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Gelation-driven component selection in the generation of constitutional dynamic hydrogels based on guanine-quartet formation Nampally Sreenivasachary and Jean-Marie Lehn* Laboratoire de Chimie Supramole´culaire, Institut de Science et d’Inge´nierie Supramole´culaires (ISIS), Universite´Louis Pasteur, 8 Alle´e Gaspard Monge, BP 70028, 67083 Strasbourg Cedex, France Contributed by Jean-Marie Lehn, March 1, 2005 The guanosine hydrazide 1 yields a stable supramolecular hydrogel Such processes form the basis of the recently developed dynamic based on the formation of a guanine quartet (G-quartet) in pres- combinatorial chemistry (5, 6), in which molecular recognition ence of metal cations. The effect of various parameters (concen- events have been implemented toward the generation of optimal tration, nature of metal ion, and temperature) on the properties of binding agents toward artificial or biological (7) molecular recep- this gel has been studied. Proton NMR spectroscopy is shown to tors through a target-driven shift in the distribution of the library allow a molecular characterization of the gelation process. Hydra- constituents toward the best binder(s). Changes in library constit- zide 1 and its assemblies can be reversibly decorated by acylhy- uents may also be caused by redistribution of components induced drazone formation with various aldehydes, resulting in formation by metal ion binding (8, 9) or environmental factors such as of highly viscous dynamic hydrogels. When a mixture of aldehydes temperature and pH (N. Giuseppone and J.-M.L., unpublished is used, the dynamic system selects the aldehyde that leads to the data). most stable gel. Mixing hydrazides 1, 9 and aldehydes 6, 8 in 1:1:1:1 The amplification of a given constituent of a CDL under the ratio generated a constitutional dynamic library containing the pressure of a self-organization process, such as the formation of an four acylhydrazone derivatives A, B, C, and D. The library consti- organized phase (for example, a gel), would be of special interest. tution displayed preferential formation of the acylhydrazone B It would represent a process of self-organization by selection (3, 4) that yields the strongest gel. Thus, gelation redirects the acylhy- by which the formation of a structured phase drives the selection of drazone distribution in the dynamic library as guanosine hydrazide the components that make up the dynamic constituent producing 1 scavenges preferentially aldehyde 8, under the pressure of the most highly organized and most stable assembly. gelation because of the collective interactions in the assemblies of Gels attract much current interest for their potential as intriguing G-quartets B, despite the strong preference of the competing materials (10, 11) and as substrates for biomedical applications (12, hydrazide 9 for 8. Gel formation and component selection are 13). In particular, hydrogels formed from low-molecular-weight thermoreversible. The process amounts to gelation-driven self- compounds that respond to pH are suitable candidates for oral drug organization with component selection and amplification in con- delivery as well as biosensor technology, especially when biochem- stitutional dynamic hydrogels based on G-quartet formation and ical components are involved. Hydrogels have also been shown to reversible covalent connections. The observed self-organization respond to ligand-receptor molecular recognition (14, 15) and and component selection occur by means of a multilevel self- redox stimuli (16). assembly involving three dynamic processes, two of supramolecu- Here, we describe our studies of a system in which the formation lar and one of reversible covalent nature. They extend constitu- of a supramolecular hydrogel drives the selection of the compo- tional dynamic chemistry to phase-organization and phase- nents that form the constituent leading to the most stable gel. It transition events. embodies a process of self-organization by selection under the pressure of gelation. It presents triple constitutional dynamics, two dynamic combinatorial chemistry ͉ component selection ͉ at the supramolecular level and a third one of covalent dynamic supramolecular chemistry nature, which involves selection by covalent self-assembly of the component that generates the hydrogel of highest cohesive upramolecular entities present the ability to reversibly modify strength. Stheir constitution through exchange and rearrangement of their The system brings together several features of particular interest, molecular components because of the lability of the noncovalent namely (i) self-organization and dynamics at both the supramo- interactions that hold them together (1, 2). Similar features may be lecular and molecular levels; (ii) generation of dynamic hydrogels; imported into molecular species if reversible covalent bonds are (iii) dynamic selection of the optimal components; (iv) implemen- introduced into their structure, allowing cleavage and formation of tation of biochemical components; and (v) adaptive behavior in interatomic connections with fragment exchange under specific response to external factors. conditions. Thus, entities, capable of reversible modification of their consti- Materials and Methods tution, define a constitutional dynamic chemistry on both the Instrumental Techniques. NMR spectra were recorded on a 400- supramolecular and the molecular levels (3). Because the consti- MHz spectrometer (Bruker, Wissembourg, France). The chemical tutional changes may be expected to respond to external factors, shifts are reported in ppm downfield from tetramethylsilane; cou- constitutional dynamic chemistry is the basis for the design and pling constants are given in Hz. Electrospray ionization (ESI)-MS development of adaptive chemical systems. It generates constitu- was carried out on a Bruker MicroTOF MS coupled with liquid tional dynamic libraries (CDLs) whose constituents are in dynamic chromatography. Samples were prepared at a concentration of 200 equilibrium, such that they can exchange their components and ␮M in Milli-Q water or in 0.5 M ammonium acetate buffer. Before express all of the entities that are potentially accessible through recombination by means of reversible covalent bonds and nonco- valent interactions. The CDL may then adapt to (internal or) Abbreviations: G-quartet, guanine quartet; CDL, constitutional dynamic library; pD, p2H. external physical factors or chemical effectors by selection (3, 4) of *To whom correspondence should be addressed. E-mail: [email protected]. the appropriate components for the optimal constituent. © 2005 by The National Academy of Sciences of the USA 5938–5943 ͉ PNAS ͉ April 26, 2005 ͉ vol. 102 ͉ no. 17 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0501663102 Downloaded by guest on September 30, 2021 Fig. 3. Temperature of gelation Tgel determined visually as a function of hydrazide 1 concentration in buffer (0.5 M) of the acetates of various cations ϩ ϩ ϩ ϩ as follows. (}), Na ;(■), K ;(Œ), NH4 ;({), Me4N .(a) Tgel values (in °C for 10 Fig. 1. Guanine derivatives self-assemble to G-quartets in the presence of ϩ ϩ ϩ ϩ and 50 mM, ion): (33, 65, Na ), (59, 87, K ), (45, 73, NH4 ), and (54, 79, Me4N ). metal ions. ϩ (b) Tgel of an aqueous solution of 1 (15 mM) as a function of K concentration (in mM, °C): (15, 41), (30, 51), (45, 61), (60, 61), and (90, 61). injection, a small aliquot of the sample was diluted 20-fold and used for ESI-MS. The following mild conditions were used to detect the signal with respect to the internal reference gave the amount of 1 supramolecular assembly of guanine quartets (G-quartets): dry still free in the gelled solution. The gel was destroyed by addition heater temperature was set at 120°C, ion polarity was positive, of a drop of concentrated DCl giving a clear solution, and then the nebulizer pressure was 0.4 bar, capillary voltage was 4,000 V, end Ϫ ͞ proton NMR spectrum was recorded; the integration of H-8 of 1 plate offset voltage was 400 V, and dry gas flow was 3.0 liters min. (100% free in the solution) with respect to the internal dioxane Viscosity measurements were performed on a digital rheometer reference gave the amount of 1. The difference between the integral (model DV-III; Brookfield, Middleboro, MA) fitted with a CPE-40 of total free 1 (100% in solution) and the integral of free 1 in the spindle model of 4 cm in diameter and a 1° angle. gelled solution yielded the percentage of gelation. The integration of the internal dioxame signal was also checked against an external CHEMISTRY Preparation of Gels and Measurement of Gel Melting Temperature. dioxane reference contained in a capillary. The guanosine hydrazide 1 was dissolved in 0.5 M acetate buffer ␮ (pH 6, 500 l) to make up a concentration of 15 mM. The container Dynamic Combinatorial Library Generation. Stock solutions (150 was heated until guanosine hydrazide 1 dissolved completely, and mM) of the aldehydes (6–8) and hydrazides (9 and 10) were 2 it was then cooled to room temperature. Gelation was observed, prepared by dissolving a given compound in H2O or deuterated and the gel melting temperature (Tgel) was determined visually by buffer solution [0.5 M sodium acetate or potassium acetate, p2H the vial-inversion method. The sample vials were immersed in an (pD) 6.0]. Guanosine hydrazide 1 (2.3 mg) was dissolved in a 500-␮l inverted position in an oil bath, and the temperature was increased buffer in an NMR tube to make up a 15 mM solution. Then, we slowly. Tgel was taken as the point at which the gel started to flow. added 50 ␮l of hydrazide (9 or 10) solutions and 50 ␮l of aldehyde (6 and 8) solutions from the stock solutions. The NMR tube was Determination of the Gelled Fraction by Proton NMR Spectroscopy. gently heated to 50–60°C for 5–6 h to reach equilibrium. It was then 2 1 We added guanosine hydrazide 1 (2.3 mg), H2O (450 ␮l), 45 ␮lof cooled to room temperature, and the H-NMR spectrum was KCl stock solution (1 M), and 5 ␮l of dioxane stock solution (300 recorded once the solution was fully gelled.

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