The 8 year thicket of triazine dendrimers: strategies, targets and applications

Abstract

This manuscript focuses on the routes, methods and reagents used to synthesize triazinebased dendrimers. Our pursuit of macromolecular architectures for drug deliverydendrimers based on triazines-has been an ongoing effort for 8 years. To date, we have produced complex dendrimers with diverse peripheries as proof-of-concept, less complex molecules tailored for specific applications including DNA and RNA delivery and drugdecorated dendrimers for potential therapeutic applications including infectious disease and cancer. These syntheses have been executed at scales that range from high milligrams to over a kilogram. The routes, reagents and diversity displayed by a target anchors it in time. Early targets derive from convergent synthetic routes while later targets are prepared using divergent syntheses. The core of early dendrimers was a simple diamine, including piperazine, yielding the so-called bow-tie structures, middle period targets boast either a trispiperazinyltriazine core or a 'super-core' with six piperazine groups. Later targets return to the trispiperazinyltriazine core. The choice of linking diamine has also changed. Over time, p-aminobenzylamine was replaced by piperazine and then by aminomethylpiperidine with more exotic diamines sprinkled in throughout. Peripheral group choice has undergone similar variations: from AB 2 to AB 4 to, more recently, AB 3 . The diversity communicated by these groups yields dendrimers ranging from those with a common surface to examples where two groups were presented to those where four orthogonally reactive groups appear. Over time, these groups have grown in complexity from protected amines to tags for biodistribution and drugs like paclitaxel. Herein, strategies adopted and lessons learned are reviewed, intuitions relayed and future directions forecast.

Dendrimers Terminated with Dichlorotriazine Groups Provide a Route to Compositional Diversity

“…11 By controlling reaction temperature, trisubstituted triazines can be readily accessed in good yields, purity and at large scale. 12 We have invested significant energies in understanding the relative reactivity of amine nucleophiles for triazines 13 and used these methods to generate a range of dendrimers targets.…”

“…12 We have invested significant energies in understanding the relative reactivity of amine nucleophiles for triazines 13 and used these methods to generate a range of dendrimers targets. 11 Early efforts to generate compositional diversity to make a dendrimer with a unique site on the periphery 8a or to install different orthogonal protecting groups both relied a convergent synthetic strategy. 8b Thayumanavan has generated similarly diverse targets using arylethers.…”

Fluorescein labelled cationic carbosilane dendritic systems for biological studies

“…The characteristics of dendritic macromolecules, as well-defined size and structure, flexibility, monodispersity and multivalent molecular surface [15][16][17][18][19][20][21][22], make them very attractive for biomedical applications [23][24][25][26][27][28][29][30][31]. http Furthermore, their multivalency can be employed to obtain multitasking therapeutics.…”

Designing, characterization, and thermal behavior of triazine-based dendrimers

“…Polyamidoamine (PAMAM) and polypropylene-imine (PPI) are traditionally the most explored classes of dendrimers. Recently, dendritic architectures based on triazine have been explored in a wide range of field of applications such as antitumor agents [2,3], molecular recognition [4], gene therapy [5], optics [6,7], catalytic supports [8], solubility enhancer of drug [9,10], and water remediation [11].…”