Alkyne Precursors Research Articles

Unveiling the anti-cancer potentiality of phthalimide-based Analogues targeting tubulin polymerization in MCF-7 cancerous Cells: Rational design, chemical Synthesis, and Biological-coupled Computational investigation

The present study deals with an anti-cancer investigation of an array of phthalimide-1,2,3-triazole molecular conjugates with various sulfonamide fragments against human breast MCF-7 and prostate PC3 cancer cell lines. The targeted 1,2,3-triazole derivatives 4a-l and 6a-c were synthesized from focused phthalimide-based alkyne precursors using a facile click synthesis approach and were thoroughly characterized using several spectroscopic techniques (IR, 1H, 13C NMR, and elemental analysis). The hybrid click adducts 4b, 4 h, and 6c displayed cytotoxic potency (IC50 values of 1.49, 1.07, and 0.56 μM, respectively) against MCF-7 cells. On the contrary, none of the synthesized compounds showed apparent cytotoxic efficacy for PC3 cells (IC50 ranging from 9.87- >100 μM). As a part of the mechanism analysis, compound 6c demonstrated a potent inhibitory effect (78.3 % inhibition) of tubulin polymerization in vitro with an IC50 value of 6.53 µM. In addition, biological assays showed that compound 6c could prompt apoptotic cell death and induce G2/M cell cycle arrest in MCF-7 cells. Accordingly, compound 6c can be further developed as an anti-breast cancer agent through apoptosis-induction.

The Role of -OEt Substituents in Molybdenum-Assisted Pentathiepine Formation-Access to Diversely Functionalized Azines.

1,2,3,4,5-pentathiepines (PTEs) are naturally occurring polysulfides of increasing scientific interest based on their identified pharmacological activities. Artificial PTEs with N-heterocyclic backbones are efficiently synthesized via mediation by a molybdenum-oxo-bistetrasulfido complex. A common feature of all precursor alkynes successfully used to date in this reaction is the presence of a -CH(OEt)2 group since the previously postulated mechanism requires the presence of one OEt- as the leaving group, and the second must become a transient ethoxonium moiety. This raised the question of whether there really is a need for two, maybe only one, or possibly even zero ethoxy substituents. This research problem was systematically addressed by respective variations in the precursor-alkyne derivatives and by employing one related allene species. It was found that the total absence of ethoxy substituents prevents the formation of PTEs entirely, while the presence of a single ethoxy group results in the possibility to distinctly functionalize the position on the resulting N-heterocyclic pyrrole five ring in the target compound. This position was previously exclusively occupied by an -OEt for all products of the molybdenum-mediated reaction. The allene was applied with similar success as precursor as with the related alkyne. The now-employable significant change in precursor composition gives access to a whole new PTE subfamily, allowing further modulation of (physico)-chemical properties such as solubility, and provides additional insight into the mechanism of PTE formation; it comprises a merely partial validation of the previous hypothesis. The new alkyne precursors and pentathiepines were characterized by a variety of instrumental analyses (NMR, mass spec, UV-vis) and in six cases (one alkyne precursor, one unexpected side product, and four PTEs) by single-crystal X-ray diffraction. Syntheses, isolation procedures, analytical data, and the impact of the findings on the previously proposed mechanism are described in detail herein.

Rapid polythioether synthesis and thioether network formation using thiol-yne chemistry of electron-deficient alkynes

The preparation of polythioethers has gained importance again after the development of click chemistry reactions. The thiol-X reactions, i.e., thiol-ene reactions based on free radical mechanism facilitated by light or heat, and thiol-Michael and thiol-epoxy reactions, which are the main synthetic pathways for the synthesis of polymers (linear, hyperbranched (HB), and network) with thioether linkages and meet most of the features of click reactions strategy, have currently been revisited. For a while, our group has focused on synthesizing linear, HB, and network polythioethers based on electron-deficient alkyne-containing precursors. We have shown that electron-deficient alkyne-containing monomers and polymers offer a suitable platform for thiol-Michael (i.e., thiol-yne) click reactions to yield linear, HB, and network structures rapidly under ambient conditions. The central structure in these polythioether syntheses is electron-deficient alkyne bonds of acetylenedicarboxylates, which are then reacted with dithiols in chloroform through an organobase 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) at ambient temperatures. Moreover, acetylenedicarboxylates are functionalized using copper-free azide-alkyne cycloaddition reaction followed by reacting with multifunctional allyl and SH derivatives through thiol-ene photopolymerization resulting in polymeric networks with thioether linkages. This feature article highlights our contribution to the synthesis of linear, HB, and network polythioether based on various electron-deficient alkyne precursors.

Concise total synthesis of (-)-berkelic acid via regioselective spiroacetal/pyran formation.

We successfully developed (1) scalable synthesis of the triol segment and (2) regio- and stereoselective synthesis of the tetracyclic skeleton by tandem spiroacetal/pyran formation from a simpler alkyne precursor, resulting in the achievement of concise total synthesis of (-)-berkelic acid.

Transferring Substituents from Alkynes to Furans and Pyrroles through Heteronorbornadienes as Intermediates: Synthesis of β-Substituted Pyrroles/Furans.

The use of 7-oxa/azanorbornadienes as synthetic intermediates for the preparation of 3/4-substituted (β-substituted) furans/pyrroles is presented. The method lies in the inverse electron demand Diels-Alder (iEDDA) cycloaddition between a substituted heteronorbornadiene and an electron-poor tetrazine followed by spontaneous fragmentation of the resulting cycloadduct via two retro-Diels-Alder (rDA) reactions affording a β-substituted furan/pyrrole. The scope of this tandem iEDDA/rDA/rDA reaction was explored in the preparation of 29 heterocycles. A one-pot procedure starting directly from the alkyne precursors of the heteronorbornadiene intermediates is also described.

Synthesis of Guaipyridine Alkaloids Rupestine M and L by Cycloaddition/Cycloreversion of an Intermediate 1,4-Oxazinone.

A new method to prepare 1,4-oxazinone intermediates was developed based on aza-conjugate addition of β-amino alcohols to electron-deficient alkyne precursors. A tandem intramolecular cycloaddition/cycloreversion reaction sequence was evaluated, leading to the synthesis of the guaipyridine alkaloid natural products rupestine M and L. Starting from (-)-citronellal and thus a known configuration of the C5 stereocenter, a revised absolute configuration of natural rupestine L is suggested based on optical rotation.

Substituent effects on helical structures and chiroptical properties of fused anthracenes with bulky phenyl groups

In order to investigate substituent effects on the structures and properties of the helically fused anthracene system, various bulky phenyl groups were introduced at the sterically crowded positions. Three derivatives with mesityl (Mes), 2,4,6-triisopropylphenyl (Tip), and pentafluorophenyl (C6F5) groups were synthesized by Pt-catalyzed cycloisomerization of the corresponding alkyne precursors. The X-ray crystallographic analyses revealed that the helical structures were significantly expanded along the helical axis in the order of steric size of the substituents, C6F5 < Mes < Tip. The structural features are discussed on the basis of intramolecular noncovalent interactions such as CH···π and π···π interactions. Enantiomers of the Tip and C6F5 derivatives, resolved by chiral HPLC, showed very intense bands in circular dichroism (CD) and circularly polarized luminescence (CPL) bands. In particular, the luminescence dissymmetry factor |glum| values of these enantiomers (ca. 0.012) were large for simple organic molecules. Regardless of the large structural changes, the substituent effects on the optical and chiroptical properties were rather small. This structure–property relationship is discussed with the aid of DFT calculations.

Practical syntheses of DOTAGA-DBCO and DFO-DBCO, strained alkyne pre-cursors to radioimmunoconjugates for targeted alpha therapy

We describe practical methods to prepare DOTAGA-DBCO and DFO-DBCO from commercially available starting materials. DOTAGA-DBCO is available in five steps from cyclen with a 33 % overall yield at gram scale. Our synthesis of DFO-DBCO also proceeds in five steps from commercially available starting materials. These bifunctional molecules possess chelating functionality for the binding of medically important radiometals and a strained alkyne suitable for Huisgen cyclization with an azide. These syntheses represent an important step toward improved radioimmunoconjugates for imaging and therapeutic applications.

7,12‐Dihydrobenzo[de]indolo[3,2‐b]quinoline: Unique Reactivity and Redox Interconversion

AbstractAcetyl‐substituted 7,12‐dihydrobenzo[de]indolo[3,2‐b]quinoline was developed as a N‐substituted polycyclic heteroaromatic molecule via Pd‐catalyzed cyclo‐isomerization of an alkyne precursor, followed by intramolecular Goldberg amination. This compound showed unique reactivity, notably, base‐mediated deacylative oxygenation and photo‐Fries rearrangement. A series of products exhibited characteristic electronic properties based on the redox state of the corresponding nitrogen atoms. The photo‐rearranged product, which possesses a 1,2‐diaminoethene substructure, akin to the redox functionality of the natural flavin adenine dinucleotide, underwent reversible interconversion with the corresponding oxidized form. The efficient stabilization of the highly electron‐rich 7,12‐dihydrobenzo[de]indolo[3,2‐b]quinoline skeleton was ascribed to the electron‐withdrawing effect, intramolecular hydrogen bonding of the acetyl group, and local aromatic stabilization in the indole moiety.

Antimicrobial and in-silico evaluation of novel chalcone and amide-linked 1,4-disubstituted 1,2,3 triazoles

Design, synthesis, spectral characterization and antimicrobial evaluation of a series of twelve chalcone-containing amide linked 1,4-disubstituted 1,2,3-triazole hybrids and their alkyne precursors are reported. The triazole hybrids displayed much lower MIC values (0.0285–0.01182 μmol/mL) compared to their chalcone-linked terminal alkyne precursors (0.8552–0.16270 μmol/mL) against tested bacterial and fungal strains, thereby, showing synergistic antimicrobial effect by conjugating three pharmacophoric units, of chalcone, amide and 1,2,3-triazole. Docking and molecular dynamics (MD) studies further supported the antimicrobial potential of these hybrids through various binding interactions and stability of the protein-ligand complex. The drug likeness is also predicted through in silico ADME and toxicity studies.

Cobalt‐Mediated Decarboxylative/Desilylative C−H Activation/Annulation Reaction: An Efficient Approach to Natural Alkaloids and New Structural Analogues

AbstractA Co(II)‐mediated decarboxylative/desilylative C−H activation/annulation reaction for the efficient synthesis of 3‐arylisoquinolines has been developed. Using alkynyl carboxylic acid and alkynyl silane as terminal alkyne precursors, providing straightforward routes for the synthesis of natural alkaloids and novel structural analogues.

Practical Syntheses of DOTAGA-DBCO and DFO-DBCO, Strained Alkyne Pre-Cursors to Radioimmunoconjugates for Targeted Alpha Therapy

Practical Syntheses of DOTAGA-DBCO and DFO-DBCO, Strained Alkyne Pre-Cursors to Radioimmunoconjugates for Targeted Alpha Therapy

Urea-thiazole/benzothiazole hybrids with a triazole linker: synthesis, antimicrobial potential, pharmacokinetic profile and in silico mechanistic studies.

Some urea-thiazole/benzothiazole hybrids with a triazole linker were synthesized via Cu(I)-catalysed click reaction. After successfully analysed by various spectral techniques including FTIR, NMR and HRMS, antimicrobial screening of the synthesized hybrids along with their precursors was carried out against two Gram (+) bacteria (Staphylococcus aureus and Bacillus endophyticus), two Gram (-) bacteria (Escherichia coli and Pseudomonas fluorescens) and two fungi (Candida albicans and Rhizopus oryzae). All the synthesized compounds (4a-4l) displayed better biological response than the standard fluconazole against both of the tested fungi. Compounds 4h and 4j were found to be the most active compounds against R. oryzae and C. albicans, respectively. Molecular docking of hybrid 4j and its alkyne precursor 1b in the active site of C. albicans target sterol 14-α demethylase was also performed and was also supported by molecular dynamics studies. In silico ADME prediction of synthesized urea-thiazole/benzothiazole hybrids with a triazole linker and their alkyne precursors was also predicted.

5,11-Diazadibenzo[hi,qr]tetracene: Synthesis, Properties, and Reactivity toward Nucleophilic Reagents.

5,11-Diazadibenzo[hi,qr]tetracene was synthesized as a new nitrogen-substituted polycyclic heteroaromatic compound by Pd-catalyzed cycloisomerization of an alkyne precursor followed by oxidative cyclization with bis(trifluoroacetoxy)iodobenzene. The substitution of imine-type nitrogen atoms significantly enhanced its electron-accepting character and facilitated the direct nucleophilic addition of arylamines under strongly basic conditions to afford the desired amino-substituted products. The introduction of amino groups induced a remarkable red-shift in their absorption spectra; the tetrasubstituted product exhibited intense near-infrared absorbing property. Furthermore, the π-electronic system, which includes a redox-active 1,4-diazabutadiene moiety, underwent reversible interconversion to its corresponding reduced form upon reduction with NaBH4 and aerobic oxidation.

Oxygen-functionalized alkyne precursors in carbon nanotube growth

Functionalization of carbon nanotubes (CNTs) with heteroatoms enables covalent attachment, opening up a world of potential material structures. However, common functionalization techniques are hazardous and lack precision. Here, we evaluate an in situ functionalization technique using oxygen-containing alkyne precursors. CNTs were successfully derived from propargyl alcohol and propiolic acid, growing at a rate of 67 ± 7 and 19 ± 3 µm min–1, respectively. While there was no substantial increase in the oxygen content of resultant CNT structures (all less than 1% O), Fourier transform infrared spectroscopy revealed subtle incorporations of carboxyl and hydroxyl functionality. An analysis of reactor effluent showed that both oxygen-containing species shed oxygen groups, where propargyl alcohol yielded a reactive atmosphere high in methylacetylene, and propiolic acid thermally degraded to acetylene and CO2, potentially explaining the enhanced catalyst lifetimes (approximately 75 min). These results support the universality of alkyne-promoting chemistries and delineate the limits of stable, oxygen-bearing alkynes to support point-directed functionalization schemes. Evidence that carbon nanotubes (CNTs) can form from intact C2-C4 subunits, primarily as alkynes, in a polymerization-like growth mechanism opened the doors for functionalized alkynes to direct the placement of heteroatoms in CNT lattice structures. If possible, this would alleviate the need for ex situ functionalization, the costs and environmental burdens associated with high concentration acid processing, and eliminate the random nature currently limiting CNT functionalization. Here, we demonstrate that oxygen-functionalized alkynes dominantly shed their oxygen-containing groups prior to or simultaneously with incorporation in the CNT, resulting in limited incorporation of oxygen groups into the CNT structure. As a whole, the work sheds light on fundamental reaction processes that give rise to carbonaceous nanostructures through polymerization and defines the limits of current in situ functionalization strategies.

Design, synthesis, antimicrobial evaluation and in silico studies of symmetrical bis (urea-1,2,3-triazole) hybrids

In search of 1,2,3-triazole-based antimicrobials, some symmetrical bis(urea-1,2,3-triazole) hybrids were synthesized via clicked Huisgen cycloaddition. The structural characterization was done by different physical and spectral techniques like NMR, FTIR and HRMS. In vitro antimicrobial evaluation of all the synthesized compounds was performed against three bacterial strains (Staphylococcus epidermidis, Escherichia coli and Bacillus subtilis) and two fungal strains (Aspergillus niger and Candida albicans). All the synthesized urea-linked bis(1,2,3-triazole) hybrids (4a–4o) were found to exhibit higher potency than their alkyne precursors (3a–3c). Also, all the synthesized hybrids elicited better antifungal activity than the reference drug Fluconazole against both the fungal strains. Compound 4e and 4o were found to be more potent toward C. albicans with lowest MIC values 0.0112 µmol/mL and 0.0105 µmol/mL, respectively. The docking studies of compounds 4e and 4o and their respective alkynes 3b and 3c were carried out in the active site of sterol 14-α-demethylase of C. albicans.

Synthesis of 2-Azapyrenes and Their Photophysical and Electrochemical Properties.

A series of 5,7,9-substituted 2-azapyrenes were synthesized for the first time. The synthesis relies on Brønsted acid promoted benzannulation of alkyne precursors prepared by palladium-catalyzed cross-coupling reactions. The synthetic strategy is efficient and the scope covers a variety of functional groups. The electrochemical behavior and photophysical properties of the products were investigated by UV-vis and fluorescence spectroscopy, cyclic voltammetry, and DFT calculations.

Facile Synthesis of Aryl-Substituted Cycloarenes via Bismuth(III) Triflate-Catalyzed Cyclization of Vinyl Ethers

Cycloarenes are an essential class of polycyclic aromatic hydrocarbons with unique electronic structure, but their synthesis is very challenging. Herein, we report a facile synthetic strategy prima...

Efficient and multi-function compatible click-reaction of organosilanes

The synthesis of organotriethoxysilanes by click chemistry was studied using the recyclable, multidentate catalyst [Cu(C18tren)]Br. For the evaluation, alkyne precursors containing some of the more common organic functions were reacted with a triethoxy silyl group containing azide. The procedure allowed the isolation of the desired products in high yields and high purity. Especially remarkable is the facility of the catalyst removal by simple filtration and evaporation. The catalyst is concluded to be ideal for the synthesis of moisture sensitive organotriethoxysilanes.

Synthesis and validation of [18F]mBPET-1, a fluorine-18 labelled mTOR inhibitor derivative based on a benzofuran backbone

BackgroundTargeted therapy of HER2 positive breast cancer has led to clinical success in some cases with primary and secondary resistance being major obstacles. Due to the substantial involvement of mTOR kinase in cell growth and proliferation pathways it is now targeted in combination treatments to counteract HER2 targeted therapy resistance. However, the selection of receptive patient populations for a specific drug combination is crucial. This work aims to develop a molecular probe capable of identifying patients with tumour populations which are receptive to RAD001 combination therapy. Based on the structure of a mTOR inhibitor specific for mTORC1, we designed, synthesised and characterised a novel benzofuran based molecular probe which suits late stage fluorination via Click chemistry.ResultsSynthesis of the alkyne precursor 5 proceeded in 27.5% yield over 7 linear steps. Click derivatisation gave the non-radioactive standard in 25% yield. Radiosynthesis of [18F]1-((1-(2-Fluoroethyl)-1H-1,2,3-triazol-4-yl) methyl)-4-((5-methoxy-2-phenylbenzofuran-4-yl) methyl) piperazine ([18F]mBPET-1) proceeded over two steps which were automated on an iPhase FlexLab synthesis module. In the first step, 2-[18F]fluoroethylazide ([18F]6) was produced, purified by automated distillation in 60% non-decay-corrected yield and subjected to Click conditions with 5. Semi-preparative RP-HPLC purification and reformulation gave [18F]mBPET-1 in 40% ± 5% (n = 6) overall RCY with a process time of 90 min. Radiochemical purity was ≥99% at end of synthesis (EOS) and ≥ 98% after 4 h at room temperature. Molar activities ranged from typically 24.8 GBq/μmol (EOS) to a maximum of 78.6 GBq/μmol (EOS). Lipophilicity of [18F]mBPET-1 was determined at pH 7.4 (logD7.4 = 0.89). [18F]mBPET-1 showed high metabolic stability when incubated with mouse S9 liver fractions which resulted in a 0.8% drop in radiochemical purity after 3 h. Cell uptake assays showed 1.3–1.9-fold increased uptake of the [18F]mBPET-1 in RAD001 sensitive compared to insensitive cells across a panel of 4 breast cancer cell lines.ConclusionMolecular targeting of mTOR with [18F]mBPET-1 distinguishes mTOR inhibitor sensitive and insensitive cell lines. Future studies will explore the ability of [18F]mBPET-1 to predict response to mTOR inhibitor treatment in in vivo models.