The synthesis and self-assembling properties of 8-aryl-2′-deoxyguanosine derivatives are described. Our studies suggest that a properly placed acetyl group can increase the stability and specificity of the resulting G-quadruplex supramolecules by enhancing noncovalent interactions such as hydrogen bonds and π-stacking.

Here we show 2'-deoxyguanosine derivatives that self-assemble in aqueous media into discrete supramolecular hexadecamers and exhibit the lower critical solution temperature (LCST) phenomenon. Spectroscopic, calorimetric and electron microscopy studies support the fact that above transition temperature (T t ) the supramolecules further assemble into nanoscopic spherical globules of low polydispersity. Furthermore, the T t can be tuned to higher values by the addition of a more hydrophilic derivative. These findings uncover a new paradigm in the development of smart thermosensitive materials with properties and applications complementary to those of polymers.Naturally occurring molecular machines self-assemble into a wide variety of nanostructures that are able to sense environmental changes and respond to them accordingly. Artificial stimuli responsive (i.e., smart) materials have found numerous applications in biomedicine and nanotechnology. 1 This is due to their ability to undergo large changes in a property triggered by a relatively small stimulus. In thermosensitive materials, when a water soluble substance is made increasingly hydrophobic, it will reach a range of compositions upon which it will show a lower critical solution temperature (LCST) before becoming completely insoluble. 2 Polymers represent the overwhelming majority of known substances that show the LCST phenomenon by undergoing a coil to globule transition and/or self-assembling into aggregates upon reaching a transition temperature (T t ). 1c,3,4 Thermally responsive polymers, most notably, elastin-like polypeptides (ELPs) 5 and poly(N-isopropylacrylamide) (pNIPAAm), 6 are attractive due to their suitability for fundamental studies as well as their practical uses in a plethora of applications. [7][8][9][10][11] Although in principle, non-polymeric and well-defined supramolecular assemblies could be developed to show this property, to the best of our knowledge, there are still no known examples of such substances. Here we show 2'-deoxyguanosine derivatives that self-assemble in aqueous media into discrete supramolecular hexadecamers and exhibit the LCST phenomenon. Furthermore, the T t can be tuned to higher values by the addition of a more hydrophilic jmrivortz@mac.com. Supporting Information Available: Detailed synthetic procedures, characterization for all new compounds, experimental protocols, and NMR data. This material is available free of charge via the Internet at http://pubs.acs.org. Supramolecular self-assembly offers a complementary biomimetic strategy to the use of polymers for the development of functional nanostructures. 1,12,13 Attractive features of supramolecular self-assembly include synthetic economy and the dynamic exchange of subunits. Our efforts in this field have been aimed at studying the self-assembly of 2'-deoxyguanosine derivatives, in particular, modulation of the resulting supramolecular structures by replacing H8 in the guanine moiety with a functionalized aryl group (Figure 1). 14 We have shown that the ...

Herein we describe the construction of hexadecameric self-assembled dendrimers (SADs) using a series of dendronized 8-(m-acetylphenyl)-2′-deoxyguanosine (mAG) subunits. The azido-substituted mAG subunits were covalently linked to alkynyl polyester dendrons using a copper-catalyzed 1,3-dipolar cycloaddition reaction. Discrete SADs are formed with high fidelity and thermal stability even with the increased steric hindrance offered by the dendrons.

An 8-(phenyl)-2′-deoxyguanosine derivative self-assembles in aqueous media into discrete hexadecamers that further self-assemble above 32 °C into microglobules that encapsulate the drug doxorubicin.Advances in supramolecular chemistry have led to the design of a variety of biomimetic materials that are suitable for the development of stimuli responsive nanocarrier systems. [1][2][3] Light, pH, magnetic fields and temperature are among the most frequently used stimuli. 4 Nano-and microscopic globular assemblies made from thermoresponsive polymers are likewise promising systems for responsive drug carriers. 5,6 Besides the Elastin-Like Polypeptides, 7 most of the work in this area has relied on the poly(N-isopropylacrylamide) 8 scaffold, and its copolymers, as environmentally responsive materials due to their sharp coilto-globule transition at biocompatible temperatures of around 32 °C. 9 Supramolecular self-assembly offers a complement ary strategy to the use of polymers for the development of functional nanostructures. 10 To circumvent some of the limitations shown by polymers (e.g., polydispersity, lack of self-correcting synthesis) and to obtain new thermoresponsives scaffolds, recently, our lab developed an 8-(meta-acetylphenyl)-2′-deoxyguanosine (mAG) derivative that self-assembles in aqueous media into discrete supramolecular hexadecamers that exhibit the Lower Critical Solution Temperature (LCST) phenomenon. 11 Such LCST phenomenon occurs with a transition temperature (T t ) of 58 °C, above which the supramolecular hexadecamers engage in a temperature induced assembly to form solid nanoscopic globules of low polydispersity. 11 We hypothesized that these globules could provide a versatile scaffold for host-guest recognition in aqueous media. Furthermore, if the T t were reduced to a value closer to and below body temperature, these systems may become suitable to prepare thermoresponsive nano-or microcarriers for bioactive materials such as drugs. Herein, we report our initial attempts towards achieving these goals.Controlling the T t via intrinsic parameters (i.e., structural information in the building blocks of supramolecules) enables the reliable construction of nanostructures of well-defined size Correspondence to: José M. Rivera, jmrivortz@mac.com. NIH Public Access Author ManuscriptChem Commun (Camb). Author manuscript; available in PMC 2011 December 7. and composition. In recent years we have developed a family of 8-aryl-2′-deoxyguanosine (8ArG) derivatives as versatile recognition motifs for the construction of supramolecular nanostructures in both organic 12,13 and aqueous media 14 (Scheme 1). Our studies suggest that properly placed functional groups can increase the stability and specificity of the resulting G-quadruplex supramolecules by enhancing non-covalent interactions such as hydrogen bonds and pi-stacking. 15 To this end, we synthesized the 8-(metaethoxycarbonylphenyl)-2′-deoxyguanosine (mECGD2OH, 1) derivative, which shows a lower T t than our previous mAG-based system. This new 8...

The naturally occurring (5Z,9Z)-5,9-hexadecadienoic acid was synthesized stereochemically pure in six steps starting with commercially available 1,5-hexadiyne. The title compound was antimicrobial against the Gram-positive bacteria Staphylococcus aureus (MIC 80 microM) and Streptococcus faecalis (MIC 200 microM), but inactive against Gram-negative bacteria such as Pseudomonas aeruginosa. In addition, the (5Z,9Z)-5,9-hexadecadienoic acid completely inhibits human topoisomerase I at a concentration of 800 microM, while 5,9-hexadecadiynoic acid and hexadecanoic acid do not inhibit topoisomerase I (>1000 microM). This comparison reveals that the cis double bond geometry in the title compound is required for topoisomerase I inhibition. Moreover, these results suggest that the antimicrobial activity of (5Z,9Z)-5,9-hexadecadienoic acid against either S. aureus or S. faecalis could be a result, at least in part, of the inhibitory activity of the acid against topoisomerases.

Here we show the reversible high fidelity switching between two discrete self-assembled supramolecules made from a lipophilic 8-phenyl-2'-deoxyguanosine derivative induced by an indirect solvent effect. A hexadecameric supramolecule containing four stacked tetramers is formed in acetonitrile aided by higher potassium concentrations. When the amount of weakly solvated potassium decreases, due the lower activity of potassium iodide in chloroform, an octamer is formed after the dissociation of the two outer tetramers in the hexadecamer. The switching process results from an unprecedented subtle interplay between the activity of potassium iodide and the steric crowding within the self-assembled structure. Besides the possible applications in nanoconstruction, this phenomenon sheds light into the mechanism of formation of self-assembled supramolecules made from guanosine derivatives.

Thermoresponsive systems are attractive due to their suitability for fundamental studies as well as their practical uses in a wide variety of applications. While much progress has been achieved using polymers, alternative strategies such as the use of well-defined nonpolymeric supramolecules are still underdeveloped. Here we report three 8-aryl-2′-deoxyguanosine derivatives (8ArGs) that self-assemble in aqueous media into precise thermoresponsive supramolecular G-quadruplexes (SGQs). We report the synthesis of such derivatives, studies of their isothermal self-assembly, and the thermally induced assembly to form higher-order meso-globular assemblies we term supramolecular hacky sacks (SHS). The lower critical solution temperature (LCST) that indicates the formation of the SHS was modulated by changing (a) intrinsic parameters (i.e., structure of the 8ArGs); (b) extrinsic parameters such as the salt used to promote the formation of the SGQ; and (c) supramolecular parameters such as the coassembly different 8ArGs to form heteromeric SGQs. Changes in the intrinsic parameters lead to LCST variations in the range of 28–59 °C. Modulating extrinsic parameters such as replacing KI with KSCN abolishes the thermoresponsive phenomenon whereas changing the cation from K+ to Na+ or adjusting the pH (in the range of 6–8) has negligible effects on the LCST. Modulating supramolecular parameters results in transition temperatures that are intermediate between those obtained by the respective homomeric SGQs, although the specific proportions of the subunits are critical in determining the reversibility of the process. Given the extensive applications of thermoresponsive polymers, the nonpolymeric supramolecular counterparts presented here may represent an attractive alternative for fundamental studies and biorelevant applications.

We have developed the 8-(m-acetylphenyl)-2′-deoxyguanosine (mAG) scaffold for the self-assembly of supramolecules in water and for the synthesis of self-assembled dendrimers (SADs) in organic media. Previously, reported mAG assemblies showed promising characteristics for the construction of SADs. Yet, none of these SADs had large enough dendrons to reach a fractal geometry characteristic of high-generation dendrimers. Here we present the synthesis, as well as the molecular and supramolecular characterization of a fourth generation hydrophilic self-assembled hexadecameric dendrimer [mAGD4(OH)16]16•3KI (316) with a size and shape akin to globular proteins. The diameter of 316 (5.0 nm) was measured by Pulsed Field Gradient NMR and Dynamic Light Scattering experiments, which enabled the construction of a computer-generated molecular model. This SAD represents an attractive platform for biomedical applications due to its water solubility, discreteness, well defined structure, thermal stability (Tm= 68 °C), and functional core.