Dipolarophiles Research Articles

Modifications of geldanamycin via CuAAC altering affinity to chaperone protein Hsp90 and cytotoxicity

Functionalization of alkyne (1) and azide (2) derivatives of geldanamycin (GDM) via dipolar cycloaddition CuAAC yielded 35 new congeners (3–37) with C(17)-triazole arms bearing caps of different nature (basic vs. acidic, hydrophilic vs. hydrophobic). Confrontation of biological data (anticancer activity vs. toxicity in normal cells) with lipophilicity (clogP), dissociation constants (Kd) of complexes with Hsp90 and binding modes to Hsp90 revealed SAR in specific subgroups of GDM derivatives. The most potent GDM congeners 14–16, bearing C(17)-triazole-benzyl-halogen arms exhibited the most optimal clogP values of 2.7–3.1 at favourable binding to Hsp90 (KdHsp90 at μM level). The anticancer activity of 14–16 (IC50 = 0.23–0.41 μM) is higher than those of GDM (IC50 = 0.58–0.64 μM) and actinomycin D (ActD, IC50 = 0.62–0.71 μM) in SKBR-3, SKOV-3 and PC-3 cell lines, with a comparable cytotoxicity in healthy cells. The relationship between structure and attractive anticancer potency (IC50 = 0.53–0.74 μM) is also observed for congeners with C(17)-triazole-saccharide or C(17)-triazole-unsaturated arms. In the former, the absolute configuration at C(4) (ᴅ-glucose vs. ᴅ-galactose) whereas in the latter the length of the unsaturated arm influences the cytotoxic effects due to different binding strength (Kd, ΔE) and modes with Hsp90. Among all triazole congeners of GDM that are biologically attractive and exhibit lower toxicity in normal cells than GDM and ActD, the derivative 22, bearing the C(17)-triazole-cinnamyl arm, shows the lowest Kd (Hsp90), optimal clogP = 2.82, the best pro-apoptotic properties in SKBR-3 and SKOV-3 and the best selectivity indices (SI). For the most potent GDM derivatives with C(17)-triazole arm, the docking studies have suggested the importance of the intermolecular stabilization between the arm and the D57 or Y61 of Hsp90.

Synthesis of Dense 1,2,3-Triazole Oligomers Consisting Preferentially of 1,5-Disubstituted Units via Ruthenium(II)-Catalyzed Azide-Alkyne Cycloaddition.

Ruthenium(II)-catalyzed azide-alkyne cycloaddition (RuAAC) polymerization of t-butyl 4-azido-5-hexynoate (tBuAH), i.e., a heterobifunctional monomer carrying azide and alkyne moieties, was investigated in this study. RuAAC of the monofunctional precursors of tBuAH yielded a dimer possessing a 1,5-disubstituted 1,2,3-triazole moiety. 1H NMR data showed that the dimer was a mixture of diastereomers. Polymerization of tBuAH using ruthenium(II) (Ru(II)) catalysts produced oligomers of Mw ≈ (2.7-3.6) × 103 consisting of 1,5-disubstituted 1,2,3-triazole units (1,5-units) as well as 1,4-disubstituted 1,2,3-triazole units (1,4-units). The fractions of 1,5-unit (f1,5) were roughly estimated to be ca. 0.8 by comparison of signals of the methine and triazole protons in 1H NMR spectra, indicating that RuAAC proceeded preferentially and thermal Huisgen cycloaddition (HC) somehow took place during the polymerization. The oligomer samples obtained were also characterized by solubility test, size exclusion chromatography (SEC), ultraviolet-visible (UV-Vis) absorption spectroscopy, and thermogravimetric analysis (TGA). The UV-Vis and TGA data indicated that the oligomer samples contained a substantial amount of Ru(II) catalysts. To the best of our knowledge, this is the first report on dense 1,2,3-triazole oligomers consisting of 1,5-units linked via a carbon atom.

Benzoquinoline Derivatives: An Attractive Approach to Newly Small Molecules with Anticancer Activity.

This study presents the synthesis, structural characterization, and in vitro evaluation of anticancer activity of some newly benzo[f]quinoline derivatives. The synthesis is facile and efficient, involving two steps: quaternization of nitrogen heterocycle followed by a [3+2] dipolar cycloaddition reaction. The synthesized compounds were characterized by FTIR, NMR, and X-ray diffraction on monocrystal in the case of compounds 6c and 7c. An in vitro single-dose anticancer assay of eighteen benzo[f]quinoline compounds, quaternary salts, and cycloadducts, was performed. The results showed that the most active compounds were quaternary salts 3d and 3f with aromatic R substituents. Quaternary salt 3d revealed non-selective activity against all types of cancer cells, while salt 3f exhibited a highly selective activity against leukemia cells. Compound 3d also presented remarkable cytotoxic efficiency against four distinct types of cancer cells-namely, non-small cell lung cancer HOP-92, melanoma LOX IMVI, melanoma SK-MEL-5, and breast cancer MDA-MB-468. Compound 3f was selected for five-dose screening. The study also includes SAR correlations.

Synthesis of a New Poly(ε-caprolactone)-g-Chitosan Amphiphilic Graft Copolymer with a "Reverse" Structure.

Hydrophilic chitosan (CHT) and hydrophobic polyε-caprolactone (PCL) are well-known biocompatible and biodegradable polymers that have many applications in the biomedical and pharmaceutical fields. But the mixtures of these two compounds are considered incompatible, which makes them not very interesting. To avoid this problem and to further extend the properties of these homopolymers, the synthesis of a new graft copolymer, the fully biodegradable amphiphilic poly(ε-caprolactone-g-chitosan) (PCL-g-CHT) is described, with an unusual "reverse" structure formed by a PCL backbone with CHT grafts, unlike the "classic" CHT-g-PCL structure with a CHT main chain and PCL grafts. This copolymer is prepared via a copper-catalyzed 1,3-dipolar Huisgen cycloaddition between propargylated PCL (PCL-yne) and a new azido-chitosan (CHT-N3 ). In order to obtain an amphiphilic copolymer regardless of the pH, chitosan oligomers, soluble at any pH, are prepared and used. The amphiphilic PCL-g-CHT copolymer spontaneously self-assembles in water into nanomicelles that may incorporate hydrophobic drugs to give novel drug delivery systems.

Synthesis of Multifunctional Protein-Polymer Conjugates via Oxygen-tolerant, Aqueous Copper-Mediated Polymerization, and Bioorthogonal Click Chemistry.

Oxygen-tolerant, aqueous copper-mediated polymerization approaches are combined with click chemistry in either a sequential or a simultaneous manner, to enable the synthesis of multifunctional protein-polymer conjugates. Propargyl acrylate (PgA) and propargyl methacrylate (PgMA) grafting from a bovine serum albumin (BSA) macroinitiator is thoroughly optimized to synthesize chemically addressable BSA-poly(propargyl acrylate) and BSA-poly(propargyl methacrylate) respectively. The produced multifunctional bioconjugates bear pendant terminal 1-alkynes which can be readily post-functionalized via both [3+2] Huisgen cycloaddition and thiol-yne click chemistry under mild reaction conditions. Simultaneous oxygen-tolerant, aqueous copper-catalyzed polymerization, and click chemistry mediate the in situ multiple chemical tailoring of biomacromolecules in excellent yields.

Machine Learning-Guided Computational Screening of New Candidate Reactions with High Bioorthogonal Click Potential.

Bioorthogonal click chemistry has become an indispensable part of the biochemist's toolbox. Despite the wide variety of applications that have been developed in recent years, only a limited number of bioorthogonal click reactions have been discovered so far, most of them based on (substituted) azides. In this work, we present a computational workflow to discover new candidate reactions with promising kinetic and thermodynamic properties for bioorthogonal click applications. Sampling only around 0.05 % of an overall search space of over 10,000,000 dipolar cycloadditions, we develop a machine learning model able to predict DFT-computed activation and reaction energies within ∼2-3 kcal/mol across the entire space. Applying this model to screen the full search space through iterative rounds of learning, we identify a broad pool of candidate reactions with rich structural diversity, which can be used as a starting point or source of inspiration for future experimental development of both azide-based and non-azide-based bioorthogonal click reactions.

Processes of 1,3-Dipolar cycloaddition in nucleoside, nucleotide and bio conjugation and its importance in medicinal chemistry

In the 1,3-dipolar cycloaddition, a 1,3-dipole and a dipolarophile interact chemically to produce a five-membered ring. The Huisgen cycloaddition occurs when an organic azide and an alkyne unite to form a 1,3-dipolar cycloaddition that results in a 1,2,3-triazole. 1,3-dipolar cycloaddition is an essential step in the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives. Some of the cycloadducts produced by these reactions were converted into enantiopure precursors known to exist in some biologically active chemicals as well as an active stereoisomer of a pine sawfly sex pheromone. The synthesis of several new enantiopure organocatalysts that were shown to be helpful in some The synthetic utility of these 1,3-dipolar cycloaddition processes with nitrones and a,b-unsaturated aldehydes was further demonstrated. There are times when these reactions have modest to moderate diastereofacial selectivity. the choose actual and nonracemic have improved. Compound collections are created in chemical biology research using the BIOS concept, which draws its inspiration from natural product scaffolds. In BIOS, the primary criterion utilized to develop hypotheses for the design and synthesis of targeted chemical libraries is biological relevance. Because they outline the chemical domains that nature has explored, the underlying scaffolds of natural product classes in particular serve as an inspiration for BIOS because they can be thought of as "trivet can often be achieved if both the azomethine ylide and the dipolarophile are chi privileged

Synthesis of Triazolo[c]coumarins and Differences in the Fluorescence Properties of Their Isomers

AbstractDespite the simple structures of 3,4‐fused tricyclo coumarins, their fluorescence properties have not been studied extensively. We have synthesized triazolo[c]coumarins using Huisgen cycloaddition and investigated their fluorescence properties. The Huisgen cycloaddition was found to proceed in excellent yields when subjected to heating under solvent‐free conditions. As is generally known, fluorescence is enhanced with an increase in the electron‐donating group at the 7‐position. The 7‐NEt2‐triazolo[c]coumarin derivatives showed useful fluorescence, and their relative fluorescence quantum yields in aprotic polar organic solvents were high. It revealed that fluorescence properties of triazolo[c]coumarins depended on the regio isomer. The electron distribution was hardly extended to alkyl side chain on triazole from the molecular orbital calculation by density functional theory (DFT) and time‐dependent DFT (TD‐DFT). This result suggests that the trend of fluorescence properties is similar to the present result even when various substituents are introduced on triazole.

Ultrasound-Assisted 1,3-Dipolar Cycloadditions Reaction Utilizing Ni-Mg-Fe LDH: A Green and Sustainable Perspective

Ultrasound-assisted synthesis of novel pyrazoles using Ni-Mg-Fe LDH as a catalyst in cyclopentyl methyl ether (CPME) is introduced. Different LDHs were tested as a catalyst for the synthesis of pyrazoles via a 1,3-dipolar cycloaddition reaction. Among them, Ni-Mg-Fe LDH was the superior catalyst for this reaction. This protocol offered high yields, a short reaction time, and a green solvent, and with the reuse of this catalyst six times with the same activity, it could be regarded as an ecofriendly, greener process. The NiMgFe LDH catalyst with the smallest particle size (29 nm) and largest surface area showed its superior efficacy for the 1,3 dipolar cycloaddition rection and can be successfully used in up to six catalytic cycles with little loss of catalytic activity. A plausible mechanism for this reaction over the Ni-Mg-Fe LDH is proposed.

One-Bond-Nucleophilicity and -Electrophilicity Parameters: An Efficient Ordering System for 1,3-Dipolar Cycloadditions.

Diazoalkanes are ambiphilic 1,3-dipoles that undergo fast Huisgen cycloadditions with both electron-rich and electron-poor dipolarophiles but react slowly with alkenes of low polarity. Frontier molecular orbital (FMO) theory considering the 3-center-4-electron π-system of the propargyl fragment of diazoalkanes is commonly applied to rationalize these reactivity trends. However, we recently found that a change in the mechanism from cycloadditions to azo couplings takes place due to the existence of a previously overlooked lower-lying unoccupied molecular orbital. We now propose an alternative approach to analyze 1,3-dipolar cycloaddition reactions, which relies on the linear free energy relationship lg k2(20 °C) = sN(N + E) (eq 1) with two solvent-dependent parameters (N, sN) to characterize nucleophiles and one parameter (E) for electrophiles. Rate constants for the cycloadditions of diazoalkanes with dipolarophiles were measured and compared with those calculated for the formation of zwitterions by eq 1. The difference between experimental and predicted Gibbs energies of activation is interpreted as the energy of concert, i.e., the stabilization of the transition states by the concerted formation of two new bonds. By linking the plot of lg k2 vs N for nucleophilic dipolarophiles with that of lg k2 vs E for electrophilic dipolarophiles, one obtains V-shaped plots which provide absolute rate constants for the stepwise reactions on the borderlines. These plots furthermore predict relative reactivities of dipolarophiles in concerted, highly asynchronous cycloadditions more precisely than the classical correlations of rate constants with FMO energies or ionization potentials. DFT calculations using the SMD solvent model confirm these interpretations.

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines.

The involvement of 1,3-dipolar cycloaddition (1,3-DP), double bond migration, metathesis, and nitrile oxide (including in situ-generated nitrile oxide) as dipoles, together with the C=C bond containing dipolarophiles, in the syntheses of 2-isoxazolines is presented. Methods for synthesizing isoxazolines (other than 1,3-DP cycloaddition) were also presented briefly. Various methods of nitrile oxide preparation, especially in situ-generated procedures, are presented. Special attention was paid to the application of various combinations of 1,3-DP cycloaddition with double bond migration (DBM) and with alkene metathesis (AM) in the syntheses of trisubstituted isoxazolines. Allyl compounds of the type QCH2CH=CH2 (Q = ArO, ArS, Ar, and others) play the role of dipolarophile precursors in the combinations of DPC mentioned, DBM and AM. Mechanistic aspects of cycloadditions, i.e., concerted or stepwise reaction mechanism and their regio- and stereoselectivity are also discussed from experimental and theoretical points of view. Side reactions accompanying cycloaddition, especially nitrile oxide dimerization, are considered. 2-Isoxazoline applications in organic synthesis and their biological activity, broad utility in medicine, agriculture, and other fields were also raised. Some remaining challenges in the field of 1,3-DP cycloaddition in the syntheses of isoxazolines are finally discussed.

Reaction profiles for quantum chemistry-computed [3 + 2] cycloaddition reactions

Bio-orthogonal click chemistry based on [3 + 2] dipolar cycloadditions has had a profound impact on the field of biochemistry and significant effort has been devoted to identify promising new candidate reactions for this purpose. To gauge whether a prospective reaction could be a suitable bio-orthogonal click reaction, information about both on- and off-target activation and reaction energies is highly valuable. Here, we use an automated workflow, based on the autodE program, to compute over 5000 reaction profiles for [3 + 2] cycloadditions involving both synthetic dipolarophiles and a set of biologically-inspired structural motifs. Based on a succinct benchmarking study, the B3LYP-D3(BJ)/def2-TZVP//B3LYP-D3(BJ)/def2-SVP level of theory was selected for the DFT calculations, and standard conditions and an (aqueous) SMD model were imposed to mimic physiological conditions. We believe that this data, as well as the presented workflow for high-throughput reaction profile computation, will be useful to screen for new bio-orthogonal reactions, as well as for the development of novel machine learning models for the prediction of chemical reactivity more broadly.

Electrochemical Synthesis of Pyrazolines and Pyrazoles via [3+2] Dipolar Cycloaddition.

Pyrazolines and pyrazoles are common and important motifs of pharmaceutical agents and agrochemicals. Herein, the first electrochemical approach for their direct synthesis from easily accessible hydrazones and dipolarophiles up to decagram scale is presented. The application of a biphasic system (aqueous/organic) even allows for the conversion of highly sensitive alkenes, wherein inexpensive sodium iodide is employed in a dual role as supporting electrolyte and mediator. In addition, mechanistic insight into the reaction is given by the isolation of key step intermediates. The relevance of the presented reaction is underlined by the synthesis of commercial herbicide safener mefenpyr-diethyl in good yields.

Elektrochemische Synthese von Pyrazolinen und Pyrazolen via [3+2] dipolarer Cycloaddition

AbstractPyrazoline und Pyrazole sind häufige und wichtige Bestandteile vieler Pharmaka und Agrochemikalien. Diese Arbeit zeigt den ersten elektrochemischen Ansatz zu deren direkter Synthese aus leicht zugänglichen Hydrazonen und Dipolarophilen bis in den Dekagrammbereich. Die Anwendung eines zweiphasigen Systems (wässrig/organisch) ermöglicht auch die Umsetzung hochempfindlicher Alkene, wobei kostengünstiges Natriumiodid gleichzeitig als Leitsalz und Mediator eingesetzt wird. Darüber hinaus wurden entscheidende Zwischenstufen isoliert, die einen Einblick in den Reaktionsmechanismus geben. Die Relevanz der vorgestellten Reaktion wird durch die Synthese des kommerziellen Herbizidsafeners Mefenpyr‐Diethyl in guter Ausbeute unterstrichen.

3+2] Dipolar Cycloaddition of a Stabilized Azomethine Ylide and an Electron-Deficient Dipolarophile: Revision of Regioselectivity.

The regioselectivity of a [3+2] dipolar cycloaddition reaction of a stabilized azomethine ylide with an electron-deficient dipolarophile was found to be counter to a report published in this journal.

Ru(II)-Catalyzed Synthesis of Bridged Tetracycles via C–H Allylation and [3+2] Dipolar Cycloaddition

Key words azomethine imines - C–H allylation - ruthenium(II) catalysis - [3+2] cycloaddition - bridged tetracycles

Novel Highly Efficient Green and Reusable Cu(II)/Chitosan-Based Catalysts for the Sonogashira, Buchwald, Aldol, and Dipolar Cycloaddition Reactions

In this study, new Cu(II)/chitosan-based systems were designed via (i) the treatment of chitosan with sodium sulfate (1a) or sodium acetate (1b); (ii) the coating of 1a or 2a with a sodium hyaluronate layer (2a and 2b, correspondingly); (iii) the treatment of a cholesterol–chitosan conjugate with sodium sulfate (3a) or sodium acetate (3b); and (iv) the succination of 1a and 1b to afford 4a and 4b or the succination of 2a and 2b to yield 5a and 5b. The catalytic properties of the elaborated systems in various organic transformations were evaluated. The use of copper sulfate as the source of Cu2+ ions results in the formation of nanoparticles, while the use of copper acetate leads to the generation of conventional coarse-grained powder. Cholesterol-containing systems have proven to be highly efficient catalysts for the cross-coupling reactions of different types (e.g., Sonogashira, Buchwald–Hartwig, and Chan–Lam types); succinated systems coated with a layer of hyaluronic acid are promising catalysts for the aldol reaction; systems containing inorganic copper(II) salt nanoparticles are capable of catalyzing the nitrile-oxide-to-nitrile 1,3-dipolar cycloaddition. The elaborated catalytic systems efficiently catalyze the aforementioned reactions in the greenest solvent available, i.e., water, and the processes could be conducted in air. The studied catalytic reactions proceed selectively, and the isolation of the product does not require column chromatography. The product is separated from the catalyst by simple filtration or centrifugation.

1,3 Dipolar Cycloaddition of Münchnones: Factors behind the Regioselectivity

The 1,3 dipolar cycloaddition reactions of münchnones and alkenes provide an expedite synthetic way to substituted pyrroles, an exceedingly important structural motif in the pharmaceutical and material science fields of research. The factors governing their regioselectivity rationalization are not well understood. Using several approaches, we investigate a set of 14 reactions (featuring two münchnones, 12 different alkenes, and two alkynes). The Natural Bond Theory and the Non-Covalent Interaction Index analyses of the noncovalent interaction energies fail to predict the experimental major regioisomer. Employing global cDFT descriptors or local ones such as the Fukui function and dual descriptor yields similarly inaccurate predictions. Only the local softness pairing, within Pearson's Hard and Soft Acids and Bases principle, constitutes a reliable predictor for the major reaction product. By taking into account an estimator for the steric effects, the correct regioisomer is predicted. Steric effects play a major role in driving the regioselectivity, as was corroborated by energy decomposition analysis of the transition states.

Design and synthesis of sinomenine D-ring tetrazole-isoxazole and tetrazole-triazole derivatives via 1, 3-dipolar cycloaddition reaction

The synthesis of D-ring tetrazole-isoxazole and tetrazole-triazole sinomenine derivatives at N–CH3via 1, 3-dipolar cycloaddition reactions were accomplished and a total of 34 novel sinomenine N-heterocyclic derivatives were obtained in 69–93% yields. The N–CH3 of sinomenine was first transformed into N–CN structure under the action of cyanogen bromide, and then N–CN reacted with sodium azide to give the N-tetrazole derivative. The N–H bond on tetrazole was replaced by different isoxazole bromides to get tetrazole-isoxazole sinomenine derivatives directly. The N–H bond on tetrazole was replaced by propargyl bromide to give sinomenine derivative with propargyl group, the terminal alkyne then reacted with the 1, 3-dipole in situ to obtain D-ring tetrazole-triazole sinomenine derivatives. All the synthesized derivatives are characterized by FT-IR, HRMS, 1H NMR, and 13C NMR spectroscopy.

Synthesis of novel menthol derivatives containing 1,2,3-triazole group and their in vitro antibacterial activities

New N-substituted ?-aminonitrile derivatives from menthol were synthesized by consecutive succinic ester formation, propargylation, 1,3-dipolar Huisgen cycloaddition and Strecker reaction. The structures of the synthesized compounds were confirmed by diverse spectroscopic techniques including 1HNMR, 13C-NMR, ESI-MS and IR. The novel synthesized compounds were evaluated for their in vitro antibacterial activities against Staphylococcus aureus as Gram-positive and Escherichia coli as Gram-negative bacteria. These compounds demonstrated a strong inhibitory effect against S. aureus with the minimum inhibitory concentration (MIC) values ranged from 32?128 ?g mL-1. Derivatives 6a2, 6b1, 6b4 and 6b5 with a MIC value of 32 ?g mL-1 exhibited the best inhibitory effects.