Green approach to the synthesis of α-aminophosphonate-tetrahydroisoquinoline hybrids and their anti-cholinesterase activity.

A series of 19 novel α-aminophosphonate-tetrahydroisoquinoline hybrids were synthesized through a cross dehydrogenative coupling reaction between N-aryl-tetrahydroisoquinolines and dialkylphosphites, using tert-butyl hydroperoxide as oxidazing agent. This simple procedure provided products with high atom economy and moderate to high yields. In vitro cholinesterase inhibitory activity of these compounds was evaluated. All the synthesized compounds showed good to excellent selective inhibition against butyrylcholinesterase. Compound 3bc was found to be the most active derivative with an IC50 of 9 nM. Molecular modelling studies suggested that the inhibitor is located in the peripheral anionic site (PAS) of the enzyme and interacts with some residue of the catalytic anionic site. Kinetic studies revealed that 3bc acts as a non-competitive inhibitor. Predicted ADME showed good pharmacokinetics and drug-likeness properties for most hybrids. Each newly synthesized compound was characterized by IR, 1H NMR, 13C NMR, 31P NMR spectral studies and also HRMS. The results of this study suggest that α-aminophosphonate-tetrahydroisoquinoline hybrids can be promising lead compounds in the discovery of new and improved drugs for the treatment of Alzheimer's disease and related neurodegenerative disorders.

Oxidative α-Functionalization of 1,2,3,4-Tetrahydroisoquinolines Catalyzed by a Magnetically Recoverable Copper Nanocatalyst. Application in the Aza-Henry Reaction and the Synthesis of 3,4-Dihydroisoquinolones.

The oxidative α-functionalization of 2-aryl-1,2,3,4-tetrahydroisoquinolines (THIQs) promoted by a versatile heterogeneous nanocatalyst consisting of copper nanoparticles immobilized on silica-coated maghemite (CuNPs/MagSilica) has been accomplished. The methodology was successfully applied in the cross-dehydrogenative coupling (CDC) reaction of N-aryl THIQs and other tertiary amines with nitromethane as a pro-nucleophile (aza-Henry reaction) and the α-oxidation of THIQs with O2 as a green oxidant. Phosphite, alkyne, or indole derivatives were also shown to be suitable candidates for their use as pro-nucleophiles in the CDC reaction with THIQs. The catalyst, with very low copper loading (0.4-1.0 mol % Cu), could be easily recovered by means of an external magnet and reused in four cycles without significant loss of activity.

A new and efficient methodology for olefin epoxidation catalyzed by supported cobalt nanoparticles.

A new heterogeneous catalytic system consisting of cobalt nanoparticles (CoNPs) supported on MgO and tert-butyl hydroperoxide (TBHP) as oxidant is presented. This CoNPs@MgO/t-BuOOH catalytic combination allowed the epoxidation of a variety of olefins with good to excellent yield and high selectivity. The catalyst preparation is simple and straightforward from commercially available starting materials and it could be recovered and reused maintaining its unaltered high activity.

Alkynyl and ß-ketophosphonates: Selective and potent butyrylcholinesterase inhibitors.

A series of thirty-three alkynyl and ß-ketophosphonates were evaluated for their in vitro acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitory activities using Ellman's spectrophotometric method. None of the examined compounds inhibited AChE activity at tested concentrations while twenty-nine of them showed significant and selective inhibition of BChE with IC50 values between 38.60 µM and 0.04 µM. In addition, structure-activity relationships were discussed. The most effective inhibitors were the dibutyl o-methoxyphenyl alkynylphosphonate 3dc and dibutyl o-methoxyphenyl ß-ketophosphonate 4dc. Activities of most potent compounds were also compared with a commercial organophosphorus compound. These results could inspire the design of new inhibitors with stronger activity against BChE.

Copper Nanoparticles in Click Chemistry.

The challenges of the 21st century demand scientific and technological achievements that must be developed under sustainable and environmentally benign practices. In this vein, click chemistry and green chemistry walk hand in hand on a pathway of rigorous principles that help to safeguard the health of our planet against negligent and uncontrolled production. Copper-catalyzed azide-alkyne cycloaddition (CuAAC), the paradigm of a click reaction, is one of the most reliable and widespread synthetic transformations in organic chemistry, with multidisciplinary applications. Nanocatalysis is a green chemistry tool that can increase the inherent effectiveness of CuAAC because of the enhanced catalytic activity of nanostructured metals and their plausible reutilization capability as heterogeneous catalysts. This Account describes our contribution to click chemistry using unsupported and supported copper nanoparticles (CuNPs) as catalysts prepared by chemical reduction. Cu(0)NPs (3.0 ± 1.5 nm) in tetrahydrofuran were found to catalyze the reaction of terminal alkynes and organic azides in the presence of triethylamine at rates comparable to those achieved under microwave heating (10-30 min in most cases). Unfortunately, the CuNPs underwent dissolution under the reaction conditions and consequently could not be recovered. Compelling experimental evidence on the in situ generation of highly reactive copper(I) chloride and the participation of copper(I) acetylides was provided. The supported CuNPs were found to be more robust and efficient catalyst than the unsupported counterpart in the following terms: (a) the multicomponent variant of CuAAC could be applied; (b) the metal loading could be substantially decreased; (c) reactions could be conducted in neat water; and (d) the catalyst could be recovered easily and reutilized. In particular, the catalyst composed of oxidized CuNPs (Cu2O/CuO, 6.0 ± 2.0 nm) supported on carbon (CuNPs/C) was shown to be highly versatile and very effective in the multicomponent and regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles in water from organic halides as azido precursors; magnetically recoverable CuNPs (3.0 ± 0.8 nm) supported on MagSilica could be alternatively used for the same purpose under similar conditions. Incorporation of an aromatic substituent at the 1-position of the triazole could be accomplished using the same CuNPs/C catalytic system starting from aryldiazonium salts or anilines as azido precursors. CuNPs/C in water also catalyzed the regioselective double-click synthesis of ß-hydroxy-1,2,3-triazoles from epoxides. Furthermore, alkenes could be also used as azido precursors through a one-pot CuNPs/C-catalyzed azidosulfenylation-CuAAC sequential protocol, providing ß-methylsulfanyl-1,2,3-triazoles in a stereo- and regioselective manner. In all types of reaction studied, CuNPs/C exhibited better behavior than some commercial copper catalysts with regard to the metal loading, reaction time, yield, and recyclability. Therefore, the results of this study also highlight the utility of nanosized copper in click chemistry compared with bulk copper sources.

Base-Free Direct Synthesis of Alkynylphosphonates from Alkynes and H-Phosphonates Catalyzed by Cu2O.

A simple and mild methodology for the direct synthesis of alkynylphosphonates is presented. The reaction of a variety of terminal alkynes with dialkyl phosphites in the presence Cu2O (14 mol %) led to the formation of the corresponding alkynylphosphonates in good to excellent yields. Reactions are performed under air, in acetonitrile as solvent, and in the absence of base or ligand additives. This new methodology is compatible with the presence of a wide variety of functional groups on the starting alkynes and can be scaled up to a gram scale.

Alkenes as azido precursors for the one-pot synthesis of 1,2,3-triazoles catalyzed by copper nanoparticles on activated carbon.

A one-pot protocol for the synthesis of 1,2,3-triazoles has been developed starting from inactivated alkenes and based on two click reactions: the azidosulfenylation of the carbon-carbon double bond and the copper-catalyzed azide-alkyne cycloaddition (CuAAC). High yields of the ß-methylsulfanyl triazoles have been attained using CuNPs/C as catalyst, with other commercial copper catalysts being completely inactive. The versatility of the methylsulfanyl group has been demonstrated through a series of synthetic transformations, including direct access to 1-vinyl and 4-monosubstituted triazoles.

Hydrothiolation of alkynes with thiol-catechol derivatives catalysed by CuNPs/TiO2: exploring the reaction mechanism by DFT calculations.

Density functional theory (DFT) calculations were applied to describe the hydrothiolation reaction of activated alkynes with thiols bearing a catechol group. The thiol-yne click (TYC) process was efficiently catalysed by a CuNPs/TiO2 nanocatalyst giving the corresponding anti-Markovnikov vinyl sulphides with high Z-stereoselectivity. Based on the experimental results and DFT studies, a plausible reaction mechanism is proposed, which implies the activation of the carbon-carbon triple bond by coordination to the copper centre, followed by a stereoselective (external) nucleophilic attack to give preferentially the Z-vinyl sulphide isomer. Additionally, experimental and theoretical studies strongly correlate with the proposed synergistic role for the TiO2 support in the catalytic process.

Design and synthesis of unnatural coordination glycopolymer particles (CGPs): unleashing the potential of catechol-saccharide derivatives.

Our study unveils an innovative methodology that merges catechols with mono- and disaccharides, yielding a diverse array of compounds. This strategic fusion achieves robust yields and introduces ligands with a dual nature: encompassing both the chelating attributes of catechols and the recognition capabilities of carbohydrates. This synergistic design led us to couple one of the novel ligands with an Fe(iii) salt, resulting in the creation of Coordination Glycopolymer Particles (CGPs). These CGPs demonstrate remarkable qualities, boasting outstanding dispersion in both aqueous media and Phosphate Buffered Saline (PBS) solution (pH ∼7.4) at higher concentrations (0.26 mg µL-1). Displaying an average Z-size of approximately 55 nm and favourable polydispersity indices (<0.25), these particles exhibit exceptional stability, maintaining their integrity over prolonged periods and temperature variations. Notably, they retain their superior dispersion and stability even when subjected to freezing or heating to 40 °C, making them exceptionally viable for driving biological assays. In contrast to established methods for synthesizing grafted glycopolymers, where typically a glycopolymer is doped with catechol derivatives to create synergy between chelating properties and those inherent to the saccharide, our approach provides a more efficient and versatile pathway for generating CGPs. This involves combining catechols and carbohydrates within a single molecule, enabling the fine-tuning of organic structure from a monomer design step and subsequently transferring these properties to the polymer.

Novel pH-sensitive catechol dyes synthesised by a three component one-pot reaction.

The synthesis and characterisation of new dyes based on indolizines bearing catechol groups in their structure is presented. The preparation was carried out through a simple three component one-pot reaction promoted by CuNPs/C, between pyridine-2-carbaldehyde, an aromatic alkyne and a tetrahydroisoquinoline (THIQ) functionalized with catechol groups. The products were isolated in 30%-34% yield, which was considered more than acceptable considering that the catechol hydroxyl groups were not protected prior to reaction. In view of the colour developed by the products and their response to the acidic and basic conditions of the medium, product 3aa was studied by UV-Vis and NMR spectroscopies at different pH values. We concluded that product 3aa suffered two deprotonations at pKa of 4.4 and 9.5, giving three species in a pH range between 2-12, with colours varying from light red to deep orange. The reversibility of the process observed for 3aa at different pH values, together with its changes in colour, make this new family of products attractive candidates to use them as pH indicators.

Multicomponent click synthesis of 1,2,3-triazoles from epoxides in water catalyzed by copper nanoparticles on activated carbon.

Copper nanoparticles on activated carbon have been found to effectively catalyze the multicomponent synthesis of ß-hydroxy-1,2,3-triazoles from a variety of epoxides and alkynes in water. The catalyst is easy to prepare, reusable at a low copper loading (0.5 mol %), and exhibits higher catalytic activity than some commercially available copper sources. The regio- and stereochemistry of the reaction has been revised and unequivocally established on the basis of X-ray crystallographic analyses. An NMR experiment has been implemented for the rapid and unmistakable determination of the regiochemistry of the process. Some mechanistic aspects of the reaction have been also undertaken which unveil the participation of copper(I) acetylides.

Click chemistry from organic halides, diazonium salts and anilines in water catalysed by copper nanoparticles on activated carbon.

An easy-to-prepare, reusable and versatile catalyst consisting of oxidised copper nanoparticles on activated carbon has been fully characterised and found to effectively promote the multicomponent synthesis of 1,2,3-triazoles from organic halides, diazonium salts, and aromatic amines in water at a low copper loading.

Thiol-yne click reaction: an interesting way to derive thiol-provided catechols.

The hydrothiolation of activated alkynes is presented as an attractive and powerful way to functionalize thiols bearing catechols. The reaction was promoted by a heterogeneous catalyst composed of copper nanoparticles supported on TiO2 (CuNPs/TiO2) in 1,2-dichloroethane (1,2-DCE) under heating at 80 °C. The catalyst could be recovered and reused in three consecutive cycles, showing a slight decrease in its catalytic activity. Thiol derivatives bearing catechol moieties, obtained through a versatile Michael addition, were reacted with different activated alkynes, such as methyl propiolate, propiolic acid, propiolamide or 2-ethynylpyridine. The reaction was shown to be regio- and stereoselective towards anti-Markovnikov Z-vinyl sulfide in most cases studied. Finally, some catechol derivatives obtained were tested as ligands in the preparation of coordination polymer nanoparticles (CNPs), by taking the advantage of their different coordination sites with metals such as iron and cobalt.

Structure-Activity Relationship Study of an Alkynylphosphonate and Vynilphosphonate Analogues of Calcitriol.

BACKGROUND: 1α,25-dihydroxy vitamin D3 (calcitriol) shows potent growth-inhibitory properties on different cancer cell lines, but its hypercalcemic effects have severely hampered its therapeutic application. Therefore, it is important to develop synthetic calcitriol analogues that retain or even increase its antitumoral effects and lack hypercalcemic activity. Based on previous evidence of the potent antitumor effects of the synthetic alkynylphosphonate EM1 analogue, we have now synthesized a derivative called SG. OBJECTIVE: The aim of the present work is to evaluate the calcemic activity and the antitumor effect of SG, comparing these effects with those exerted by calcitriol and with those previously published for EM1. In addition, we propose to analyze by in silico studies, the chemical structure-biological function relationship of these molecules. METHODS: We performed the synthesis of vinylphosphonate SG analogue; in vitro assays on different cancer cell lines; in vivo assays on mice; and in silico assays applying computational molecular modeling. RESULTS: The SG compound lacks hypercalcemic activity, similar to the parent compound EM1. However, the antitumor activity was blunted, as no antiproliferative or anti-migratory effects were observed. By in silico assays, we demonstrated that SG analogue has a lower affinity for the VDRligand- binding domain than the EM1 compound due to lack of interaction with the important residues His305 and His397. CONCLUSION: These results demonstrate that the chemical modification in the lateral side chain of the SG analogue affects the antitumoral activity observed previously for EM1 but does not affect the calcemic activity. These results contribute to the rational design and synthesis of novel calcitriol analogues.

One-step synthesis of xanthones catalyzed by a highly efficient copper-based magnetically recoverable nanocatalyst.

A versatile and highly efficient strategy to construct a xanthone skeleton via a ligand-free intermolecular catalytic coupling of 2-substituted benzaldehydes and a wide range of phenols has been developed. For this purpose, a novel and magnetically recoverable catalyst consisting of copper nanoparticles on nanosized silica coated maghemite is presented. The reaction proceeds smoothly with easy recovery and reuse of the catalyst. The methodology is compatible with various functional groups and provides an attractive protocol for the generation of a small library of xanthones in very good yield.

Novel alkynylphosphonate analogue of calcitriol with potent antiproliferative effects in cancer cells and lack of calcemic activity.

Here, we describe the design and synthesis of diethyl [(5Z,7E)-(1S,3R)-1,3-dihydroxy-9,10-secochola-5,7,10(19)-trien-23-in-24-yl] phosphonate (compound 10), which combines the low calcemic properties of phosphonates with the decreased metabolic inactivation due to the presence of a triple bond in C-24 and studied its in vitro effects on several cancer cell lines and its in vivo effects on blood calcium levels. We demonstrate that this compound is a potent antiproliferative vitamin D analogue, showing lack of calcemic effects in vivo.