Organic Chemistry Research Articles

Synthesis of novel cyanopyridine compounds as potential EGFR inhibitors targeting A549 and PC3 cancer cell lines: In vitro, In vivo and ADME pharmacokinetics studies

Developing new leads for fighting cancer is a challenge for organic and medicinal chemists; hence, new functionalized pyridines have been synthesized via several transformations, including new amide bond formation, cyclization, and hydrazone synthesis. Aminolysis of the ethyl ester 2 with benzylamine affords the benzyl amide 3. Hydrazinolysis of the ester 2 afforded hydrazide 4. Hydrazide 4 used as precursor to obtain new hydrazino- and cyclized derivatives 5–10. Moreover, new series of hydrazone derivatives 11–17 were synthesized by condensation 2-((3-Cyano-4,6-dimethylpyridin-2-yl)oxy)acetohydrazide 4 with aromatic aldehydes and ketones. The synthesized compounds were subjected to cytotoxic screening against A549 and PC3 cells. Compounds 6 and 15 exhibited remarkable cytotoxic activities with IC50 values of 0.85 μM and 1.88 μM against A549 cells and IC50 values of 3.63 μM and 1.58 μM against PC-3 cells. Compounds 6, 8, and 15 exhibited promising EGFR inhibition with IC50 values of 42.6, 60.36, and 89.6 nM, respectively, compared to Erlotinib (93.7 %, IC50 = 78.6 nM). Moreover, compound 6 significantly activated apoptotic cell death in A549 cells, increasing the cell apoptosis by 76.7-fold (37.6 % in treated compared to 0.48 % for control) and arresting the cell cycle at S-phase by 32.56 % compared to control 24.03 %. Additionally, compound 6 caused tumor inhibition by 50.1 % of solid tumor in the SEC-bearing mice by interfering with EGFR enzymatic activity via considerable apoptosis-induction, which make it an attractive lead compound for the development of a chemotherapeutics to treat lung cancer.

[Contribution to Pharmacy/pharmacist Education through Writing].

The Education Award of the Pharmaceutical Society of Japan (PSJ) was conferred for "Contribution to pharmacy/pharmacist education through writing on organic chemistry." The award-winning activities were described in three parts section 1-3. Section 1 Importance of Research and Education in Organic Chemistry: In this section, it is explained that organic chemistry serves as the fundamental basis for a wide range of natural science disciplines studied in pharmaceutical departments. It emphasizes that having a solid foundation in organic chemistry is essential for pharmacists to understand pharmaceuticals. This knowledge contributes significantly in healthcare settings such as team-based medical care (interprofessional cooperation) with physicians and nurses, as well as in interactions with patients, providing a unique contribution that other professions cannot achieve. Section 2 Two Serial Articles Written on Organic Chemistry: This part mentions two serial articles that are beneficial for pharmacists and pharmaceutical researchers. These articles aimed to broaden specialized knowledge and provide practical information, contributing to pharmaceutical education and professional training for pharmacists. Section 3 Publication of New Organic Chemistry Textbooks: In this section, the introduction of textbooks and reference books in the field of organic chemistry for pharmaceutical education is highlighted. These educational materials were published to offer valuable information to pharmaceutical students and aspiring pharmacists, enhancing their expertise. These three writing activities significantly contributed to pharmaceutical education and the improvement of the professional work of pharmacists.

Mutualism in organic synthetic chemistry: Simultaneous heterodehydrocoupling of hydrostannane and reduction of quinoline

Here we report a one-pot strategy to simultaneously achieve both the heterodehydrocoupling of hydrostannane and reduction of quinoline by using B(C6F5)3 as catalyst under mild conditions. This method realizes the synthesis of heteroatom-tin complexes (NSn/OSn/PSn/SSn) by the same catalyst system. With the assistance of quinoline, the substrate scope was broadened and ESn yield was significantly enhanced. During the reaction, the generated heterodehydrocoupling intermediate [ESnH]+[HB(C6F5)3]− would accelerate the quinoline reduction by transforming 1,4-N-stannyl-dihydroquinoline intermediate into N-stannyl-tetrahydroquinoline whereas 1,4-N-stannyl-dihydroquinoline could serve as hydrogen acceptor to facilitate the conversion of [ESnH]+[HB(C6F5)3]− intermediate to produce ESn (E = N/O/P/S). The metathetical reaction of N-stannyl-tetrahydroquinoline and EH rapidly generates ESn and tetrahydroquinolines, thus mutually promoting the above process. The reaction mechanism is proposed on the basis of control experiments, capture and synthesis of key intermediates and deuterium experiments.

Живот, посветен на науката. 100 години от рождението на проф. д.х.н. Елена Киркова

In this article we'll present the life path, the teaching and scientific work of the outstanding Bulgarian scientist in the field of inorganic chemistry Prof. Dr. Elena Kirkova. A brief review of her now classic textbooks on general and inorganic chemistry, her main achievements in the field of crystallization and co-crystallization processes, her contribution to linking education with scientific research and their application in practice is made.

An Overview of Preparation for Different Azo Compounds

Azo compounds are a class of organic materials that have the group R-N=N-R' where the substitution group R and R' are aromatic or heterocyclic sides. The azo compounds have a variety of applications including dyes, pigments, and pharmaceuticals. The preparation and characterization of different azo compounds is an important area of research in organic synthesis. The azo compound synthesis typically involves the diazotization process for coupling between an aromatic amine and another aromatic compound containing an activating group such as -OH, -NH2, or -NR2. The reaction conditions must be carefully controlled to prevent side reactions, such as the formation of unwanted byproducts. Once synthesized, azo compounds can be characterized using a variety of techniques including UV-Vis spectroscopy, NMR spectroscopy, and mass spectrometry. UV-Vis spectroscopy is a commonly used technique for characterizing azo compounds. The absorption spectrum of an azo compound typically exhibits a strong absorption band in the visible region due to the delocalized π-electrons in the azo group. While in FTIR, the loss of the amine peak and showing a weak peak at about 1550 cm−1forthe (N=N) group, indicates the presence of Azo. The preparation and characterization of different azo compounds is a significant field of research in organic chemistry, which are applied as acid and base indicators, food coloring, optical switches, liquid crystal and in medicine. By carefully controlling the synthesis conditions and using a variety of characterization techniques, researchers can gain a better understanding of the properties and applications of these compounds.

Recent Developments and Applications of Biocatalytic and Chemoenzymatic Synthesis for the Generation of Diverse Classes of Drugs.

Biocatalytic and chemoenzymatic biosynthesis are powerful methods of organic chemistry that use enzymes to execute selective reactions and allow the efficient production of organic compounds. The advantages of these approaches include high selectivity, mild reaction conditions, and the ability to work with complex substrates. The utilization of chemoenzymatic techniques for the synthesis of complicated compounds has lately increased dramatically in the area of organic chemistry. Biocatalytic technologies and modern synthetic methods are utilized synergistically in a multi-step approach to a target molecule under this paradigm. Chemoenzymatic techniques are promising for simplifying access to essential bioactive compounds because of the remarkable regio- and stereoselectivity of enzymatic transformations and the reaction diversity of modern organic chemistry. Enzyme kits may include ready-to-use, reproducible biocatalysts. Its use opens up new avenues for the synthesis of active therapeutic compounds and aids in drug development by synthesizing active components to construct scaffolds in a targeted and preparative manner. This study summarizes current breakthroughs as well as notable instances of biocatalytic and chemoenzymatic synthesis. To assist organic chemists in the use of enzymes for synthetic applications, it also provides some basic guidelines for selecting the most appropriate enzyme for a targeted reaction while keeping aspects like cofactor requirement, solvent tolerance, use of whole cell or isolated enzymes, and commercial availability in mind.

Spinning Reactors for Process Intensification of Flow Photochemistry.

The design of new and more sustainable synthetic protocols to access new materials or valuable compounds will have a high impact on the broader chemistry community. In this sense, continuous-flow photochemistry has emerged as a powerful technique which has been employed successfully in various areas such as biopharma, organic chemistry, as well as materials science. However, it is important to note that chemical processes must not only advance towards new or improved chemical transformations, but also implement new technologies that enable new process opportunities. For this reason, the design of novel photoreactors is key to advancing photochemical strategies. In this sense, the use of equipment and techniques embracing processes intensification is important in developing more sustainable protocols. Among the most recent applications, spinning continuous flow reactors, such as rotor reactors or vortex reactors, have shown promising performance as new synthetic tools. Nevertheless, there is currently no review in the literature that effectively summarizes and showcases the most recent applications of such type of photoreactors. Herein, we highlight fundamental aspects and applications of two categories of spinning reactors, the Spinning Disc Reactors (SDRs) and Thin Film Vortex reactors, critiquing the scope and limitations of these advanced processing technologies. Further, we take a view on the future of spinning reactors in flow as a synthetic toolbox to explore new photochemical transformations.

Developing Student Heuristic Characterizations to Help Them “Bond” with Organic Chemistry

The volume of content and abstract nature of organic chemistry is challenging and potentially intimidating for students. I describe a strategy for facilitating student development of heuristic tools for engaging with the subject. By using experimental and researched data on carbon, oxygen, nitrogen, and hydrogen, the bulk chemical elements of organic chemistry, my students were encouraged to develop a “character reference” for each. The heuristics of characterization enabled them to relate more easily and engage more creatively with the work, including when working with complex organic molecules later on. I used this approach when teaching carbohydrates, alcohols, fats and proteins to 12- to 14-year-old students.

Synthesis and Characterization of Hexathiosianatoiron(II) [Fe(NCS)6] 4- Complex Compound and Tetrapyridindithiosianatoiron(II) [Fe(NCS)2(Py)4] Complex Compound

This research aims to synthesize and characterize the complex compounds Hexathiocyanatoiron(II) [Fe(NCS)6] 4- and Tetrapyridinedithiocyanatoiron(II) [Fe(NCS)2(Py)4]. The synthesis of these complex compounds was conducted in the Chemistry Laboratory, Faculty of Mathematics and Natural Sciences, Medan State University, while magnetic susceptibility measurements were carried out using the Magnetic Susceptibility Balance (MSB) instrument in the Inorganic Chemistry Laboratory, Bandung Institute of Technology. The complex compound synthesis involved the reaction of Iron(II) sulfate heptahydrate with Potassium thiocyanate and Pyridine compound in a 1:2 and 1:2:4 molar ratio. The synthesis process was conducted through a direct reaction method in a polar solvent. The obtained results include Hexathiocyanatoiron(II) complex compound, [Fe(NCS)6] 4-, which is pale yellow crystalline with a yield of 32.76%, and Tetrapyridinedithiocyanatoiron(II) complex compound, [Fe(NCS)2(Py)4] which is dark purple crystalline with a yield of 52.62%. These compounds exhibit a melting point of 219℃. Magnetic susceptibility measurements using the MSB instrument revealed a magnetic susceptibility of 6.69 BM (paramagnetic) for the Hexathiocyanatoiron(II) complex[Fe(NCS)6] 4-, and a magnetic moment of 5.61 BM (diamagnetic) for the Tetrapyridinedithiocyanatoiron(II ) complex [Fe(NCS)2(Py)4].

A Focussed Analysis of β-cyclodextrins for Quinoxaline Derivatives Synthesis

Abstract: Cyclodextrins (CDs), which are a type of cyclic oligosaccharides, are widely used in supramolecular chemistry. For example, they can be used to encapsulate volatile compounds, such as drugs, within their hydrophobic cavity. This encapsulation reduces the volatility of the compounds and helps to retain their desired properties. Due to its extraordinary properties, cyclodextrins have been utilized as catalysts in numerous organic synthesis processes. An intrinsic objective of organic chemists is to optimize the efficacy of organic synthesis through the mitigation of chemical waste and energy expenditure. Utilizing water as a green solvent is, therefore, economical, environmentally sustainable, and secure. It appears that employing water in conjunction with a recyclable catalyst is the most effective method for supramolecular catalysis. As a consequence, we focused this review on the use of water as a solvent and cyclodextrin as a polymer catalyst to produce quinoxaline derivatives in an environmentally friendly and sustainable manner.

Palladium(0) π-Lewis Base Catalysis: Concept and Development.

The development of a new catalytic strategy plays a vital role in modern organic chemistry since it permits bond formation in an unprecedented and more efficient manner. Although the application of preformed metal complexes as π-base-activated reagents have enabled diverse transformations elegantly, the concept and strategy by directly utilizing transition metals as efficient π-Lewis base catalysts remain underdeveloped, especially in the field of asymmetric catalysis. Here, we outline our perspective on the discovery of palladium(0) as an efficient π-Lewis base catalyst, which is capable of increasing the highest occupied molecular orbital (HOMO) energy of both electron-neutral and electron-deficient 1,3-dienes and 1,3-enynes upon flexible η2-complexes formed in situ and resultant π-backdonation. Thus, fruitful carbon-carbon-forming reactions with diverse electrophiles can be achieved enantioselectively in a vinylogous addition pattern, which is conceptually different from the classical oxidative cyclization mechanism. Emphasis will be given to the concept and mechanism elucidation, catalytic features, and reaction design together with perspective on the further development of this emerging field.

Abstract 1909 Linking Organic Chemistry II, Physical Chemistry, and Biochemistry Laboratories in the Study of the Inhibition of Alkaline Phosphatase by Phenylalanine Derivatives

Abstract 1909 Linking Organic Chemistry II, Physical Chemistry, and Biochemistry Laboratories in the Study of the Inhibition of Alkaline Phosphatase by Phenylalanine Derivatives

QM/MM Study of the Catalytic Mechanism and Substrate Specificity of the Aromatic Substrate C-Methyltransferase Fur6.

In the field of medical chemistry and other organic chemistry, introducing a methyl group into a designed position has been difficult to achieve. However, owing to the vigorous developments in the field of enzymology, methyltransferases are considered potential tools for addressing this problem. Within the methyltransferase family, Fur6 catalyzes the methylation of C3 of 1,2,4,5,7-pentahydroxynaphthalene (PHN) using S-adenosyl-l-methionine (SAM) as the methyl donor. Here, we report the catalytic mechanism and substrate specificity of Fur6 based on computational studies. Our molecular dynamics (MD) simulation studies reveal the reactive form of PHN and its interactions with the enzyme. Our hybrid quantum mechanics/molecular mechanics (QM/MM) calculations suggest the reaction pathway of the methyl transfer step in which the energy barrier is 8.6 kcal mol-1. Our free-energy calculations with a polarizable continuum model (PCM) indicate that the final deprotonation step of the methylated intermediate occurs after it is ejected into the water solvent from the active center pocket of Fur6. Additionally, our studies on the protonation states, the highest occupied molecular orbital (HOMOs), and the energy barriers of the methylation reaction for the analogs of PHN demonstrate the mechanism of the specificity to PHN. Our study provides valuable insights into Fur6 chemistry, contributing to a deeper understanding of molecular mechanisms and offering an opportunity to engineer the enzyme to achieve high yields of the desired product(s).

Developing interactive multimedia learning materials for chemistry pre-lab training

Developing interactive multimedia learning materials for chemistry pre-lab training

Zirconium and hafnium catalyzed C–C single bond hydroboration

Selective cleavage and subsequent functionalization of C−C single bonds present a fundamental challenge in synthetic organic chemistry. Traditionally, the activation of C−C single bonds has been achieved using stoichiometric transition-metal complexes. Recently, examples of catalytic processes were developed in which use is made of precious metals. However, the use of inexpensive and Earth-abundant group IV metals for catalytic C−C single-bond cleavage is largely underdeveloped. Herein, the zirconium-catalyzed C−C single-bond cleavage and subsequent hydroboration reactions is realized using Cp2ZrCl2 as a catalytic system. A series of structures of various γ-boronated amines are readily obtained, which are otherwise difficult to obtain. Mechanistic studies disclose the formation of a N–ZrIV species, and then a β-carbon elimination route is responsible for C–C single bond activation. Besides zirconium, hafnium exhibits a similar performance for this transformation.

Tuning light-driven oxidation of styrene inside water-soluble nanocages

Selective functionalization of innate sp2 C-H bonds under ambient conditions is a grand synthetic challenge in organic chemistry. Here we combine host-guest charge transfer-based photoredox chemistry with supramolecular nano-confinement to achieve selective carbonylation of styrene by tuning the dioxygen concentration. We observe exclusive photocatalytic formation of benzaldehyde under excess O2 (>1 atm) while Markovnikov addition of water produced acetophenone in deoxygenated condition upon photoexcitation of confined styrene molecules inside a water-soluble cationic nanocage. Further by careful tuning of the nanocage size, electronics, and guest preorganization, we demonstrate rate enhancement of benzaldehyde formation and a complete switchover to the anti-Markovnikov product, 2-phenylethan-1-ol, in the absence of O2. Raman spectroscopy, 2D 1H-1H NMR correlation experiments, and transient absorption spectroscopy establish that the site-selective control on the confined photoredox chemistry originates from an optimal preorganization of styrene molecules inside the cavity. We envision that the demonstrated host-guest charge transfer photoredox paradigm in combination with green atom-transfer reagents will enable a broad range of sp2 carbon-site functionalization.

Development of (NO)Fe(N2S2) as a Metallodithiolate Spin Probe Ligand: A Case Study Approach.

ConspectusThe ubiquity of sulfur-metal connections in nature inspires the design of bi- and multimetallic systems in synthetic inorganic chemistry. Common motifs for biocatalysts developed in evolutionary biology include the placement of metals in close proximity with flexible sulfur bridges as well as the presence of π-acidic/delocalizing ligands. This Account will delve into the development of a (NO)Fe(N2S2) metallodithiolate ligand that harnesses these principles. The Fe(NO) unit is the centroid of a N2S2 donor field, which as a whole is capable of serving as a redox-active, bidentate S-donor ligand. Its paramagnetism as well as the ν(NO) vibrational monitor can be exploited in the development of new classes of heterobimetallic complexes. We offer four examples in which the unpaired electron on the {Fe(NO)}7 unit is spin-paired with adjacent paramagnets in proximal and distal positions.First, the exceptional stability of the (NO)Fe(N2S2)-Fe(NO)2 platform, which permits its isolation and structural characterization at three distinct redox levels, is linked to the charge delocalization occurring on both the Fe(NO) and the Fe(NO)2 supports. This accommodates the formation of a rare nonheme {Fe(NO)}8 triplet state, with a linear configuration. A subsequent FeNi complex, featuring redox-active ligands on both metals (NO on iron and dithiolene on nickel), displayed unexpected physical properties. Our research showed good reversibility in two redox processes, allowing isolation in reduced and oxidized forms. Various spectroscopic and crystallographic analyses confirmed these states, and Mössbauer data supported the redox change at the iron site upon reduction. Oxidation of the complex produced a dimeric dication, revealing an intriguing magnetic behavior. The monomer appears as a spin-coupled diradical between {Fe(NO)}7 and the nickel dithiolene monoradical, while dimerization couples the latter radical units via a Ni2S2 rhomb. Magnetic data (SQUID) on the dimer dication found a singlet ground state with a thermally accessible triplet state that is responsible for magnetism. A theoretical model built on an H4 chain explains this unexpected ferromagnetic low-energy triplet state arising from the antiferromagnetic coupling of a four-radical molecular conglomerate. For comparison, two (NO)Fe(N2S2) were connected through diamagnetic group 10 cations producing diradical trimetallic complexes. Antiferromagnetic coupling is observed between {Fe(NO)}7 units, with exchange coupling constants (J) of -3, -23, and -124 cm-1 for NiII, PdII, and PtII, respectively. This trend is explained by the enhanced covalency and polarizability of sulfur-dense metallodithiolate ligands. A central paramagnetic trans-Cr(NO)(MeCN) receiver unit core results in a cissoid structural topology, influenced by the stereoactivity of the lone pair(s) on the sulfur donors. This {Cr(NO)}5 radical bridge, unlike all previous cases, finds the coupling between the distal Fe(NO) radicals to be ferromagnetic (J = 24 cm-1).The stability and predictability of this S = 1/2 moiety and the steric/electronic properties of the bridging thiolate sulfurs suggest it to be a likely candidate for the development of novel molecular (magnetic) compounds and possibly materials. The role of synthetic inorganic chemistry in designing synthons that permit connections of the (NO)Fe(N2S2) metalloligand is highlighted as well as the properties of the heterobi- and polymetallic complexes derived therefrom.

Exo-Selective Diels-Alder Reactions.

The Diels-Alder reaction stands as one of the most pivotal transformations in organic chemistry. Its efficiency, marked by the formation of two carbon-carbon bonds and up to four new stereocenters in a single step, underscores its versatility and indispensability in synthesizing natural products and pharmaceuticals. The most significant stereoselectivity feature is the "endo rule". While this rule underpins the predictability of the stereochemical outcomes, it also underscores the challenges in achieving the opposite diastereoselectivity, making the exo-Diels-Alder reactions often considered outliers. This review delves into recent examples of exo-Diels-Alder reactions, shedding light on the factors inverting the intrinsic tendency. We explore the roles of steric, electrostatic, and orbital interactions, as well as thermodynamic equilibriums in influencing exo/endo selectivity. Furthermore, we illustrate strategies to manipulate these factors, employing approaches such as bulky substituents, s-cis conformations, transient structural constraints, and innovative control physics. Through these analyses, our aim is to provide a comprehensive understanding of how to predict and design exo-Diels-Alder reactions, paving the way for new diastereoselective catalyst systems and expanding the chemical scope of Diels-Alder reactions.

Cobalt‐Catalyzed Hydrosilylation across Carbon‐Carbon, Carbon‐Oxygen, and Carbon‐Nitrogen Multiple Bonds – A Comprehensive Review

AbstractThe selective conversion of unsaturated compounds has emerged as a crucial method in chemical synthesis, enabling the synthesis of functional organic molecules. In recent decades, transition metal‐catalyzed hydrosilylation has emerged as a highly successful exemplar of industrialization within the realm of organic chemistry for the production of organosilanes, which have a pivotal role in organic chemistry and materials science. Precious metal complexes are typically employed as catalysts in most industrial hydrosilylation processes. The exploration of Earth‐abundant alternatives has emerged as a focal point of considerable research attention due to the high cost, poor selectivity, and many side reactions reported for precious metal catalysts. Ligand skeleton construction, selectivity, and mechanism research are areas where cobalt catalysts have more potential than iron and nickel. This review discusses the recent advances in cobalt‐catalyzed hydrosilylation across carbon‐carbon, carbon‐oxygen, and carbon‐nitrogen multiple bonds from 2019 to 2023.

Amoebicidal effect of synthetic indoles against Acanthamoeba spp.: a study of cell death.

Organic and synthetic chemistry plays a crucial role in drug discovery fields. Moreover, chemical modifications of available molecules to enhance their efficacy, selectivity and safety have been considered as an attractive approach for the development of new bioactive agents. Indoles, a versatile group of natural heterocyclic compounds, have been widely used in pharmaceutical industry due to their broad spectrum of activities including antimicrobial, antitumoral and anti-inflammatory among others. Herein, we report the amoebicidal activity of different indole analogs on Acanthamoeba castellanii Neff. Among the 40 tested derivatives, eight molecules were able to inhibit this protistan parasite. The structure-activity relationship (SAR) analysis of their anti-Acanthamoeba activity would suggest that a carboxylation of C-3 position and the incorporation of halogen as chlorine/fluorine would enhance their biological profile, presumably by increasing their lipophilicity and therefore their ability to cross the cell membrane. Fluorescence image base system was used to investigate the effect of indole 6o c-6 on the cytoskeleton network and various programmed cell death features. We were able to highlight that the methyl 6-chloro-1H-indole-3-carboxylate could induce program cell death by the mitochondrial dysfunction.