supramolecular

Valeria’s comment on: Reversible Regulation of Thermoresponsive Property of Dithiomaleimide-Containing Copolymers via Sequential Thiol Exchange Reactions

By Valeria Burgos Caldero

The main purpose of this article was to synthesize multi-responsive polymers that could be reversibly modified to adjust their LCST. Indeed, these researchers were able to develop a system in which multiple thiol exchanges were made, and in turn, they could determine how the thiols affected the transition temperature of the polymer. They used a copolymer containing P(TEGA) and DMMA. By performing transmission measurements at various temperatures, they concluded that as the thiol changed, the transition temperature of polymer varied depending on the resulting hydrophobicity. More polar functionalities increased the transition temperature and less polar ones decreased it. They were able to demonstrate the reversibility of the modifications since they managed to return to their original functionality after various thiol exchanges. Finally, they implemented a fluorescence signal to monitor the reaction progress. They found that thioglucose quenches the polymer’s fluorescence while making the compound soluble throughout the range of temperatures. With these findings, a wide range of possibilities were opened, since now, if you want a polymer for a specific type of function where a specific temperature response is needed, it is easily accessible by adding the corresponding thiol to the polymer solution. The mechanism of turning off the fluorescence may give access to reversible systems in aqueous conditions.
In general, I found it much simpler to prepare for this article than for the first one I presented. I feel that by doing these exercises of presenting scientific articles I have been acquiring maturity in the analysis process since it was difficult for me to understand articles in the beginning. Something that I found missing in the article is that they never explained the experimental procedure on how they achieved reversibility after adding different thiols to the same sample. I liked that they used common thiols, some of which we use in our research and others that maybe we could apply. In general, the article relates a lot to the research I’m doing with Diana. It could be useful to try to see the stimuli-responsive variations in the compounds that we are synthesizing. Maybe because it is related to variations in functionalities with thiols, similar to my own research, I found it more enjoyable to prepare the discussion and understand the material in the article.

Tang, 2016. Reversible Regulation of Thermoresponsive Property of Dithiomaleimide-Containing Copolymers via Sequential Thiol Exchange Reactions

2018-05-232018-05-23 by supramolecular Categories: group meetings, literature discussionTags: copolymers, group meetings, LCST, polymers, thermoresponsive, thiols, Valeria 7 Comments

Luxene’s comment on: Selective Tuning of Elastin-like Polypeptide Properties via Methionine Oxidation

By Luxene Belfleur

Figure 1. Kekule structure of and synthesis of ELP 2 and 3. Cartoon representation of ELPs solution, the LCST behavior and measurement of ELPs

In this article, the authors reported the LCST modulation of Elastin-like polymers (ELP) by the modification towards oxidation reactions of the methionine thioester group of the ELP 1 to form sulfoxide and sulfone ELPs derivatives 2 and 3 respectively (Figure 1). They isolated ELP 1 from plasmid DNA of E.coli bacteria and purified it by SDS-Page. In acidic media, using 30% hydrogen peroxide and 1% of acetic acid or formic acid in water, they obtained ELP derivatives 2 and 3 respectively and the molecular weight and structural elucidation of ELP 1 and its derivatives 2 and 3 had been examined and confirmed by mass spectrometry and NMR respectively.
They performed turbidity experiments to determine the cloud points of those three ELPs. As expected, both ELP derivatives 2 and 3 had a higher LCST behavior (55 °C and 43 °C for 2 and 3 respectively) compared to ELP 1 which is 25 °C (Figure 1). This is due to the increasing of water solubility of the modified ELPs (2 and 3), which required more energy to break the interaction between water and them (ELP 2 and 3) in order to evacuate the hydration shell around these ELPs and favored the collapse of the letters. Moreover, it was expected that ELP 3 would have a higher cloud point than the ELP 2 counterpart, however, this was not the case because the large dipole moment of ELP 3 favored intramolecular and intermolecular interactions between them and the protein respectively which promoted a decrease of the water solubility. They evaluated the influence of the I¯ and NO3¯ anions on the phase transition of the three ELPs and found that those anions had no significant effect on the LCST point of the ELP 1 while I¯ increased the LCST of ELP 2 and NO3¯ decreased the solubility of ELP 3 in agreement with the Hofmeister series effect.
They reported an interesting and straightforward work by turning the LCST behavior of ELPs towards synthetic modification. This work has inspired and motivated my team for designing and synthesizing sulfoxides and sulfones containing guanosine derivatives in order to both, stabilize the thioester containing guanosine derivatives compounds that we synthesize, and modulate the LCST properties of the SGQs that will be made from oxidizing 8ArG derivatives product.

Petitdemange, 2017. Selective Tuning of Elastin-like Polypeptide Properties via Methionine Oxidation

2018-05-232018-05-23 by supramolecular Categories: group meetings, literature discussionTags: article, ELP, LCST, Luxene, peptides 10 Comments

Luis’ comment on: Guanidinium can both Cause and Prevent the Hydrophobic Collapse of Biomacromolecules

By Luis A. Prieto

Heyda, Jungwirth and Cremer collaborated in a study of guanidinium (Gnd⁺) salts and their effect in lower critical solution temperature (LCST). They studied molecular details of the cause of these transitions by IR-ATR and molecular dynamics simulation where they wanted to understand how Gnd⁺ salts interacted with the backbone of the Elastin-like peptides (ELP). In previous studies ELPs showed a change in LCST that followed the Hofmeister series in sodium salts but using Gnd⁺ salts proved to be different, especially Guanidinium thiocyanate (GndSCN) that at low concentrations the LCST decreases, but at high concentrations the LCST increases. They studied particular phenomenon using ATR-IR where they found GndSCN binds strongly with ELPs and resulted in an interesting behavior when the concentration of salt is increased. At low concentrations the polymer collapsed (salting-out) because of cross-linking of the peptide and at high concentrations resolubilization occurred (salting-in). Other salts followed typical behavior of salting-in (guanidinium chloride, weak binding) or salting-out (guanidinium sulfate, poor binding). Coarse-grain and all atom simulations corroborated this finding where they found particular detail of the interaction of the carbonyl groups of the peptide backbone with Gnd⁺, most likely through H-bonds.

The thermodynamics of this paper I found particularly interesting since it reminded me of everything that I have to re-learn. An attractive experiment was that they used a melting point apparatus to measure the LCST, meaning the use of small amount of sample to gather fundamental information of the system which is also the case with ATR-IR. An elegant work and also inspirational since our lab works with responsive systems and we will definitively see if we can do the LCST measurement with a melting point instrument. I got to say that I particularly like the all atom simulations and Figure 5, where we can see in molecular detail the interactions of the salts with the peptide where thiocyanate and Gnd⁺ interact strongly with the hydrophobic parts (V, G) and hydrophilic part (peptide bond), respectively.

LAPC: Heyda, 2017. Guanidinium can both Cause and Prevent the Hydrophobic Collapse of Biomacromolecules

2018-05-222018-05-23 by supramolecular Categories: group meetings, literature discussionTags: group meetings, LCST, Luis 7 Comments

Our last three papers…

mAGi16-Top2_white Below are the references to our last three papers. I will post a brief overview of each one soon, but in the meantime:

Structural studies of supramolecular G-quadruplexes formed from 8-aryl-2’-deoxyguanosine derivatives. García-Arriaga, M.; Hobley, G.; Rivera, J. M., J. Org. Chem.2016, 81, Advance Online Publication; DOI: 10.1021/acs.joc.6b01113. PMID: 27303787

The first 50 people can download a free reprint of the paper directly from the publisher by going to this link.
Abstract. Self-assembly is a powerful tool for the construction of complex nanostructures. Despite the advances in the field, the development of precise self-assembled structures remains a challenge. We have shown that in the presence of suitably sized cations like K+, 8-aryl-2′-deoxyguanosine (8ArG) derivatives self-assemble into sets of coaxially stacked planar tetramers, we term supramolecular G-quadruplexes (SGQs). Previously, we reported that when the 8-aryl group is a phenyl ring with a meta-carbonyl group, the resulting supramolecule is a hexadecamer, which is remarkably robust as illustrated by its isostructural assembly in both organic and aqueous environments. We report here a detailed three-dimensional structure of the SGQs formed by lipophilic, and hydrophilic, 8ArG derivatives with either 8-(meta-acetylphenyl), 8-(para-acetylphenyl), and 8-(meta-ethoxycarbonylphenyl) groups. The chirality and close contacts between the subunits impose different levels of steric and electrostatic constraints on opposite sides of the tetrads, which determine their preferred relative orientation. The balance between attractive non-covalent interactions juxtaposed with repulsive steric and electrostatic interactions explains the high cooperativity, fidelity and stability of these SGQs. These structural studies, together with titration experiments and molecular dynamics simulations provide insight on the mechanism of formation of these SGQs.

Organic Nanoflowers From a Wide Variety of Molecules Templated By A Hierarchical Supramolecular Scaffold. Negrón, L. M.; Diaz, T. L.; Ortiz-Quiles, E. O.; Dieppa, D.; Madera-Soto, B.; Rivera, J. M., Langmuir 2016, 32 (10), 2283–2290. DOI: 10.1021/acs.langmuir.5b03946; PMCID: PMC4896646

Abstract. Nanoflowers (NFs) are flowered-shaped particles with overall sizes or features in the nanoscale. Beyond their pleasing aesthetics, NFs have found a number of applications ranging from catalysis, to sensing, to drug delivery. Compared to inorganic based NFs, their organic and hybrid counterparts are relatively underdeveloped mostly because of the lack of a reliable and versatile method for their construction. We report here a method for constructing NFs from a wide variety of biologically relevant molecules (guests), ranging from small molecules, like doxorubicin, to biomacromolecules, like various proteins and plasmid DNA. The method relies on the encapsulation of the guests within a hierarchically structured particle made from supramolecular G-quadruplexes. The size and overall flexibility of the guests dictate the broad morphological features of the resulting NFs, specifically, small and rigid guests favor the formation of NFs with spiky petals, while large and/or flexible guests promote NFs with wide petals. The results from experiments using confocal fluorescence microscopy, and scanning electron microscopy provides the basis for the proposed mechanism for the NF formation.

Tuning Thermoresponsive Supramolecular G-Quadruplexes. José E. Betancourt & José M. Rivera, Langmuir 2015, 31 (7), 2095-2103. DOI:10.1021/la504446k; PMCID: PMC4863471 [Free PMC Article]

Abstract. 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.

2016-06-212016-06-30 by supramolecular Categories: RiveraLab-Publications, UncategorizedTags: colloidal particles, encapsulation, G-quadruplex, LCST, molecular dynamics simulations, nanoflowers, NMR, supramolecular G-quadruplex, supramolecular particles, thermoresponsive Leave a comment

Exploring the periodic table with supramolecular G-quadruplexes

Our latest article just came out on the web: Tuning supramolecular G-quadruplexes with mono- and divalent cations (Mariana Martín-Hidalgo, Marilyn García-Arriaga, Fernando González, José M. Rivera, Supramolecular Chemistry, DOI: 10.1080/10610278.2014.924626) In it we describe a series of systematic studies of the effect of a series of cations on the structure and other properties of supramolecular G-quadruplexes. You can download a free (!) copy of the article here, but you better hurry as this is a limited time offer available only to the first 50 people to take advantage of it. If, however, you are not one of the “50 lucky winners”, don’t despair, you can still get a copy article by simply leaving a request in the comments. In the meantime, here’s the abstract:

“Supramolecular G-quadruplexes (SGQs) are formed via the cation promoted self-assembly of guanine derivatives into stacks of planar hydrogen-bonded tetramers. Here, we present results on the formation of SGQs made from the 8-(m-acetylphenyl)-2′-deoxyguanosine (mAGi) derivative in the presence of various mono- and divalent cations. NMR and HR ESI-MS data indicate that varying the cation can efficiently tune the molecularity, the fidelity and stability (thermal and kinetic) of the resulting SGQs. The results show that, parallel to the previously reported potassium-templated hexadecamer (mAGi₁₆·3K⁺), Na⁺, Rb⁺and NH₄⁺ also promote the formation of similar supramolecules with high fidelity and molecularity. In contrast, the divalent cations Pb²⁺, Sr²⁺ and Ba²⁺ template the formation of octamers (mAGi₈), with the latter two inducing higher thermal stabilities. Molecular dynamics simulations for the hexadecamers containing monovalent cations enabled critical insights that help explain the experimental observations.”

2014-06-26 by supramolecular Categories: RiveraLab-PublicationsTags: article, cation, self-assembly 1 Comment

The phoenix finally rises from the ashes…

Every research paper is special and it’s the source of great satisfaction when it finally gets published. Seeing our latest article “A Photoresponsive Supramolecular G-Quadruplex” finally published is particularly satisfying because of the long arduous road to publication. Our internal code name for this manuscript was “Phoenix” because of the parallel between the mythical beast (burning down and raising from the ashes) and the supramolecule described in the article, which is destroyed after photoirradiation and eventually leads to a new (heteromeric) supramolecule to rise from the ashes. What we didn’t know the first time we submitted this work for publication was that the manuscript would ended up being “burned down to ashes” by the referees at multiple journals before finally raising for good. The whole process was very humbling and tested our character, but in the end, the final product was a much refined piece of work for which we should be proud of. And now, to continue writing with the hope that our next submissions don’t have to travel such a rough path.

2013-05-032013-05-03 by supramolecular Categories: RiveraLab-PublicationsTags: chemistry, peer-review, publication, self-assembly, supramolecular 1 Comment

Synthesis of the antiviral cyclobutyl guanosine derivative Lobucavir

Asymmetric Synthesis of Cyclobutanones: Synthesis of Cyclobut-G

Benjamin Darses, Andrew E. Greene & Jean-François Poisson*

J. Org. Chem., 2012, 77 (4), 1710; DOI: 10.1021/jo202261z

A synopsis by Peddabuddi Gopal

Cycloalkanes are less stable than simple (acyclic) alkanes because of bond angle strain, which increases as the number of carbons in a ring decreases. Cyclopropanes (bond strain energy 27.5 kcal/mol) and cyclobutanes (bond strain energy 26.3 kcal/mol) are particularly unstable relative to a cyclohexane ring. Nonetheless, natural products containing the cyclobutane ring have been found to possess significant biological activity with (−)-biyouyanagin A, (+)-kelsoene and (−)-bielschowskysin providing just a few examples. Thus, although developing efficient synthetic protocols for these natural products is very challenging, it shows great potential to improve the quality of our lives.

Therefore four-membered carbocycles are valuable building blocks in synthesis. Piperidines, tetrahydropyrans, cyclohexanones, and oxazepines are some examples that can be efficiently accessed through an approach that uses donor−acceptor cyclobutane derivatives as 1,4-dipole precursors. Cyclobutanes have also been used in transition-metal-catalyzed ring-opening reactions for the construction of larger rings and functionalized non-cyclic products.

In general, the significant protocol to prepare cyclobutane derivatives involves [2 + 2] cycloaddition, intramolecular nucleophilic substitution, and ring contraction/expansion reactions. It should be noted that the reported approaches to four-membered carbocycles are generally limited in scope and few are able to provide enantioselection.

The authors J. F. Poisson et al. established a very efficient strategy for the stereoselective synthesis of cis– and trans-disubstituted cyclobutanones from readily (although non commercially) available alkyl- and functionalized alkylsubstituted enol ethers. On the basis of this methodology they have made an enantioselective synthesis of biologically active cyclobut-G (Lobucavir). This cyclobutyl guanine nucleoside analogue, a derivative of the highly potent anti-HIV natural product, oxetanocin A, was firstly developed by Bristol Myers Squibb some 20 years ago.

In 2008, the J. F. Poisson et al. exploited the diastereoselective [2 + 2] thermal cycloaddition of dichloroketene (DCK) with chiral enol ethers for the enantioselective synthesis of a variety of five-membered ring-containing natural products. In the first step of the sequence, Stericol [(S)-(−)-1-(2,4,6-triisopropylphenyl)ethanol] was treated sequentially with potassium hydride and trichloroethylene, which yielded the corresponding dichloroenol ether. The latter was treated with n-butyllithium followed by methyliodide to form the methylated ynol ether, which was directly hydrogenated to afford the Z enol ether.

Consequently, the authors prepared different types of Z/E ketenophiles using different alkylhalides and polyformaldehyde. However, Z olefins are very useful to prepare both cis and trans cyclobutane derivatives, while E olefins show very poor in stereoselectivity. Based on different types of ketenophiles they made different types of cyclobutane derivatives. In this process they have explained very well about optimization of the most important dechlorination of the unstable α,α- dichlorocyclobutanone intermediates.

Finally, the synthesis of the nucleoside analogue Lobucavir is somewhat related to our research. The author’s stepwise illustration is very good, actually the same work was published in OL, 2008 but in this article, in addition to that article they prepared E alkenes and trans cyclobutane derivatives and also they reported failure reaction in preparation of cyclobut-G.

2012-04-19 by supramolecular Categories: literature discussionTags: angle strain, asymmetric synthesis, G-analogue, science, stereoselective synthesis, synthesis 13 Comments

Moving our lab’s web presence here

Since Apple will discontinue the .Mac service and will no longer develop the iWeb software used to create our current site, we will transition (in the next few months) to this new site. More details to come later…

2012-02-102012-02-10 by supramolecular Categories: announcement 2 Comments

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