Search results for: nucleophile

Authors: Saman Hajmohamadi, Sohrab Hajmohamadi

Abstract:

The objectives of this experiment were to investigate the application of new ligands including different atoms and evaluation of their nucleophile effects against various metals. Chemistry researchers are really interested in this field. From among various ligands, there are some ligands with different coordinating ligands as well. There are great number of intermediate complexes and major elements of organic compositions with various atoms. There is a regular adding of new compositions. Complexes are the most important chemical combinations with various catalysts and biological, medicinal and other applications. Those complexes with ligands including different atom givers are really important and their synthesis could solve most of chemical problems. Supplying of new ligands is an important and key part of coordination chemistry which may cause some varieties and different properties in complexes with equal central nucleus. As a result, this research has evaluated new ligands including different coordination atoms, such as oxygen, nitrogen etc. along with their behavior against various metals like copper, nickel, iron etc.

Keywords: ligands, nucleophile, iron, cobalt, copper

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Authors: David Ryan, Martin Breugst, Turlough Downes, Peter A. Byrne, Gerard P. McGlacken

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An ambident nucleophile is a nucleophile that possesses two or more distinct nucleophilic sites that are linked through resonance and are effectively “in competition” for reaction with an electrophile. Examples include enolates, pyridone anions, and nitrite anions, among many others. Reactions of ambident nucleophiles and electrophiles are extremely prevalent at all levels of organic synthesis. The principle of hard and soft acids and bases (the “HSAB principle”) is most commonly cited in the explanation of selectivities in such reactions. Although this rationale is pervasive in any discussion on ambident reactivity, the HSAB principle has received considerable criticism. As a result, the principle’s supplantation has become an area of active interest in recent years. This project focuses on developing a model for rationalizing ambident reactivity. Presented here is an approach that incorporates computational calculations and experimental kinetic data to construct Gibbs energy profile diagrams. The preferred site of alkylation of nitrite anion with a range of ‘hard’ and ‘soft’ alkylating agents was established by ¹H NMR spectroscopy. Pseudo-first-order rate constants were measured directly by ¹H NMR reaction monitoring, and the corresponding second-order constants and Gibbs energies of activation were derived. These, in combination with computationally derived standard Gibbs energies of reaction, were sufficient to construct Gibbs energy wells. By representing the ambident system as a series of overlapping Gibbs energy wells, a more intuitive picture of ambident reactivity emerges. Here, previously unexplained switches in reactivity in reactions involving closely related electrophiles are elucidated.

Keywords: ambident, Gibbs, nucleophile, rates

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Authors: Desta Gebretekle Shiferaw, Balakrishna Kalluraya

Abstract:

Pyrazole is an aromatic five-membered heterocycle with two nitrogen and three carbon atoms in its ring structure. According to the literature, pyrazoline, pyrazole, and thiazole-containing moieties are found in various drug structures and are responsible for nearly all pharmacological effects. The pyrazoline linked to pyrazole moiety carbothioamides was synthesized via the reaction of pyrazole-bearing chalcones (3-(5-chloro-3-methyl-¹-phenyl-1H-pyrazol-4-yl)-¹-(substituted aryl) prop-2-ene-¹-one derivatives) with a nucleophile thiosemicarbohyrazide by heating in ethanol using fused sodium acetate as a catalyst. Then the carbothioamide derivatives were converted into the pyrazoline hybrid to pyrazole and thiazole derivatives by condensing with substituted phenacyl bromide in alcohol in a basic medium. Next, the chemical structure of the newly synthesized molecules was confirmed by IR, 1H-NMR, and mass spectral data. Further, they were screened for their in vitro antioxidant activity. Compared to butylated hydroxy anisole (BHA)., the antioxidant data showed that the synthesized compounds had good to moderate activity.

Keywords: pyrazoline-pyrazole carbothioamide derivatives, pyrazoline-pyrazole-thiazole derivatives, spectral studies, antioxidant activity

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Authors: Rafat M. Mohareb

Abstract:

Several D-ring alkylated estrone analogues display exceptionally high affinity for estrogen receptors. In particular, compounds in which an E-ring is formed are known to be involved in the inhibition of steroidogenic enzymes. Such compounds also have an effect on steroid dehydrogenase activity and the ability to inhibit the detrimental action of the steroid sulfatase enzyme. Generally, E-ring extended steroids have been accessed by modification of the C17-ketone in the D-ring by either arylimine or oximino formation, addition of a carbon nucleophile or hydrazone formation. Other approaches have included ketone reduction, silyl enol ether formation or ring-closing metathesis (giving five- or six-membered E-rings). Chemical modification of the steroid D-ring provides a way to alter the functional groups, sizes and stereochemistry of the D-ring, and numerous structure-activity relationships have been established by such synthetic alterations. Steroids bearing heterocycles fused to the D-ring of the steroid nucleus have been of pharmaceutical interest. In the present paper, we report on the efficient synthesis of estrone possessing pyran, pyrimidine and thiazole ring systems. This study focused on the synthesis and biochemical evaluation of newly synthesized heterocyclic compounds which were then subjected through inhibitory evaluations towards human cancer and normal cell lines.

Keywords: estrone, heterocyclization, cytotoxicity, biomedicine

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Authors: Sara Torabi, Sadegh Khazalpour, Mahdi Jamshidi

Abstract:

Nitro aromatic compounds are valuable materials because of their applications in the preparation of chemical intermediates for the synthesis of dyes, plastics, perfumes, energetic materials, and pharmaceuticals. Chemical and electrochemical procedures are reported for nitration of aromatic compounds. Flavonoid derivatives are present in many vegetables and fruits and are constituent of many common pharmaceuticals and dietary supplements. Electrochemistry provides very versatile means for the electrosynthesis, mechanistic and kinetic studies. To the best of our knowledge, and despite the importance of these compounds in numerous scientific fields, there are no reports on the electrochemical nitration of Quercetin derivatives. Herein, we describe a green electrochemical synthesis of a nitro compound. In this work, electrochemical oxidation of Quercetin has been studied in the presence of nitrite ion as a nucleophile in acetate buffer solution (c = 0.2 M, pH = 6.0), by means of cyclic voltammetry and controlled-potential coulometry. The results indicate the participation of produced o-benzoquinones in Michael reaction with nitrite ion (in the divided cell) to form the corresponding nitro diol (EC mechanism). The purity of product and characterization was done using ¹H NMR, ¹³C NMR, FTIR spectroscopic techniques. The presented strategies use a water/ethanol mixture as solvent. Ethanol as cosolvent was also used in the previous studies because of its low cost, safety, easy availability, recyclability, bioproductability, and biodegradability. These strategies represent a one-pot and facile process for the synthesis of nitro compound in high yield and purity under green conditions.

Keywords: electrochemical synthesis, green chemistry, cyclic voltammetry, molecular docking

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Authors: Elene Tatunashvili, Bun Chan, Philippe E. Nashar, Christopher S. P. McErlean

Abstract:

The reduction of aryl diazonium salts is one of the most efficient ways to generate aryl radicals for use in a wide range of transformations, including Sandmeyer-type reactions, Meerwein arylations of olefins and Gomberg-Bachmann-Hey arylations of heteroaromatic systems. The aryl diazonium species can be reduced electrochemically, by UV irradiation, inner-sphere and outer-sphere single electron transfer processes (SET) from metal salts, SET from photo-excited organic catalysts or fragmentation of adducts with weak bases (acetate, hydroxide, etc.). This paper details an approach for the metal-free reduction of aryl diazonium salts, which facilitates the efficient synthesis of various aromatic compounds under exceedingly mild reaction conditions. By measuring the oxidation potential of a number of organic molecules, a series of nucleophiles were identified that reduce aryl diazonium salts via the addition-fragmentation mechanism. This approach leads to unprecedented operational simplicity: The reactions are very rapid and proceed in the open air; there is no need for external irradiation or heating, and the process is compatible with a large number of radical reactions. We illustrate these advantages by using the addition-fragmentation strategy to regioselectively arylate a series of heterocyclic compounds, to synthesize ketones by arylation of silyl enol ethers, and to synthesize benzothiophene and phenanthrene derivatives by radical annulation reactions.

Keywords: diazonium salts, hantzsch esters, oxygen, radical reactions, synthetic methods

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Authors: Nicholas C. Rose, Christopher D. Spicer

Abstract:

The regeneration of damaged or diseased tissues would provide an invaluable therapeutic tool in biological research and medicine. Cells must be provided with a number of different biochemical signals in order to form mature tissue through complex signaling networks that are difficult to recreate in synthetic materials. The ability to attach and detach bioactive proteins from material in an iterative and dynamic manner would therefore present a powerful way to mimic natural biochemical signaling cascades for tissue growth. We propose to reversibly attach these bioactive proteins using ortho-boronoimine (oBI) linkages and related derivatives formed by the reaction of an ortho-boronobenzaldehyde with a nucleophilic amine derivative. To enable the use of oBIs for biomaterial modification, we have studied binding and cleavage processes with precise detail in the context of small molecule models. A panel of oBI complexes has been synthesized and screened using a novel Förster resonance energy transfer (FRET) assay, using a cyanine dye FRET pair (Cy3 and Cy5), to identify the most reactive boron-aldehyde/amine nucleophile pairs. Upon conjugation of the dyes, FRET occurs under Cy3 excitation and the resultant ratio of Cy3:Cy5 emission directly correlates to conversion. Reaction kinetics and equilibria can be accurately quantified for reactive pairs, with dissociation constants of oBI derivatives in water (KD) found to span 9-orders of magnitude (10⁻²-10⁻¹¹ M). These studies have provided us with a better understanding of oBI linkages that we hope to exploit to reversibly attach bioconjugates to materials. The long-term aim of the project is to develop a modular biomaterial platform that can be used to help combat chronic diseases such as osteoarthritis, heart disease, and chronic wounds by providing cells with potent biological stimuli for tissue engineering.

Keywords: dynamic, bioconjugation, bornoimine, rapid, physiological

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Authors: Ved Vrat Verma, Rani Gupta, Manisha Goel

Abstract:

γ-glutamyltranspeptidase (GGT: EC 2.3.2.2) is an N-terminal nucleophile hydrolase conserved in all three domains of life. GGT plays a key role in glutathione metabolism where it catalyzes the breakage of the γ-glutamyl bonds and transfer of γ-glutamyl group to water (hydrolytic activity) or amino acids or short peptides (transpeptidase activity). GGTs from bacteria, archaea, and eukaryotes (human, rat and mouse) are homologous proteins sharing >50% sequence similarity and conserved four layered αββα sandwich like three dimensional structural fold. These proteins though similar in their structure to each other, are quite diverse in their enzyme activity: some GGTs are better at hydrolysis reactions but poor in transpeptidase activity, whereas many others may show opposite behaviour. GGT is known to be involved in various diseases like asthma, parkinson, arthritis, and gastric cancer. Its inhibition prior to chemotherapy treatments has been shown to sensitize tumours to the treatment. Microbial GGT is known to be a virulence factor too, important for the colonization of bacteria in host. However, all known inhibitors (mimics of its native substrate, glutamate) are highly toxic because they interfere with other enzyme pathways. However, a few successful efforts have been reported previously in designing species specific inhibitors. We aim to leverage the diversity seen in GGT family (pathogen vs. eukaryotes) for designing specific inhibitors. Thus, in the present study, we have used DIVERGE software to identify sites in GGT proteins, which are crucial for the functional and structural divergence of these proteins. Since, type II divergence sites vary in clade specific manner, so type II divergent sites were our focus of interest throughout the study. Type II divergent sites were identified for pathogen vs. eukaryotes clusters and sites were marked on clade specific representative structures HpGGT (2QM6) and HmGGT (4ZCG) of pathogen and eukaryotes clade respectively. The crucial divergent sites within 15 A radii of the binding cavity were highlighted, and in-silico mutations were performed on these sites to delineate the role of these sites on the mechanism of catalysis and protein folding. Further, the amino acid network (AAN) analysis was also performed by Cytoscape to delineate assortative mixing for cavity divergent sites which could strengthen our hypothesis. Additionally, molecular dynamics simulations were performed for wild complexes and mutant complexes close to physiological conditions (pH 7.0, 0.1 M ionic strength and 1 atm pressure) and the role of putative divergence sites and structural integrities of the homologous proteins have been analysed. The dynamics data were scrutinized in terms of RMSD, RMSF, non-native H-bonds and salt bridges. The RMSD, RMSF fluctuations of proteins complexes are compared, and the changes at protein ligand binding sites were highlighted. The outcomes of our study highlighted some crucial divergent sites which could be used for novel inhibitors designing in a species-specific manner. Since, for drug development, it is challenging to design novel drug by targeting similar protein which exists in eukaryotes, so this study could set up an initial platform to overcome this challenge and help to deduce the more effective targets for novel drug discovery.

Keywords: γ-glutamyltranspeptidase, divergence, species-specific, drug design

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Authors: Guillaume Bélanger, Jean-Philippe Fontaine, Clémence Hauduc

Abstract:

There is an undeniable thirst from organic chemists and from the pharmaceutical industry to access complex alkaloids with short syntheses. While medicinal chemists are interested in the fascinating wide range of biological properties of alkaloids, synthetic chemists are rather interested in finding new routes to access these challenging natural products of often low availability from nature. To synthesize complex polycyclic cores of natural products, reaction cascades or sequences performed one-pot offer a neat advantage over classical methods for their rapid increase in molecular complexity in a single operation. In counterpart, reaction cascades need to be run on substrates bearing all the required functional groups necessary for the key cyclizations. Chemoselectivity is thus a major issue associated with such a strategy, in addition to diastereocontrol and regiocontrol for the overall transformation. In the pursuit of synthetic efficiency, our research group developed an innovative one-pot transformation of linear substrates into bi- and tricyclic adducts applied to the construction of Aspidospermatan-type alkaloids. The latter is a rich class of indole alkaloids bearing a unique bridged azatricyclic core. Despite many efforts toward the synthesis of members of this family, efficient and versatile synthetic routes are still coveted. Indeed, very short, non-racemic approaches are rather scarce: for example, in the cases of aspidospermidine and aspidospermine, syntheses are all fifteen steps and over. We envisaged a unified approach to access several members of the Aspidospermatan alkaloids family. The key sequence features a highly chemoselective formamide activation that triggers a Vilsmeier-Haack cyclization, followed by an azomethine ylide generation and intramolecular cycloaddition. Despite the high density and variety of functional groups on the substrates (electron-rich and electron-poor alkenes, nitrile, amide, ester, enol ether), the sequence generated three new carbon-carbon bonds and three rings in a single operation with good yield and high chemoselectivity. A detailed study of amide, nucleophile, and dipolarophile variations to finally get to the successful combination required for the key transformation will be presented. To complete the indoline fragment of the natural products, we developed an original approach. Indeed, all reported routes to Aspidospermatan alkaloids introduce the indoline or indole early in the synthesis. In our work, the indoline needs to be installed on the azatricyclic core after the key cyclization sequence. As a result, typical Fischer indolization is not suited since this reaction is known to fail on such substrates. We thus envisaged a unique photocatalyzed decarboxylative radical cyclization. The development of this reaction as well as the scope and limitations of the methodology, will also be presented. The original Vilsmeier-Haack and azomethine ylide cyclization sequence as well as the new photocatalyzed decarboxylative radical cyclization will undoubtedly open access to new routes toward polycyclic indole alkaloids and derivatives of pharmaceutical interest in general.

Keywords: Aspidospermatan alkaloids, azomethine ylide cycloaddition, decarboxylative radical cyclization, indole and indoline synthesis, one-pot sequential cyclizations, photocatalysis, Vilsmeier-Haack Cyclization

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