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.