoded by specific interactions at the atomic scale, but the computational cost of modeling proteins at this level often requires use of simplified energy models and limited conformational flexibility. In particular, use of all-atom energy functions and backbone and side-chain flexibility results in rugged energy landscapes that are difficult to explore. In this study, we develop a protein-protein docking algorithm, EvoDOCK, that combines the strength of a differential evolution algorithm for efficient exploration of the global search space with the benefits of a local optimization method to refine detailed atomic interactions. EvoDOCK enabled accurate and fast local and global protein-protein docking using an all-atom energy function with side-chain flexibility. Comparison with a standard method built on Monte Carlo optimization demonstrated improved accuracy and increases in computational speed of up to 35 times. The evolutionary algorithm also enabled efficient atomistic docking with backbone flexibility.

Fully Supramolecular Chiral Hydrogen-Bonded Molecular Tweezer.

Molecular tweezers are open-ended, cavity-possessing U-shaped molecular architectures with high potential for various applications in supramolecular chemistry. Their covalent synthesis, however, is often tedious and the structures obtained lack structural responsiveness beyond the limited conformational flexibility of the scaffold. Herein we present a proof-of-concept study on the design, synthesis, assembly, and transformations of a novel supramolecular construct─a fully noncovalent molecular tweezer. The supramolecular tweezer was assembled from a set of four building blocks, composed of two identical molecular angle bars and two flat aromatic extension wings, using hydrogen bonding only. The chirality-assisted aggregation process was utilized to ensure scaffold bending directionality using enantiomerically pure bicyclic angle bars. To address the challenges associated with shifting of the equilibrium from strong cooperative narcissistic self-sorting of self-complementary angle bars in cyclic aggregates toward integrative self-sorting in molecular tweezers, a rational desymmetrization strategy was applied. The dynamic supramolecular tweezer has been shown to display rich supramolecular chemistry, allowing for stimuli-responsive change in aggregate topology and solvent-responsive supramolecular polymerization.

Dark-Binding Process Relevant to Preventing Photosensitized Oxidation: Conformation-Dependent Light and Dark Mechanisms by a Dual-Functioning Diketone.

Few photosensitizers function in both light and dark processes as they usually have no function when the lights are turned off. We hypothesized that light and dark mechanisms in an α-diketone will be decoupled by dihedral rotation in a conformation-dependent binding process. Successful decoupling of these two functions is now shown. Namely, anti- and syn-skewed conformations of 4,4′-dimethylbenzil promote photosensitized alkoxy radical production, whereas the syn conformation promotes a binding shutoff reaction with trimethyl phosphite. Less rotation of the diketone is better suited to the photosensitizing function since phosphite binding arises through the syn conformer of lower stability. The dual function seen here with the α-diketone is generally not available to sensitizers of limited conformational flexibility, such as porphyrins, phthalocyanines, and fullerenes.

Molecular Dynamics Simulation of Homo-DNA: The Role of Crystal Packing in Duplex Conformation

The (4′→6′)-linked DNA homolog 2′,3′-dideoxy-β-D-glucopyranosyl nucleic acid (dideoxy-glucose nucleic acid or homo-DNA) exhibits stable self-pairing of the Watson–Crick and reverse-Hoogsteen types, but does not cross-pair with DNA. Molecular modeling and NMR solution studies of homo-DNA duplexes pointed to a conformation that was nearly devoid of a twist and a stacking distance in excess of 4.5 Å. By contrast, the crystal structure of the homo-DNA octamer dd(CGAATTCG) revealed a right-handed duplex with average values for helical twist and rise of ca. 15° and 3.8 Å, respectively. Other key features of the structure were strongly inclined base-pair and backbone axes in the duplex with concomitant base-pair slide and cross-strand stacking, and the formation of a dimer across a crystallographic dyad with inter-duplex base swapping. To investigate the conformational flexibility of the homo-DNA duplex and a potential influence of lattice interactions on its geometry, we used molecular dynamics (MD) simulations of the crystallographically observed dimer of duplexes and an isolated duplex in the solution state. The dimer of duplexes showed limited conformational flexibility, and key parameters such as helical rise, twist, and base-pair slide exhibited only minor fluctuations. The single duplex was clearly more flexible by comparison and underwent partial unwinding, albeit without significant lengthening. Thus, base stacking was preserved in the isolated duplex and two adenosines extruded from the stack in the dimer of duplexes were reinserted into the duplex and pair with Ts in a Hoogsteen mode. Our results confirmed that efficient stacking in homo-DNA seen in the crystal structure of a dimer of duplexes was maintained in the separate duplex. Therefore, lattice interactions did not account for the different geometries of the homo-DNA duplex in the crystal and earlier models that resembled inclined ladders with large base-pair separations that precluded efficient stacking.

Development of novel macrocyclic small molecules that target CTG trinucleotide repeats

We describe the molecular design, synthesis, and investigation of a series of acridine-triaminotriazine macrocycles that selectively bind to CTG trinucleotide repeats in DNA with minimal nonspecific binding. The limited conformational flexibility enforces the stacking of the triaminotriazine and acridine units. Isothermal titration calorimetry studies and Job plot analyses revealed that the ligands bound to d(CTG) mismatched sites. The acridine and triaminotriazine units were shown to intramolecularly π-stack in aqueous solutions. Compared to a noncyclic analog, the macrocycles showed an almost 10-fold lower cytotoxicity in HeLa cells and up to 4-fold higher transcription inhibition of d(CTG·CAG)74.

Dynamics and Thermodynamics of Ibuprofen Conformational Isomerism at the Crystal/Solution Interface.

Conformational flexibility of molecules involved in crystal growth and dissolution is rarely investigated in detail and usually considered to be negligible in the formulation of mesoscopic models of crystal growth. In this work, we set out to investigate the conformational isomerism of ibuprofen as it approaches and is incorporated in the morphologically dominant {100} crystal face, in a range of different solvents: water, 1-butanol, toluene, cyclohexanone, cyclohexane, acetonitrile, and trichloromethane. To this end, we combine extensive molecular dynamics and well-tempered metadynamics simulations to estimate the equilibrium distribution of conformers, compute conformer-conformer transition rates, and extract the characteristic relaxation time of the conformer population in solution, adsorbed at the solid/liquid interface, incorporated in the crystal in contact with the mother solution, and in the crystal bulk. We find that, while the conformational equilibrium distribution is weakly dependent on the solvent, relaxation times are instead significantly affected by it. Furthermore, differences in the relaxation dynamics are enhanced on the crystal surface, where conformational transitions become slower and specific conformational transition pathways are hindered. This leads us to observe that the dominant mechanisms of conformational transition can also change significantly moving from the bulk solution to the crystal interface, even for a small molecule with limited conformational flexibility such as ibuprofen. Our findings suggest that understanding conformational flexibility is key to provide an accurate description of the solid/liquid interface during crystal dissolution and growth, and therefore, its relevance should be systematically assessed in the formulation of mesoscopic growth models.

Cis/trans isomerization of proline peptide bonds in the backbone of cyclic disulfide‐bridged peptides

AbstractPeptides are of interest as potential therapeutic agents, including cyclic disulfide‐bridged peptides because of their limited conformational flexibility and enhanced stability toward proteolysis. To further constrain the flexibility of the peptide backbone, the disulfide‐bridged rings often contain a proline residue, which also serves to facilitate the formation of reverse‐turn structures. However, the proline residue increases the conformational diversity because the tertiary amide peptide bond to proline can exist as significant populations of both the cis and trans isomers. To identify features that affect the distribution between the cis and trans isomers of proline peptide bonds in disulfide‐bridged peptide rings, we have characterized by 1H NMR the kinetics and equilibria of the cis/trans isomerization of the proline peptide bonds for the linear dithiol and cyclic disulfide‐bridged forms of three families of proline‐containing peptides: Ac‐Cys‐Pro‐[NH(CH2)nCO]‐Cys‐NH2, where n = 1‐4; Ac‐Cys‐Xaa‐Pro‐Cys‐NH2 and Ac‐Cys‐Pro‐Xaa‐Cys‐NH2, where Xaa is Gly, Ala and Val; and Ac‐Cys‐Pro‐His‐(Ala)n‐Cys‐NH2, where n = 0‐5. The peptide Ac‐Cys‐Pro‐(4‐AMBA)‐Cys‐NH2, where 4‐AMBA is 4‐aminomethylbenzoic acid, was also studied to determine the effect of a rigid aromatic ring in the peptide backbone on the conformational properties of the Cys‐Pro peptide bond. Equilibrium constants were determined for cis/trans isomerization from the relative intensities of resonances for the cis and trans isomers, and rate constants for cis‐to‐trans and trans‐to‐cis isomerization were determined by the magnetization transfer NMR method. The cis/trans equilibrium is a dynamic equilibrium, and the equilibrium constants vary widely due to the wide range of kinetic stabilities of the various cis and trans isomers.

Cyclic mismatch binding ligand CMBL4 binds to the 5'-T-3'/5'-GG-3' site by inducing the flipping out of thymine base.

A newly designed cyclic bis-naphthyridine carbamate dimer CMBL4 with a limited conformational flexibility was synthesized and characterized. Absorption spectra revealed that two naphthyridines in CMBL4 were stacked on each other in aqueous solutions. The most efficient binding of CMBL4 to DNA was observed for the sequence 5′-T-3′/5′-GG-3′ (T/GG) with the formation of a 1:1 complex, which is one of possible structural elements involved in the higher order structures of (TGG)n repeat DNA triggering the genome microdeletion. Surface plasmon resonance assay also showed the binding of CMBL4 with TGG repeat DNA. Potassium permanganate oxidation studies of CMBL4-bound duplex containing the T/GG site showed that the CMBL4-binding accelerated the oxidation of thymine at that site, which suggests the flipping out of the thymine base from a π-stack. Preferential binding was observed for CMBL4 compared with its acyclic variants, which suggests the marked significance of the macrocyclic structure for the recognition of the T/GG site.

Scaffold-Hopping of Multicationic Amphiphiles Yields Three New Classes of Antimicrobials.

Quaternary ammonium compounds (QACs) are a vital class of antiseptics. Recent investigations into their construction are uncovering novel and potent multicationic variants. Based on a trisQAC precedent, we have implemented a scaffold-hopping approach to develop alternative QAC architectures that display 1-3 long alkyl chains in specific projections from cyclic and branched core structures bearing 3-4 nitrogen atoms. The preparation of 30 QAC structures allowed for correlation of scaffold structure with antimicrobial activity. We identified QACs with limited conformational flexibility that have improved bioactivity against planktonic bacteria as compared to their linear counterparts. We also confirmed that resistance, as evidenced by an increased minimum inhibitory concentration (MIC) for methicillin-resistant Staphylococcus aureus (MRSA) compared to methicillin-susceptible Staphylococcus aureus (MSSA), can reduce efficacy up to 64-fold for monocationic QACs. Differentiation of antimicrobial and anti-biofilm activity, however, was not observed, suggesting that these compounds utilize a non-specific mode of eradication.

Tribenzotriquinacene‐Based Triscyclophanes: Intra‐ and Inter‐Wing C3v‐Symmetrical Extension of the Bowl‐Shaped Tribenzotriquinacene Core

AbstractThe syntheses and structural properties of novel triscyclophanes that bear the rigid, bowl‐shaped tribenzotriquinacene (TBTQ) core are reported. Condensation of the 2,3,6,7,10,11‐hexakis(chloromethyl) derivative with catechols and 1,2‐benzenedithiol gives rise to elongation of the three indane wings (intra‐wing extension), whereas incorporation of resorcinol, hydroquinone, and 1,3‐ and 1,4‐benzenedithiol units occurs by bridging the 3D bays of the TBTQ framework (inter‐wing extension), yielding TBTQ‐based cavitands. Constitutional and conformational details were studied by X‐ray diffraction, VT‐NMR spectroscopy, and molecular modeling. The bay‐bridged TBTQ‐based triscyclophanes bearing 1,3‐dioxy‐ and 1,3‐dithiophenylene units adopt globular and cone‐like C3‐symmetrical shapes, respectively, with limited conformational flexibility. Bay‐bridging by 1,4‐dioxy‐ and 1,4‐dithiophenylene units generates a more complanate coverage of the bowl face with even less conformational flexibility.

De novo discovery of bioactive cyclic peptides using bacterial display and flow cytometry.

Cyclic peptides are increasingly desired for their enhanced stability and pharmacologic properties. Due to their limited conformational flexibility, cyclic peptides with C-to-N-terminal peptide bond and a disulfide bridge can confer high target binding affinity and resistance to proteolytic enzymes. Challenging drug targets including protein interaction surfaces can be successfully targeted using peptides rather than small molecules or proteins. Peptides, capable of antibody-like affinities with increased potency, can be designed to fill in the gap between small molecules and larger proteins. However, cysteine-rich peptides with several disulfide bonds have limitations in production and purification. Therefore, we devised a strategy to identify cyclic peptides with single disulfide connectivity that offers desired properties along with ease in synthesis and production. Here, de novo design of cyclic peptides is demonstrated through screening of peptide libraries using bacterial display and cell sorting. Herein, a step-by-step protocol is presented to design and screen diverse peptide libraries to identify cyclic peptides with desired specificity and affinity towards arbitrary target proteins.

Phage selection of bicyclic peptides based on two disulfide bridges.

Bicyclic peptides can bind with high affinity and selectivity to protein targets, making this format attractive for biotechnological and medicinal applications. The good binding properties are based to a large extent on the limited conformational flexibility of the two connected peptide rings. Bicyclic peptides with desired binding specificity can be isolated from phage display libraries that are generated by chemically cyclizing linear peptide on phage with alkylating reagents. Recently, we presented a strategy for the phage selection of bicyclic peptides based on two disulfide bridges. This approach allows the generation and screening of topologically highly diverse bicyclic peptide structures. Herein, we describe step-by-step protocols to clone and produce disulfide-cyclized bicyclic peptide libraries as well as to screen the libraries and to synthesize and characterize isolated bicyclic peptides.

Ferrocenes Bearing Highly Extended π Systems with Nitrile, Nitro, and Dimethylamino End Groups

AbstractOligophenylene‐ethynylenes are a popular class of molecular wires for molecular electronics. Replacement of some, not all, of the 1,4‐phenylene units by 1,1′‐ferrocenylene moieties generates less rigid entities with a limited conformational flexibility. Within this concept, the syntheses of some 1,1′‐disubstituted ferrocenes that bear arylethynyl or 4‐(arylethynyl)phenyl substituents is presented. In contrast to related compounds with sulfur end groups that were prepared previously, the versions presented here have nitrile end groups, which, according to reported precedence, may serve as points of attachment to gold surfaces. A crystal structure analysis of an unusual diferrocenylethyne derivative is included. In addition, one representative with a push‐pull disubstitution that has a nitro and a dimethylamino end group is presented. Many of the prepared compounds have been characterized by cyclic voltammetry.

The SAMPL4 host–guest blind prediction challenge: an overview

Prospective validation of methods for computing binding affinities can help assess their predictive power and thus set reasonable expectations for their performance in drug design applications. Supramolecular host-guest systems are excellent model systems for testing such affinity prediction methods, because their small size and limited conformational flexibility, relative to proteins, allows higher throughput and better numerical convergence. The SAMPL4 prediction challenge therefore included a series of host-guest systems, based on two hosts, cucurbit[7]uril and octa-acid. Binding affinities in aqueous solution were measured experimentally for a total of 23 guest molecules. Participants submitted 35 sets of computational predictions for these host-guest systems, based on methods ranging from simple docking, to extensive free energy simulations, to quantum mechanical calculations. Over half of the predictions provided better correlations with experiment than two simple null models, but most methods underperformed the null models in terms of root mean squared error and linear regression slope. Interestingly, the overall performance across all SAMPL4 submissions was similar to that for the prior SAMPL3 host-guest challenge, although the experimentalists took steps to simplify the current challenge. While some methods performed fairly consistently across both hosts, no single approach emerged as consistent top performer, and the nonsystematic nature of the various submissions made it impossible to draw definitive conclusions regarding the best choices of energy models or sampling algorithms. Salt effects emerged as an issue in the calculation of absolute binding affinities of cucurbit[7]uril-guest systems, but were not expected to affect the relative affinities significantly. Useful directions for future rounds of the challenge might involve encouraging participants to carry out some calculations that replicate each others' studies, and to systematically explore parameter options.

Limited conformational flexibility in the paratope may be responsible for degenerate specificity of HIV epitope recognition

Exquisite specificity is the hallmark of antigen-antibody recognition. However, breakdown in the specific recognition potential culminating in the binding to multiple antigens by a single antibody has been observed, even after the maturation of the humoral response. While such a broad specificity may be expected to assist the host to counter the antigenic variations associated with an immune-evading pathogen, escape from immune surveillance by subtle epitopic mutations in pathogens like HIV and influenza virus has been clearly established. In the light of this dichotomy, the issues of degeneracy/specificity in the humoral response against such epitopes were analysed using three HIV-neutralizing epitopes and their variants as a model system. Cross-reactivity was observed in the polyclonal response against two of the epitopes. Multi-reactive mAb KEL10 was isolated against one of the epitopes, ELDKWA from this response. It is evident that even after the affinity maturation, antibodies showing binding to multiple variants of an immunizing peptide epitope existed. Binding kinetics and in silico structural analyses indicated that conserved interactions across epitopes and limited conformational flexibility in the paratope may account for the observed multi-reactivity. Though the affinity maturation process is expected to incorporate an extent of specificity to the paratope, there appear to be still some B-cell clones producing antibodies with subtle flexibility in their binding site, as demonstrated in case of KEL10. Generation of such antibodies against effective immunogens could be a possible approach for countering the antibody neutralization escape by various immune-evading pathogens.

1,1′‐Diaryl‐Substituted Ferrocenes: Up to Three Hinges in Oligophenyleneethynylene‐Type Molecular Wires

AbstractMolecular wires of the oligophenyleneethynylene (OPE)‐type are potentially rigid entities. The idea of the work reported herein was to replace some, not all, of the phenylene moieties with ferrocene units, thereby introducing limited conformational flexibility with the ferrocene units acting as hinges as a consequence of the facile rotation around the Cp–Fe–Cp axis. In this context, the syntheses of a number of 1,1′‐diaryl‐disubstituted ferrocene building blocks are described. The new terminal diynes 22 and 24 were used to construct the first representatives of ferrocene‐based molecular wires with three ferrocene hinges. The study includes an X‐ray structure analysis of the thiophene‐based diyne 24 as well as cyclovoltammetric analyses of a number of the compounds prepared.