Nitrogen-containing Ring Research Articles

SÍNTESE DE NOVOS 1,2,3-TRIAZÓIS INSPIRADOS NO SRPIN340 E AVALIAÇÃO DE SEUS EFEITOS EM LINHAGEM CELULAR DE GLIOBLASTOMA HUMANO

SYNTHESIS OF NOVEL 1,2,3-TRIAZOLES INSPIRED ON THE SRPIN340 AND EVALUATION OF THEIR EFFECTS ON HUMAN GLIOBLASTOMA CELL LINE. It is herein described the synthesis of a series of thirty novel 1,2,3-triazole1,4-disubstituted compounds inspired on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and biological evaluation of them against human glioblastoma multiforme cell line U87MG. Starting with 1-fluoro2-nitro-4- (trifluoromethyl)benzene (1), the substances were prepared via a five-step synthetic route. The crucial step corresponded to the copper-catalyzed cycloaddition reaction between trifluoromethyl phenyl azides and different alkynes. In general, the compounds were obtained with good yields and they were characterized utilizing spectroscopic (IR and NMR) and spectrometric (HRMS) techniques. The evaluation of the synthesized compounds at three different treatment time (24 h, 48 h, and 72 h) and concentrations (50, 100, and 150 µmol L-1) revealed that five derivatives were capable of reducing cell viability by 50% after 72 h of treatment at the highest concentration. On the contrary, three derivatives significantly increased cell viability being this effect more pronounced after 48 h of treatment. In this regard, it stands out the compound 2-((1-(2-morpholino-5-(trifluoromethyl)phenyl)-1H-1,2,3-triazol4-yl)methyl)isoindoline-1,3-dione (7) which increased cell viability in approximately 300% after 48 h of treatment at 100 µmol L-1. The substances that increased cell viaiblity present as common structural features the presence of a saturated nitrogen-containing six-membered ring and carbonylated fragments.

Structure-Photochemical Function Relationships in the Photobasicity of Aromatic Heterocycles Containing Multiple Ring Nitrogen Atoms.

Photobases are compounds that become more basic when promoted to an excited electronic state. Previous experimental and computational studies have demonstrated that several quinoline and quinoline-derived compounds are strong photobases (pKa* > 14). Moreover, the strength of photobasicity was shown to depend strongly on the identity and position of the substituent group(s), with the strongest photobases having multiple electron-donating substituents on a fused benzene ring as opposed to the ring containing the photobasic nitrogen atom. These electron-donating substituents build up electron density on one side of the molecule that shifts onto the nitrogen-containing ring in the electronic transition. This shift in electron density produces an increase in negative charge on the ring nitrogen atom responsible for the photobasicity. In this paper, we expand on our previous investigation to study the effect of an additional ring nitrogen atom on photobasicity in aromatic heterocycles. In particular, we consider how the thermodynamic driving force for excited-state protonation can be tuned by changing the relative placement of the ring nitrogen atoms and varying the position and number of electron-donating substituents. In the set of 112 molecules screened, we identified 42 strong photobases with generally comparable pKa* but lower vertical excitation energies than the quinoline derivatives with only a single ring nitrogen atom. We additionally explored photobasicity in substituted azaindole and carboline derivatives, identifying 76 strongly photobasic compounds with pKa* as large as 22.6 out of the 155 compounds that we considered. Overall, this work provides new insights into the design principles necessary to develop next-generation photocatalysts that employ photobasicity.

Gramine-based structure optimization to enhance anti-gastric cancer activity

Gramine is a natural indole alkaloid with a wide range of biological activities, but its anti-gastric cancer activity is poor. Herein, a pharmacophore fusion strategy was adopted to design and synthesize a new series of indole-azole hybrids on the structural basis of gramine. Based on our previous studies, different nitrogen-containing five-membered heterocyclic rings and terminal alkyne group were introduced into the indole-based scaffold to investigate their effect on improving the anti-gastric cancer activity of gramine derivatives. Structure-activity relationship (SAR) studies highlighted the role played by terminal alkyne in enhancing the inhibitory effect, and compound 16h displayed the best antiproliferative activity against gastric cancer MGC803 cells with IC50 value of 3.74 μM. Further investigations displayed compound 16h could induce mitochondria-mediated apoptosis, and caused cell cycle arrest at G2/M phase. Besides, compound 16h could inhibit the metastasis ability of MGC803 cells. Our studies may provide a new strategy for structural optimization of gramine to enhance anti-gastric cancer activity, and provide a potential candidate for the treatment of gastric cancer.

Difference between ammonia and urea on nitrogen doping of graphene quantum dots

Nitrogen-doped graphene quantum dots (N-GQDs) with prime fluorescence properties were synthesized through a simple one-pot hydrothermal method by using citric acid as carbon source and ammonia (A-GQDs) or urea (U-GQDs) as nitrogen source. Both A-GQDs and U-GQDs exhibited a graphene-like structure, but their average particle size is about ten times different. A-GQDs exhibited an evident excitation-dependent photoluminescence (PL) behavior. By contrast, the emission of U-GQDs can be divided into two regions with the development of excitation wavelength: a wavelength-independent emission peak at approximately 540 nm (green) with the excitation wavelength from 400 nm to 500 nm and an excitation-dependent emission peak with the excitation wavelength below 400 nm. Ammonia was introduced into citric acid polycondensator in the form of five membered ring and urea in the form of seven membered ring, respectively, which further affected the subsequent crystallization and surface functionalization. At this time, the structural instability of the nitrogen-containing doped ring itself, coupled with the progress of carbonization, mostly forms a stable nitrogen-containing ring structure, which is likely to be pyrrolic nitrogen or graphitized nitrogen. Therefore, the differences in particle size and nitrogen-containing doped rings partially between A-GQDs and U-GQDs lead to the differences in optical properties. Finally, U-GQDs with high quantum yield (QY) of 54 % were obtained at the molar ratio of 9:10 (citric acid/urea) by optimizing the reaction conditions.

Oryzamutaic acid K and oryzadiamine C, alkaloids from an Oryza sativa mutant with yellow endosperm

Two new alkaloids, oryzamutaic acid K and oryzadiamine C, were isolated from the yellow endosperm of an Oryza sativa mutant. The structures of oryzamutaic acid K and oryzadiamine C were elucidated with spectroscopic analyses. Oryzamutaic acid K and oryzadiamine C are new C23N4- and C19N3-type alkaloids, respectively, that possess nitrogen-containing heterocyclic ring systems. Oryzadiamine C may play a significant role in the yellow color of the endosperm.

Thermochemical conversion of lignocellulosic bio-waste via fast pyrolysis in molten salts

This study, for the first time, investigated the volatiles emission and thermochemical conversion mechanism of bio-waste during pyrolysis in molten salts (NaNO3-KNO3-NaNO2) at 300 °C. Cations of molten salts acted as catalysts while anions participated in the pyrolysis reaction. Compared with salt-free pyrolysis, more bio-waste was decomposed in molten salts, to produce more than 14 times the mass of gaseous products and twice the mass of liquid products. Furthermore, the thermochemical conversion behavior of typical biomass constituents, i.e. cellulose, hemicellulose and lignin, was also distinguished. The results suggested that lignin was most easily pyrolyzed to form numerous liquid acids, some nitrated aromatic compounds and more CO, H2. In contrast, the decomposition of cellulose was certainly restricted while more significant effects of anions were found in hemicellulose cracking by generating nitrogen-containing heterocyclic rings and amines. Besides, interactions among different biomass constituents were confirmed to affect the generation of bio-waste pyrolysis products.

Synthesis and Anticancer Activity of Thiadiazole Containing Thiourea, Benzothiazole and Imidazo[2,1-b][1,3,4]thiadiazole Scaffolds.

A great array of nitrogen-containing heterocyclic rings were being extensively explored for their functional versatility in the field of medicine, especially in anticancer research. 1,3,4- thiadiazole is one of such heterocyclic rings with promising anticancer activity against several cancer cell lines, inhibiting diverse biological targets. The 1,3,4-thiadiazole, when equipped with other heterocyclic scaffolds, has displayed enhanced anticancer properties. The thiourea, benzothiazole, imidazo[2,1,b][1,3,4]-thiadiazoles are such potential scaffolds with promising anticancer activity. A new series of 5-substituted-1,3,4-thiadiazoles linked with phenyl thiourea, benzothiazole and 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized and tested for invitro anticancer activity on various cancer cell lines. The National Cancer Institute's preliminary anticancer screening results showed compounds 4b and 5b having potent antileukemic activity. Compound 4b selectively showed 32 percent lethality on Human Leukemia-60 cell line. The docking studies of the derivatives on aromatase enzyme (Protein Data Bank: 3S7S) have shown reversible interactions at the active site with good docking scores comparable to Letrozole and Exemestane. Furthermore, the selected derivatives were tested for anticancer activity on HeLa cell line based on the molecular docking studies. Compounds 4b and 5b showed effective inhibition equivalent to Letrozole. These preliminary biological screening studies have given positive anticancer activity for these new classes of derivatives. An additional research study like the mechanism of action of the anticancer activity of this new class of compounds is necessary. These groundwork studies illuminate a future pathway for research of this class of compounds enabling the discovery of potent antitumor agents.

Catalytic Asymmetric Formal [3+2] Cycloaddition of Azoalkenes with 3-Vinylindoles: Synthesis of 2,3-Dihydropyrroles

SummaryChiral phosphoric acid-catalyzed highly enantioselective formal [3 + 2] cycloaddition reaction of azoalkenes with 3-vinylindoles has been established. Under mild conditions, the projected cycloaddition proceeded smoothly, affording a variety of 2,3-dihydropyrroles in high yields and excellent enantioselectivities, and also in a diastereospecific manner. As opposed to the common 4-atom synthons in the previous literature reports, azoalkenes served as 3-atom synthons. Besides, the observed selectivity was supported by primary theoretical calculation. The unique chemistry of azoalkenes disclosed herein will empower asymmetric synthesis of nitrogen-containing ring structural motifs in a broader context.

Tetra-aqua-[3-oxo-1,3-bis-(pyridinium-2-yl)propan-1-olato]nickel(II) tribromide dihydrate.

The crystal structure of the title compound, [Ni(C13H11N2O2)(H2O)4]Br3·2H2O, contains an octa-hedral NiII atom coordinated to the enol form of 1,3-di-pyridyl-propane-1,3-dione (dppo) and four water mol-ecules. Both pyridyl rings on the ligand are protonated, forming pyridinium rings and creating an overall ligand charge of +1. The protonated nitro-gen-containing rings are involved in hydrogen-bonding inter-actions with neighoring bromide anions. There are many additional hydrogen-bonding inter-actions involving coordinated water mol-ecules on the NiII atom, bromide anions and hydration water mol-ecules.

Oryzadiamines A and B, alkaloids from Oryza sativa with yellow grain

Two new alkaloids, oryzadiamines A and B, were isolated from the bran of an Oryza sativa mutant with yellow grains. The structures of oryzadiamines A and B were elucidated with spectroscopic analyses. Oryzadiamines A and B are new natural products possessing unique nitrogen-containing heterocyclic ring systems. Oryzadiamine A may play a significant role in the yellow color of the grain.

Quantitative Structure-Cytotoxicity Relationship of 2-Arylazolylchromones and 2-Triazolylchromones.

4H-1-Benzopyran-4-one (chromone), present in various flavonoids as a backbone structure, has been used for the synthesis of anticancer drugs. The study aimed at investigating the cytotoxicity of eight 2-arylazolylchromones and twelve 2-triazolylchromones against four human oral squamous cell carcinoma (OSCC) cell lines and three human normal mesenchymal oral cells, and then performed a quantitative structure-activity relationship (QSAR) analysis. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The distribution of cells to various phases of cell cycle was determined by cell cycle analysis. A total of 3,218 physicochemical, structural and quantum chemical features were calculated for QSAR analysis from the most stabilized structure optimized using CORINA. 2-[4-(4-fluorophenyl)-1H-imidazol-1-yl]-4H-1-benzopyran-4-one [6] had the highest tumor-specificity (TS), comparable with that of 5-flurouracil (5-FU) and doxorubicin, inducing cytostatic growth inhibition, accumulation of G2+M phase cells with no cells in the G1 phase. All eight 2-triazolylchromones showed much lower tumor-specificity, confirming our previous finding. Tumor-specificity was also correlated with 3D shape, topological shape, size, ionization potential, and the presence of more than two aromatic rings in the molecule and imidazole ring in the nitrogen-containing heterocyclic ring. [6] can be a lead compound for designing anticancer drugs.

Oxidative stress-mediated photoactivation of carbazole inhibits human skin cell physiology.

Prolonged exposure of the earth's surface to the sun's ultraviolet radiation may result in various skin diseases and cataract. Carbazole (CBZ), as a polycyclic-aromatic hydrocarbon (PAH), is blended with a five-member nitrogen-containing ring. It is found in cigarette smoke, coal, eye kohl, tattoo ink, and wood combustion and affects various types of flora and fauna. Our findings suggest that CBZ generates reactive oxygen species (ROS) like through type-I photodynamic reaction and causes phototoxicity in the human keratinocyte cell line (HaCaT), which has been proved by mitochondrial dehydrogenase and neutral red uptake assays. CBZ induces single strand DNA damage. We have investigated the involvement of the apoptotic pattern of cell death and confirmed it by cytochrome C release from mitochondria and caspase-9 activation. Similarly, photo-micronuclei formation was associated to CBZ-induced phototoxicity. The results of this study strongly support that the upregulation of bax, cyto-C, apaf-1, casp-9 and down regulation of bcl2, keap-1, nrf-2, and hmox-1 genes cause apoptopic cell death. Downregulation of antioxidant genes showed a significant amount of ROS generation by photosensitized CBZ. Therefore, the current study will be a step forward to safeguard human beings from sunlight-induced photosensitive CBZ prolonged exposure.

Indolines made easy

Chemists don’t have great options if they want to make molecules containing indoline—a scaffold featuring a benzene ring fused to a nitrogen-containing five-membered ring. Indolines appear in many ...

Natural thiopeptides as a privileged scaffold for drug discovery and therapeutic development

Since the start of the 21st century, antibiotic drug discovery and development from natural products has experienced a certain renaissance. Currently, basic scientific research in chemistry and biology of natural products has finally borne fruit for natural product-derived antibiotics drug discovery. A batch of new antibiotic scaffolds were approved for commercial use, including oxazolidinones (linezolid, 2000), lipopeptides (daptomycin, 2003), and mutilins (retapamulin, 2007). Here, we reviewed the thiazolyl peptides (thiopeptides), an ever-expanding family of antibiotics produced by Gram-positive bacteria that have attracted the interest of many research groups thanks to their novel chemical structures and outstanding biological profiles. All members of this family of natural products share their central azole substituted nitrogen-containing six-membered ring and are classified into different series. Most of the thiopeptides show nanomolar potencies for a variety of Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumonia (PRSP). They also show other interesting properties such as antiplasmodial and anticancer activities. The chemistry and biology of thiopeptides has gathered the attention of many research groups, who have carried out many efforts towards the study of their structure, biological function, and biosynthetic origin. Here we reviewed a total of 119 natural thiopeptides discovered during the last 50 years. Moreover, we summarized biological profiles, mechanisms of action, and biosynthesis of these thiopeptides.

Raman, SERS, and DFT Analysis of the Main Alkaloids Contained in Syrian Rue

Syrian Rue, obtained from the seeds of the Peganum harmala plant, is a reddish colorant especially popular for dyeing carpets and wool fabrics in Western Asia and traditionally used as an alternative source for the madder-derived Turkey Red dye. The main constituents of the Syrian Rue dye are harmane, harmine, harmaline and harmalol, which belong to a group of substances collectively known as harmala alkaloids. These compounds are also called β-carboline alkaloids, as they display very similar molecular structures that consist of either a pyridine ring or a nitrogen-containing six-atom ring with two conjugated double bonds, each fused to an indole skeleton. In the present study, density functional theory was employed to perform a vibrational analysis of the four constituents of Syrian Rue by means of the Gaussian package. First, the molecular geometry of each compound was optimized and its Raman spectrum was calculated. Then, all the observed Raman bands were assigned to specific vibrational normal modes ...

Photo-Modification of Melanin by a Mid-infrared Free-electron Laser.

Melanin is rigidly constructed by several nitrogen-containing aromatic rings, and its excess accumulation in skin tissue is closely associated with melanosis. Although visible lasers (wavelength: 600-1000nm) are conventionally used for the photo-thermolysis of melanocyte, several pigmented nevi are difficult to be treated. Here, we propose an alternate method for targeting the molecular structure of melanin using an infrared free-electron laser (FEL) tuned to 5.8μm that corresponds to the stretching vibrational mode of carboxylate group. A drastic morphological change on the black-colored surface of melanin powder was observed after the pulse irradiation with power energy of 500mJcm-2 , and the minimum irradiation time for damage to the morphology was 1.4s. Analyses by mass spectroscopy, infrared spectroscopy, and 13 C-nuclear magnetic resonance implied that a pyrrole group was removed by the FEL irradiation. In addition, the FEL irradiation dispersed almost all of the melanoma cells from a culture solution without any influence on other ingredients in the medium, and one-cell analysis by infrared microscopy showed that the structure of melanoma could be substantially damaged by the irradiation. This study proposes the potency of intense mid-infrared laser as novel alternative way to reduce melanin.

An insight into the therapeutic potential of piperazine-based anticancer agents

The piperazine ring system is among the medicinally important nitrogen-containing heterocyclic ring systems and is exploited for the synthesis of various drug molecules. A number of FDA-approved anticancer drugs contain piperazine rings and thus it is considered as an attractive scaffold having extraordinary potential for the development of new anticancer agents. In recent decades there has been an alarming increase in the number of people suffering from cancerous diseases all over the world, which resulted in an extraordinary increase in research reports on new anticancer drug candidates. The aim of this article is to highlight the structural parameters imparting anticancer activity to piperazine derivatives and to indicate future perspectives for the discovery of new anticancer agents.

Photooxygenation of 2-propargylfurans: a path to structurally diverse nitrogen-containing 5-membered rings.

The photooxygenation of 2-propargylfurans enabled access to original nitrogen-containing cyclopentenones and related compounds in a one-pot fashion. By employing readily-available substrates such as furans and amines, we succeeded in achieving a high degree of molecular complexity. Relying on the introduction of an alkyne moiety and tailored substrates, this transformation reveals a new facet for reaction sequences featuring the photooxygenation of furans.

Metal-mediated synthesis of pyrrolines.

The five-membered, nitrogen-containing pyrroline ring is a privileged structure. This ring is present in many bioactive compounds from natural sources. Pyrrolines—the dihydro derivatives of pyrroles—have three structural isomer classes, depending on the location of the double bond: 1-pyrrolines (3,4-dihydro-2H-pyrroles), 2-pyrrolines (2,3-dihydro-1H-pyrroles) and 3-pyrrolines (2,5-dihydro-1H-pyrroles). This review aims to describe the latest advances for the synthesis of pyrrolines by transition metal-catalyzed cyclizations. Only reactions in which the pyrroline ring is formed by metal promotion are described. Transformations of the pyrroline ring in other heterocycles, and the structural manipulations of the pyrroline itself are not discussed. The review is organized into three parts, each covering the metal-mediated synthesis of the three pyrroline isomers. Each part is subdivided according to the metal involved, and concludes with a brief description of notable biological activities within the class.

Intermolecular Regio- and Stereoselective Hetero-[5+2] Cycloaddition of Oxidopyrylium Ylides and Cyclic Imines.

We have developed the first intermolecular hetero-[5+2] cycloaddition reaction between oxidopyrylium ylides and cyclic imines with excellent control of regio- and stereoselectivity. Surprisingly, divergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide. This new reaction provides quick access to highly substituted nitrogen-containing seven-membered rings-azepanes. Notably, a broad range of oxidopyrylium ylides and cyclic imines participate in this novel hetero-[5+2] cycloaddition reaction and the cycloadducts can be readily transformed into the core skeletons of bioactive natural products. DFT calculations revealed that the cycloaddition proceeds through a stepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition.