Substituted 1,3,5‐Triazaadamantanes: Biocompatible and Degradable Building Blocks

Abstract

Basic groups from acid hydrolysis: 1,3,5-Triazaadamantanes (TAAs) are shown to degrade in acidic conditions to produce basic by-products. The rate of hydrolysis can be tuned by changing the substituents present on the aromatic rings. TAA containing dendrimers can be synthesized readily as a result of their branched architecture.Keywords controlled degradation; dendrimers; macromolecule synthesis; guest binding Degradable polymers are important constituents of environmentally benign products and are used in applications that range from tissue engineering [1] to gene [2] and drug delivery. [1,3] Hydrolytically labile polymers, such as polyesters, are particularly useful because of the ubiquitous presence of water in the environment and in living organisms. However, polyesters produce acidic byproducts upon degradation, a limitation for a number of applications. [4] Poly-phosphazenes [5] are promising alternatives, but there is a need for new monomers that degrade to benign byproducts. Herein we report the synthesis and study of 1,3,5-triazaadamantane (TAA) as a water-soluble unit for controlled degradation and aldehyde release. Formed from the condensation of a tris(aminomethyl)methane unit and three aromatic aldehydes, [6] the TAA unit hydrolyzes under physiological conditions reverting to its precursors that are basic. We show that the degradation rate of the TAA unit can be tuned with substituents and further synthesize a hydrophilic TAA based dendrimer that is capable of binding solvatochromic probes.The preparation of TAA 2 by the condensation of trisamine 1 and benzaldehyde (Figure 1a) was reported by Woulfe. [6a] In our hands, this procedure produced 2a and 2b in a 9:1 ratio ( 1 H NMR). Difference nuclear Overhauser effect (NOE) studies were performed on 2a to establish the relative spatial orientation of the methine protons (Figure 1b). To confirm further its identity, an X-ray analysis was performed on crystals of 2a grown by the slow evaporation of an acetonitrile solution (Figure 1c). Submitting minor isomer 2b to the reaction conditions resulted in a 9:1 ratio of 2a to 2b, indicating the reaction to be thermodynamically controlled.

2,4,9‐Triazaadamantanes with “Clickable” Groups: Synthesis, Structure and Applications as Tripodal Platforms

“…The stability of a 1,3,5‐triazacyclohexane unit can be greatly increased by its incorporation into a cage structure, as demonstrated by several experimental [ 1h,17 ] and theoretical studies. [ 17d,18 ] For this reason, azaadamantanes, [ 19 ] triazawurtzitanes, [ 1h ] and triaza[3]peristylanes [ 20 ] containing nitrogen atoms in bridge positions are considered to be promising molecular platforms for various applications (Scheme 1, chart c). Moreover, the reversible cleavage of a 1,3,5‐triazacyclohexane ring in these heterocage systems does not lead to a loss of covalent integrity between the functional units, thus providing a way to control the topology of the scaffold.…”

“…Recently, our group introduced 1,4,6,10‐tetraazaadamantane (TAAD) as a readily available, stable, and easy‐to‐modify multifunctional platform (Scheme 1, chart c). [ 17c,19c,21 ] Our group and others have shown the application of TAAD derivatives in the design of fluorophore‐labelled natural molecules, [ 22 ] biodegradable polymers, [ 22 ] polymer‐bound organocatalysts, [ 22 ] scavengers for boronic acids, [ 22 ] water‐soluble phthalocyanines, [ 23 ] capped metal complexes, [ 24 ] and dynamic combinatorial libraries. [ 22 ] Surprisingly, 2,4,9‐triazaadamantane (TRIAD), which is a simpler analog of TAAD, has received much less attention and was not considered for applications as a molecular platform (Scheme 1, chart c).…”

Photoresponsive Crosslinked Hyperbranched Polyglycerols as Smart Nanocarriers for Guest Binding and Controlled Release

“…Many successful pH‐cleavable dendritic nanocarriers have been reported 11–19. However, there are far fewer investigations of light‐responsive dendritic hosts.…”

“…Many successful pH-cleavable dendritic nanocarriers have been reported. [11][12][13][14][15][16][17][18][19] However, there are far fewer investiga-tions of light-responsive dendritic hosts. Shabat and coworkers have reported dendrons that release their end-groups through a photo-triggered self-immolative process initiated by a single photocleavage at a focal point.…”

Tuning hydrogel properties and function using substituent effects

“…As shown schematically in Fig. 1, these cross-linkers possess a hydrolytically labile TAA unit with three aromatic groups to control hydrolysis rates through substituent effects,5,6 three acrylamide groups for cross-linking, and a poly-(ethylene glycol) chain for water solubility. Reports by several groups have shown that the rate of degradation of acetal-containing hydrogels can be tuned under acidic conditions 7.…”