Rational design, synthesis, pharmacophore modeling, and docking studies for identification of novel potent DNA-PK inhibitors.

Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates. Based upon the modeling results, we gave a report of synthesis of fifteen novel 2-((8-methyl-2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-7-yl)oxy)acetamide derivatives and in vitro evaluation for DNA-PK inhibitory and antiproliferative activities. These fifteen compounds overall are satisfied with Lipinski's rule of five. The biological testing of target compounds showed five promising active compounds 7c, 7d, 7f, 9e and 9f with micromolar DNA-PK activity range from 0.25 to 5µM. In addition, SAR of the compounds activity was investigated and confirmed that the terminal aryl moiety was found to be quite crucial for DNA-PK activity. Moreover flexible docking simulation was done for the potent compounds into the putative binding site of the 3D homology model of DNA-PK enzyme and the probable interaction model between DNA-PK and the ligands was investigated and interpreted.

Synthesis and characterization of fluorescent pyrrolyldipyrrinato Sn(IV) complexes.

A series of neutral, 5-coordinate pyrrolyldipyrrinato Sn(IV) complexes have been synthesized via reaction of a pyrrolyldipyrrin, or its corresponding hydrochloride salt, with dibutyltin or diphenyltin oxide. The complexes are structurally unique in that all three nitrogen atoms of the pyrrolyldipyrrinato ligand bind to the tin center, making these complexes the first examples of pyrrolyldipyrrins behaving as LX(2) ligands. The complexes are highly fluorescent, exhibiting fluorescence quantum yields between 0.28 and 0.61, and display interesting preliminary biological activity.

Design, Synthesis, Molecular Modeling, Anticancer Studies, and Density Functional Theory Calculations of 4-(1,2,4-Triazol-3-ylsulfanylmethyl)-1,2,3-triazole Derivatives.

New conjugates of substituted 1,2,3-triazoles linked to 1,2,4-triazoles were synthesized starting from the appropriate S-propargylated 1,2,4-triazoles 7 and 8. Ligation of 1,2,4-triazoles to the 1,2,3-triazole core was performed through Cu(I)-catalyzed cycloaddition of 1,2,4-triazole-based alkyne side chain 7 and/or 8 with several un/functionalized alkyl- and/or aryl-substituted azides 9-15 to afford the desired 1,4-disubstituted 1,2,3-triazoles 16-27, using both classical and microwave methods. After their spectroscopic characterization (infrared, 1H, 13C nuclear magnetic resonance, and elemental analyses), an anticancer screening was carried out against some cancer cell lines including human colon carcinoma (Caco-2 and HCT116), human cervical carcinoma (HeLa), and human breast adenocarcinoma (MCF-7). The outcomes of this exploration revealed that compounds 17, 22, and 25 had a significant anticancer activity against MCF-7 and Caco-2 cancer cell lines with IC50 values of 0.31 and 4.98 µM, respectively, in relation to the standard reference drug, doxorubicin. Enzyme-docking examination was executed onto cyclin-dependent kinase 2; a promising aim for cancer medication. Synthesized compounds acquiring highest potency showcased superior interactions with the active site residue of the target protein and exhibited minimum binding energy. Finally, the density functional theory (DFT) calculations were carried out to confirm the outcomes of the molecular docking and the experimental findings. The chemical reactivity descriptors such as softness (δ), global hardness (η), electronegativity (χ), and electrophilicity were calculated from the levels of the predicted frontier molecular orbitals and their energy gap. The DFT results and the molecular docking calculation results explained the activity of the most expectedly active compounds 17, 22, and 25.

Formation of vinylic dipyrroles by the deprotonation of meso-alkyl and meso-benzyl dipyrrin HCl salts.

Under basic conditions, dipyrrin salts bearing alkyl and benzyl groups at the meso-position undergo deprotonation to give vinylic dipyrroles, rather than the corresponding free-base dipyrrins. The deprotonation is reversible and quantitatively returns the dipyrrinato framework under acidic conditions.

Highly diastereoselective templated complexation of dipyrromethenes.

[reaction: see text] Bis(dipyrromethene)s with relatively long spacers (>5 atoms) form helical monomeric complexes as the two binding units of the bis(dipyrromethene) chelate around the same tetrahedrally coordinated metal ion. Herein we report the first highly diastereoselective mononuclear helicate-forming complexation reactions of bis(dipyrromethene)s using homochiral binol and tartrate motifs which serve as both linkers and asymmetric templates.