Conformational Selection in Glycomimetics: Human Galectin‐1 Only Recognizes syn‐Ψ‐Type Conformations of β‐1,3‐Linked Lactose and Its C‐Glycosyl Derivative

The human lectin galectin‐1 (hGal‐1) translates sugar signals, that is, β‐galactosides, into effects on the level of cells, for example, growth regulation, and has become a model for studying binding of biopharmaceutically relevant derivatives. Bound‐state conformations of Galβ‐C‐(1→3)‐Glcβ‐OMe ( 1 ) and its βGal‐(1→3)‐βGlc‐OMe disaccharide parent compound were studied by using NMR spectroscopy (transferred (TR)‐NOESY data), assisted by docking experiments and molecular dynamics (MD) simulations. The molecular recognition process involves a conformational selection event. Although free C‐glycoside access four distinct conformers in solution, hGal‐1 recognizes shape of a local minimum of compound 1 , the syn‐Φ/syn‐Ψ conformer, not the structure at global minimum. MD simulations were run to explain, in structural terms, the observed geometry of the complex.     

The Ambident Reactivity of 2,4,6‐Tris(trifluoromethanesulfonyl)anisole in Methanol: Using the SO2CF3 Group as a Tool to Reach the Superelectrophilic Dimension in σ‐Complexation Processes

The kinetics of σ complexation of 2,4,6‐tris(trifluoromethanesulfonyl)anisole ( 7 d ) have been investigated over a large pH range of 2–13.70 at T=20 °C in methanol. Two competitive processes associated with the initial addition of MeO^? at the unsubstituted 3‐position of 7 d to give a 1,3‐dimethoxy adduct ( 9 d ‐Me) and a subsequent and slow conversion of this species into a 1,1‐dimethoxy isomer ( 8 d ‐Me) have been identified. Both adducts 8 d ‐Me and 9 d ‐Me are 10⁵–10⁶ times more stable than the related adducts 8 a ‐Me and 9 a ‐Me of 2,4,6‐trinitroanisole ( 7 a ), a conventional reference aromatic electrophile in Meisenheimer complex chemistry. The high stability of 8 d ‐Me and 9 d ‐Me is shown to derive from greater rates of formation and lower rates of decomposition than previously determined for 8 a ‐Me and 9 a ‐Me, thereby emphasising the especially high activation of a benzene ring by SO₂CF₃ group(s). Analysis of the collected rate and equilibrium data for σ complexation in the anisole series 2,4,6‐tris(SO₂CF₃)‐, 2,6‐bis(SO₂CF₃)‐4‐nitro‐, 4‐SO₂CF₃‐2,6‐dinitro‐ and 2,4,6‐trinitro‐ supports the idea that the especially high capacity of resonance stabilisation of the negative charge of the adducts through an F_π‐type (as defined in ref. 49 ) polarisation effect is a major factor that accounts for the strong activation provided by SO₂CF₃ groups. A most significant result is the finding that the 1,1‐dimethoxy adduct 8 d ‐Me is by far the most stable benzene σ adduct so far reported. With a p value of 7.32, this adduct is formed exclusively through methanol addition up to pH≈10. This is consistent with the location of 7 d in the superelectrophilic region defined by p ≤9.5–10.5. For comparison, the solvent contribution is negligible in the formation of the 1,3‐isomer 9 d ‐Me, the p (10.59) of which is situated on the upper limit of the boundary. Taking advantage of the simple relationship linking pK_a values for σ complexation in methanol and water, a ranking of the triflone 7 d on the general thermodynamic scale constructed for Meisenheimer electrophiles in water is informative. An approximate calibration on the electrophilicity scale kinetically derived by Mayr et al. has also been made.     

Trimodal Control of Ion‐Transport Activity on Cyclo‐oligo‐(1→6)‐β‐D‐glucosamine‐Based Artificial Ion‐Transport Systems

Cyclo‐oligo‐(1→6)‐β‐D ‐glucosamines functionalized with hydrophobic tails are reported as a new class of transmembrane ion‐transport system. These macrocycles with hydrophilic cavities were introduced as an alternative to cyclodextrins, which are supramolecular systems with hydrophobic cavities. The transport activities of these glycoconjugates were manipulated by altering the oligomericity of the macrocycles, as well as the length and number of attached tails. Hydrophobic tails of 3 different sizes were synthesized and coupled with each glucosamine scaffold through the amide linkage to obtain 18 derivatives. The ion‐transport activity increased from di‐ to tetrameric glucosamine macrocycles, but decreased further when flexible pentameric glucosamine was introduced. The ion‐transport activity also increased with increasing length of attached linkers. For a fixed length of linkers, the transport activity decreased when the number of such tails was reduced. All glycoconjugates displayed a uniform anion‐selectivity sequence: Cl^?>Br^?>I^?. From theoretical studies, hydrogen bonding between the macrocycle backbone and the anion bridged through water molecules was observed.     

Concise Synthesis and Biological Assessment of (+)‐Neopeltolide and a 16‐Member Stereoisomer Library of 8,9‐Dehydroneopeltolide: Identification of Pharmacophoric Elements

We describe herein a concise synthesis of (+)‐neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond‐forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross‐metathesis reaction directed by H‐bonding, and a ring‐closing metathesis conducted under non‐high dilution conditions. Moreover, we developed a 16‐member stereoisomer library of 8,9‐dehydroneopeltolide to systematically explore the stereostructure–activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF‐7 human breast adenocarcinoma, HT‐1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure–activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency.     

Odds and Trends: Recent Developments in the Chemistry of Odorants

Fragrance chemistry is, together with the closely related area of flavor chemistry, one of the few domains, if not the only one, in which chemists can immediately experience structure–activity relationships. This review presents structure–odor correlations and olfactophore models for the main odor notes of perfumery: “fruity”, “marine”, “green”, “floral”, “spicy”, “woody”, “amber”, and “musky”. New trendsetters and so‐called captive odorants of these notes are introduced, and recent activities and highlights in fragrance chemistry are summarized. The design of odorants, their chemical synthesis, and their use in modern perfumery is discussed. Our selection is guided and illustrated by creative fragrances, and features new odorants which encompassed current trends in perfumery. New odorants for grapefruit and blackcurrant, for galbanum, and leafy top notes are presented. Compounds with fashionable marine, ozonic, and aquatic facets are treated, as well as new odorants for classical lily‐of‐the‐valley, rose, and jasmine accords. Compounds with sweet and spicy tonalities are also discussed, as are the most recent developments for woody notes such as sandalwood and vetiver. We conclude with musky and ambery odorants possessing uncommon or unusual structural features. Some odor trends and effects are illustrated by microencapsulated fragrance samples, and areas where there is need for the development of new synthetic materials and methodologies are pointed out. Thus, chemists are invited to explore fragrance chemistry and participate in the design and synthesis of new odorants. This review gives the latest state of the art of the subject.     

Rationally Developed Organic Salts of Tolfenamic Acid and Its β‐Alanine Derivatives for Dual Purposes as an Anti‐Inflammatory Topical Gel and Anticancer Agent

A new series of primary ammonium monocarboxylate (PAM) salts of a nonsteroidal anti‐inflammatory drug (NSAID), namely, tolfenamic acid ( TA ), and its β‐alanine derivatives were generated. Nearly 67 % of the salts in the series showed gelling abilities with various solvents, including water (biogenic solvent) and methyl salicylate (typically used for topical gel formulations). Gels were characterized by rheology, electron microscopy, and so forth. Structure–property correlations based on single‐crystal and powder XRD data of several gelator and nongelator salts revealed intriguing insights. Studies (in vitro) on an aggressive human breast cancer cell line (MDA‐MB‐231) with the l ‐tyrosine methyl ester salt of TA ( S7 ) revealed that the hydrogelator salt was more effective at killing cancer cells than the mother drug TA (3‐(4,5‐ di methyl thiazol ‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay); displayed better anti‐inflammatory activity compared with that of TA (prostaglandin E₂ assay); could be internalized within the cancer cells, as revealed by fluorescence microscopy; and inhibited effectively migration of the cancer cells. Thus, the easily accessible ambidextrous gelator salt S7 can be used for two purposes: as an anti‐inflammatory topical gel and as an anticancer agent.     

Stabilization of the Cysteine‐Rich Conotoxin MrIA by Using a 1,2,3‐Triazole as a Disulfide Bond Mimetic

The design of disulfide bond mimetics is an important strategy for optimising cysteine‐rich peptides in drug development. Mimetics of the drug lead conotoxin MrIA, in which one disulfide bond is selectively replaced of by a 1,4‐disubstituted‐1,2,3‐triazole bridge, are described. Sequential copper‐catalyzed azide–alkyne cycloaddition (CuAAC; click reaction) followed by disulfide formation resulted in the regioselective syntheses of triazole–disulfide hybrid MrIA analogues. Mimetics with a triazole replacing the Cys4–Cys13 disulfide bond retained tertiary structure and full in vitro and in vivo activity as norepinephrine reuptake inhibitors. Importantly, these mimetics are resistant to reduction in the presence of glutathione, thus resulting in improved plasma stability and increased suitability for drug development.     

4‐Aryl‐3,5‐bis(arylethynyl)aryl‐4H‐1,2,4‐triazoles: Multitasking Skeleton as a Self‐Assembling Unit

The synthesis of a series of 4‐aryl‐3,5‐bis(arylethynyl)aryl‐4H‐1,2,4‐triazoles derivatives is reported and the influence exerted by peripheral substitution on the morphology of the aggregates generated from these 1,2,4‐triazoles is investigated by SEM imaging. The presence of paraffinic side chains results in long fibrillar supramolecular structures, but unsubstituted triazoles self‐assemble into thinner ribbons and needle‐like aggregates. The crystals obtained from methoxy‐substituted triazoles have been utilised to elaborate a model that helps to justify aggregation of the investigated 1,2,4‐triazoles, in which the operation of arrays of C?H???π non‐covalent interactions plays a significant role. The results presented herein demonstrate the ability of simple molecules to behave as multitasking scaffolds with different properties, depending on peripheral substitution. Thus, although 1,2,4‐triazoles without long paraffinic side chains exhibit optical waveguiding behaviour, triazoles endowed with peripheral paraffinic side chains exhibit hexagonal columnar mesomorphism.     

Study on 1,3,5‐Triazine Chemistry in Dehydrocondensation: Gauche Effect on the Generation of Active Triazinylammonium Species

The reaction of 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine (CDMT) with various nitrogen‐containing compounds, particularly tertiary amines (tert‐amines), has been studied for the preparation of 2‐(4,6‐dimethoxy‐1,3,5‐triazinyl)trialkylammonium salts [DMT‐Am(s)]. DMT‐Ams derived from aliphatic tert‐amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT‐Ams and tert‐amines by NMR and X‐ray diffraction methods, we concluded that a β‐alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert‐amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β‐alkyl groups in the stable conformations, does not react at all. The theory of “gauche β‐alkyl group effect” proposed here provides useful guidelines for the preparation of DMT‐Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert‐amines in a CDMT/tert‐amine system that involves in situ generation of DMT‐Am, showed that the gauche effect of the β‐alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert‐amines possessing an unavoidable gauche β‐alkyl group. Thus, the tert‐amine/CDMT systems are useful for judging whether tert‐amines can readily react with CDMT without isolation of DMT‐Ams.     

Conformationally Homogeneous Heterocyclic Pseudotetrapeptides as Three‐Dimensional Scaffolds for Rational Drug Design: Receptor‐Selective Somatostatin Analogues

A would‐be amide : A 1,4‐disubstituted 1,2,3‐triazole was used as a surrogate for a trans amide bond to create a library of 16 diastereomeric pseudotetrapeptides as β‐turn mimetics. High‐resolution structural analysis indicated that these scaffolds adopt distinct, rigid, conformationally homogeneous β‐turn‐like structures (see example), some of which bind somatostatin receptor subtypes selectively, and some of which show broad‐spectrum activity.

     

Synthesis and Structure–Activity Relationship of Vicenistatin,a Cytotoxic 20‐Membered Macrolactam Glycoside

We have developed two syntheses of vicenistatin and its analogues. Our first‐generation strategy included the rapid and sequential assembly of the macrocyclic lactam by using an intermolecular Horner–Wadsworth–Emmons reaction between the C3–C13 fragment and the C1–C2, C14–C19 fragment, followed by an intramolecular Stille coupling reaction. The second‐generation strategy utilized a ring‐closing metathesis of a hexaene intermediate to generate the desired 20‐membered macrolactam. This second‐generation strategy made it possible to prepare synthetic analogues of vicenistatin, including the C20‐ and/or C23‐demethyl analogues. Evaluation of the cytotoxic effect of these analogues indicated the importance of the fixed conformation of aglycon for determining the biological activity of the vicenistatins.     

Towards Molecular Design Rationalization in Branched Multi‐Thiophene Semiconductors: The 2‐Thienyl‐Persubstituted α‐Oligothiophenes

The introduction of branching in multi‐thiophene semiconductors, although granting the required solubility for processing, results in an increased molecular fluxionality and a higher level of distortion, thus hampering π conjugation. Accordingly, branched oligothiophenes require rationalization of their structure–reactivity relationships for target‐oriented design and optimization of the synthetic effort. Our current research on spiderlike oligothiophenes affords deep insight into the subject, and introduces new, easily accessible molecules with attractive functional properties. In particular, a regular series, T′X _Y , of five new multi‐thiophene systems, T′5₃ , T′8₄ , T′11₅ , T′14₆ , and T′17₇ , constituted by five, eight, 11, 14, and 17 thiophene units, respectively, their longest α‐conjugated chain consisting of tri‐, tetra‐, penta‐, hexa‐, and heptathiophene moieties, respectively, has been synthesized and fully characterized from the structural, spectroscopic, and electrochemical point of view. The electronic properties of the monomers and their electropolymerization ability are discussed and rationalized as a function of their molecular structure, particularly in comparison with the series of 5‐(2,2′‐dithiophene)yl‐persubstituted α‐oligothiophenes ( TX _Y ) previously reported by us. These oligothiophenes are easily accessible materials, with promising properties for applications as active layers in multifunctional organic devices including solar cells.     

A Precoordination Complex of 1,2,3‐Trimethyl‐1,3,5‐triazacyclohexane with tert‐Butyllithium as Key Intermediate in Its Methylene Group Deprotonation

α‐Lithiated tertiary methylamines are important building blocks in all fields of chemistry, such as for the synthesis of new ligand or catalyst systems. However, the access to these compounds is still limited and the reaction mechanism, in general, not fully understood. We present herein X‐ray diffraction analyses of organolithium compounds with 1,2,3‐trimethyl‐1,3,5‐triazacyclohexane ( 1 ), such as a precoordination adduct of tert‐butyllithium, [(tBuLi)₃?C₆H₁₅N₃], which represents a potential intermediate of the lithiation of the methylene group of this ligand. By means of molecular structures and computational studies, the regioselectivity of this deprotonation reaction can be understood. Furthermore, the tBuLi adduct gives a hint to an alternative deaggregation process of organolithium compounds.     

Synthesis and Conformation of Fluorinated β‐Peptidic Compounds

Experimental and theoretical data indicate that, for α‐fluoroamides, the F? C? C(O)? N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C? F and C? N(CO) bonds in N‐β‐fluoroethylamides. This study details the synthesis of a series of fluorinated β‐peptides ( 1 – 8 ) designed to use these stereoelectronic effects to control the conformation of β‐peptide bonds. X‐ray crystal structures of these compounds revealed the expected conformations: with fluorine β to a nitrogen adopting a gauche conformation, and fluorine α to a C?O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a β‐peptide bond, with the possibility of directing the secondary structures of β‐peptides.     

N‐Substituted Azacalixphyrins: Synthesis,Properties, and Self‐Assembly

Pre‐ and postintroduction of substituents with respect to the macrocyclization step leads to previously unknown N‐substituted azacalixphyrins. The stepwise synthetic approach has been studied in detail to highlight the key role of the N‐substituents of the precursors and/or intermediates in terms of reactivity. Based on a combined experimental and theoretical investigation, the relationship between the properties of the macrocycles and their degree of substitution is rationalized. Depending on the nature of the N‐substituents, the formation of supramolecular ribbon‐like structures could also be observed, as demonstrated by combined TEM, SEM, AFM, and FTIR experiments.     

Electrochemical Properties of Substituted 2‐Methyl‐1,4‐Naphthoquinones: Redox Behavior Predictions

In the context of the investigation of drug‐induced oxidative stress in parasitic cells, electrochemical properties of a focused library of polysubstituted menadione derivatives were studied by cyclic voltammetry. These values were used, together with compatible measurements from literature (quinones and related compounds), to build and evaluate a predictive structure–redox potential model (quantitative structure–property relationship, QSPR). Able to provide an online evaluation (through Web interface) of the oxidant character of quinones, the model is aimed to help chemists targeting their synthetic efforts towards analogues of desired redox properties