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TFA-catalyzed Q-Tube Reactor-Assisted Strategy for the Synthesis of Pyrido[1,2-b][1,2,4]triazine and Pyrido[1',2':2,3][1,2,4]triazino[5,6-b]indole Derivatives.

ABSTRACT: An efficient high-pressure-assisted trifluoroacetic acid-catalyzed protocol for synthesizing unreported novel pyrido[1,2-b][1,2,4]triazine and pyrido[1',2':2,3][1,2,4]triazino[5,6-b]indole derivatives has been established. This strategy includes the condensation reactions of various 1-amino-2-imino-4-arylpyridine-3-carbonitrile derivatives with indoline-2,3-dione (isatin) derivatives and α-keto acids such as pyruvic acid and phenylglyoxylic acid. This strategy includes utilizing the Q-tube reactor as an efficient and safe tool to conduct these reactions under high-pressure conditions. In addition, trifluoroacetic acid was used to induce this transformation. In this research, conducting the targeted reactions under high pressure using the Q-tube reactor was found to be superb in comparison to that under the traditional refluxing conditions. X-ray single-crystal analysis was utilized in this study to authenticate the structure of the synthesized products.

SUBMITTER: Ibrahim HM

PROVIDER: S-EPMC8223412 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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TFA-catalyzed Q-Tube Reactor-Assisted Strategy for the Synthesis of Pyrido[1,2-b][1,2,4]triazine and Pyrido[1',2':2,3][1,2,4]triazino[5,6-b]indole Derivatives.

Ibrahim Hamada Mohamed HM Behbehani Haider H

ACS omega 20210608 24

An efficient high-pressure-assisted trifluoroacetic acid-catalyzed protocol for synthesizing unreported novel pyrido[1,2-b][1,2,4]triazine and pyrido[1',2':2,3][1,2,4]triazino[5,6-b]indole derivatives has been established. This strategy includes the condensation reactions of various 1-amino-2-imino-4-arylpyridine-3-carbonitrile derivatives with indoline-2,3-dione (isatin) derivatives and α-keto acids such as pyruvic acid and phenylglyoxylic acid. This strategy includes utilizing th ...[more]

PMID: 34179654

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Project description:BackgroundFor the development of properties in molecular crystals, such as electrical conductivities, magnetic properties, or non-linear optical properties, not only the electronic properties of molecules themselves matter, but also the molecular arrangements in the crystals are very important. Therefore, the design of the crystal structures and the control of molecular arrangements have attracted much attention in recent years. Among various ligands, triazine moieties have been especially interesting because of their biological, pharmacological and medicinal properties.ResultsCrystal structure of 5-Methoxy-5,6-diphenyl-4,5-dihydro-2H-1,2,4-triazine-3-thione is Monoclinic, which consists of space group P21/c with a = 9.699(1), b = 8.500(1), c = 18.044(2) Å, β = 101.290(7)° and Z = 4, R1 = 0.0371 and wR2 = 0.1008 with 2456 reflections (I > 2σ(I)). Intermolecular H bonds between NH groups are acting as donors and S atoms as acceptors. There are also shorted face-to-face as well as edge to face π-π stacking interactions between the parallel aromatic rings. The behavior of solvatochromic of the mentioned compound that involved interhydrogen bonding was investigated by studying its electronic absorption spectra in pure organic solvents of different characters.ConclusionsThe crystal structure of C16H15N3OS, shows the expected face-to-face π-π stacking interactions between aromatic rings of the neighbor chains in this compound. The centroid-centroid distance between the aromatic rings is 3.325 Å. It was found that the monomer of the ligand 5-Methoxy-5,6-diphenyl-4,5-dihydro-2H-1,2,4-triazine-3-thione, further extends into 3D networks via hydrogen bonding and pi-pi stacking interactions. The solvatochromic behavior of the title compound was also investigated by studying its spectra in a selection of different organic solvents. While progressing from the non-polar solvent to the polar one, the main intense band at 310 nm, which is due to the π-π* transition, was red shifted by 13 nm. Thus, the title compound showed positive solvatochromic behavior.

Project description:2-Amino-9H-pyrido[2,3-b]indole (A?C) is a carcinogenic heterocyclic aromatic amine (HAA) that arises in tobacco smoke. UDP-glucuronosyltransferases (UGTs) are important enzymes that detoxicate many procarcinogens, including HAAs. UGTs compete with P450 enzymes, which bioactivate HAAs by N-hydroxylation of the exocyclic amine group; the resultant N-hydroxy-HAA metabolites form covalent adducts with DNA. We have characterized the UGT-catalyzed metabolic products of A?C and the genotoxic metabolite 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-A?C) formed with human liver microsomes, recombinant human UGT isoforms, and human hepatocytes. The structures of the metabolites were elucidated by (1)H NMR and mass spectrometry. A?C and HONH-A?C underwent glucuronidation by UGTs to form, respectively, N(2)-(?-D-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (A?C-N(2)-Gl) and N(2)-(?-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (A?C-HON(2)-Gl). HONH-A?C also underwent glucuronidation to form a novel O-linked glucuronide conjugate, O-(?-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (A?C-HN(2)-O-Gl). A?C-HN(2)-O-Gl is a biologically reactive metabolite and binds to calf thymus DNA (pH 5.0 or 7.0) to form the N-(deoxyguanosin-8-yl)-A?C adduct at 20-50-fold higher levels than the adduct levels formed with HONH-A?C. Major UGT isoforms were examined for their capacity to metabolize A?C and HONH-A?C. UGT1A4 was the most catalytically efficient enzyme (V(max)/K(m)) at forming A?C-N(2)-Gl (0.67 ?l·min(-1)·mg of protein(-1)), and UGT1A9 was most catalytically efficient at forming A?C-HN-O-Gl (77.1 ?l·min(-1)·mg of protein(-1)), whereas UGT1A1 was most efficient at forming A?C-HON(2)-Gl (5.0 ?l·min(-1)·mg of protein(-1)). Human hepatocytes produced A?C-N(2)-Gl and A?C-HN(2)-O-Gl in abundant quantities, but A?C-HON(2)-Gl was a minor product. Thus, UGTs, usually important enzymes in the detoxication of many procarcinogens, serve as a mechanism of bioactivation of HONH-A?C.

Project description:2-Amino-9H-pyrido[2,3-b]indole (AαC) is the most abundant carcinogenic heterocyclic aromatic amine (HAA) formed in mainstream tobacco smoke. AαC is a liver carcinogen in rodents, but its carcinogenic potential in humans is not known. To obtain a better understanding of the genotoxicity of AαC in humans, we have investigated its metabolism and its ability to form DNA adducts in human hepatocytes. Primary human hepatocytes were treated with AαC at doses ranging from 0.1-50 μM, and the metabolites were characterized by ultra-performance LC/ion trap multistage mass spectrometry (UPLC/MSn). Six major metabolites were identified: a ring-oxidized doubly conjugated metabolite, N2-acetyl-2-amino-9H-pyrido[2,3-b]indole-6-yl-oxo-(β-d-glucuronic acid) (N2-acetyl-AαC-6-O-Gluc); two ring-oxidized glucuronide (Gluc) conjugates: 2-amino-9H-pyrido[2,3-b]indol-3-yl-oxo-(β-d-glucuronic acid) (AαC-3-O-Gluc) and 2-amino-9H-pyrido[2,3-b]indol-6-yl-oxo-(β-d-glucuronic acid) (AαC-6-O-Gluc); two sulfate conjugates, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (AαC-3-O-SO3H) and 2-amino-9H-pyrido[2,3-b]indol-6-yl sulfate (AαC-6-O-SO3H); and the Gluc conjugate, N2-(β-d-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N2-Gluc). In addition, four minor metabolites were identified: N2-acetyl-9H-pyrido[2,3-b]indol-3-yl sulfate (N2-acetyl-AαC-3-O-SO3H), N2-acetyl-9H-pyrido[2,3-b]indol-6-yl sulfate (N2-acetyl-AαC-6-O-SO3H), N2-acetyl-2-amino-9H-pyrido[2,3-b]indol-3-yl-oxo-(β-d-glucuronic acid) (N2-acetyl-AαC-3-O-Gluc), and O-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN2-O-Gluc). The latter metabolite, AαC-HN2-O-Gluc is a reactive intermediate that binds to DNA to form the covalent adduct N-(2'-deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AαC). Preincubation of hepatocytes with furafylline, a selective mechanism-based inhibitor of P450 1A2, resulted in a strong decrease in the formation of AαC-HN2-O-Gluc and a concomitant decrease in DNA adduct formation. Our findings describe the major pathways of metabolism of AαC in primary human hepatocytes and reveal the importance of N-acetylation and glucuronidation in metabolism of AαC. P450 1A2 is a major isoform involved in the bioactivation of AαC to form the reactive AαC-HN2-O-Gluc conjugate and AαC-DNA adducts.

Dataset Information

TFA-catalyzed Q-Tube Reactor-Assisted Strategy for the Synthesis of Pyrido[1,2-b][1,2,4]triazine and Pyrido[1',2':2,3][1,2,4]triazino[5,6-b]indole Derivatives.

Publications

TFA-catalyzed Q-Tube Reactor-Assisted Strategy for the Synthesis of Pyrido[1,2-<i>b</i>][1,2,4]triazine and Pyrido[1',2':2,3][1,2,4]triazino[5,6-<i>b</i>]indole Derivatives.

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