Synthesis of pyrido-annelated [1,2,4,5]tetrazines, [1,2,4]triazepine, and [1,2,4,5]tetrazepines for anticancer, DFT, and molecular docking studies.

In this strategy, we attempt to design various novel nitrogen-rich heterocycles in one molecule. Green, simple, and efficient aza-annulations of an active, versatile building block, 1-amino-4-methyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile (1), with different bifunctional reagents were developed under solvent-free conditions, resulting in the bridgehead tetrazines and azepines (triazepine and tetrazepines). Pyrido[1,2,4,5]tetrazines have been synthesized through two pathways; [3 + 3]- and [5 + 1]-annulations. In addition, pyrido-azepines have been developed by applying [4 + 3]-and [5 + 2]-annulations. This protocol establishes an efficient technique for synthesizing essential biological derivatives of 1,2,4,5-tetrazines, 1,2,4-triazepines, and 1,2,4,5-tetrazepine, tolerating a diverse variety of functionalities without the need for catalysis and fast reaction rates in high yields. The National Cancer Institute (NCI, Bethesda, USA) examined twelve compounds produced at a single high dosage (10-5 M). Compounds 4, 8, and 9 were discovered to have potent anticancer action against certain cancer cell types. To explain NCI results, the density of states was calculated to conduct a better description of the FMOs. The molecular electrostatic potential maps were created to explain a molecule's chemical reactivity. In silico ADME experiments were performed to better understand their pharmacokinetic characteristics. Finally, the molecular docking investigations on Janus Kinase-2 (PDB ID: 4P7E) were carried out to study the binding mechanism, binding affinity, and non-bonding contacts.

Dry Grinding Synthesis and Docking Study of Cyclopentanone-Sulfur Containing Compounds with Anti-Proliferative Activity for HepG-2 and A-549 Cancer Cell Lines.

BACKGROUND: The dry grinding method is a green technique for efficient organic synthesis with numerous advantages, such as mild reaction conditions, environmental acceptability, simple segregation, and refinement, as well as elevated selectivity and efficiency. OBJECTIVE: The aim of the present work is to design and synthesize cyclopentylidene-hydrazino)- thiazole derivatives using dry grinding conditions to investigate their antitumor activity against two cell lines, namely, HepG-2 and A-549. METHODS: In this context, we synthesized a series of thiazole incorporated cyclopentane through hydrazone- group and 2-cyclopentylidenehydrazine-1-carbimidic-2-ethoxy-N-aryl-2-oxoacetohydrazonic thioanhydride under dry grinding within minutes and excellent to good yield. RESULTS: All spectral data confirmed the proposed structures. In addition to antitumor activity investigations against the two kinds of cancer cells, molecular docking studies were conducted using Macrophage Migration Inhibitory Factor (Pdb: 4k9g) and Lysozyme C (Pdb: 2f4a), the overexpressed proteins in the human liver cancer cell (HepG-2) and lung cancer cell lines (A-549), respectively. CONCLUSION: Two derivatives, 9b, and 9d, showed the highest antitumor activity against the two cell lines HepG-2 and A-549. Also, docking results revealed a high energy score ranging from -7.1590 to -5.9364 Kcal/mol with Macrophage Migration Inhibitory Factor (Pdb: 4k9g), more than that the energy score = -4.118 Kcal/mol of co-crystallized ligand. Moreover, the tested derivatives showed energy score varies from -6.0802 to -4.5503 Kcal/mol against Lysozyme C (Pdb: 2f4a).

DNA binding studies of novel diazatruxenones analogs as potential anticancer agents: Synthesis, antitumor investigation, DNA binding, SAR and molecular modeling calculation.

A series of polycyclic skeleton of truxene and triazatruxene analogs has been synthesized and evaluated for antitumor and DNA binding activities. The synthesized structures were confirmed by different spectroscopic techniques such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The antitumor screening was performed adopting the NCI protocol against 60 different cell lines. Compounds 2 and 8 proved to be the most active ones among the other target compounds. In a trial to investigate the mechanism of action of the target compounds, DNA binding activity was also investigated. Compounds 3f, 4-8 exhibited good binding activity explaining their mechanism. In addition, molecular modeling studies were also performed for more clearance of the data obtained from the biological screening.