Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule

Metal-ion misregulation and oxidative stress continue to be components of the continually evolving hypothesis describing the molecular origins of Alzheimer’s disease. Therefore, these features are viable targets for synthetic chemists to explore through hybridizations of metal-binding ligands and antioxidant units. To date, the metal-binding unit in potential therapeutic small molecules has largely been inspired by clioquinol with the exception of a handful of heterocyclic small molecules and open-chain systems. Heterocyclic small molecules such as cyclen (1,4,7,10-tetraazacyclododecane) have the advantage of straightforward N-based modifications, allowing the addition of functional groups. In this work, we report the synthesis of a triazine bridged system containing two cyclen metal-binding units and an antioxidant coumarin appendage inspired by nature. This new potential therapeutic molecule shows the ability to bind copper in a unique manner compared to other chelates proposed to treat Alzheimer’s disease. DPPH and TEAC assays exploring the activity of <i>N</i>-(2-((4,6-di­(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)­amino)­ethyl)-2-oxo-2<i>H</i>-chromene-3-carboxamide (molecule <b>1</b>) show that the molecule is antioxidant. Cellular studies of molecule <b>1</b> indicate a low toxicity (EC₅₀ = 80 μM) and the ability to protect HT-22 neuronal cells from cell death induced by Aβ + copper­(II), thus demonstrating the potential for molecule <b>1</b> to serve as a multimodal therapeutic for Alzheimer’s disease

Design, Synthesis and Biological Assessment of a Triazine Dendrimer with Approximately 16 Paclitaxel Groups and 8 PEG Groups

The synthesis and characterization of a generation three triazine dendrimer that displays a phenolic group at the core for labeling, up to eight 5 kDa PEG chains for solubility, and 16 paclitaxel groups is described. Three different diamine linkersdipiperidine trismethylene, piperazine, and aminomethylpiperidinewere used within the dendrimer. To generate the desired stoichiometric ratio of 8 PEG chains to 16 paclitaxel groups, a monochlorotriazine was prepared with two paclitaxel groups attached through their 2′-hydroxyls using a linker containing a labile disulfide. This monochlorotriazine was linked to a dichlorotriazine with aminomethylpiperidine. The resulting dichlorotriazine bearing two paclitaxel groups could be reacted with the eight amines of the dendrimer. NMR and MALDI-TOF confirm successful reaction. The eight monochlorotriazines of the resulting material are used as the site for PEGylation affording the desired 2:1 stoichiometry. The target and intermediates were amenable to characterization by ¹H and ¹³C NMR, and mass spectrometry. Analysis revealed that 16 paclitaxel groups were installed along with 5–8 PEG chains. The final construct is 63% PEG, 22% paclitaxel, and 15% triazine dendrimer. Consistent with previous efforts and computational models, 5 kDa PEG groups were essential for making the target water-soluble. Molecular dynamics simulations showed a high degree of hydration of the core, and a radius of gyration of 2.8 ± 0.2 nm. The hydrodynamic radius of the target was found to be 15.8 nm by dynamic light scattering, an observation indicative of aggregation. Drug release studies performed in plasma showed slow and identical release in mouse and rat plasma (8%, respectively). SPECT/CT imaging was used to follow biodistribution and tumor uptake. Using a two component model, the elimination and distribution half-lives were 2.65 h and 38.2 h, respectively. Compared with previous constructs, this dendrimer persists in the vasculature longer (17.33 ± 0.88% ID/g at 48 h postinjection), and showed higher tumor uptake. Low levels of dendrimer were observed in lung, liver, and spleen (∼6% ID/g). Tumor saturation studies of small prostate cancer tumors (PC3) suggest that saturation occurs at a dose between 23.2 mg/kg and 70.9 mg/kg