Our last three papers…

mAGi16-Top2_whiteBelow 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.

Exploring the periodic table with supramolecular G-quadruplexes

20130815_mAGi-C+_TOC

 

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.

 

The phoenix finally rises from the ashes…

Image

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.

Updated guidelines for article synopses and blogging

At the end of the GM Schedules page you’ll find the updated guidelines for article synopses and blogging. They are a “work in progress” and I hope we can improve them further by incorporating some of the suggestions discussed recently. Your comments and suggestions regarding this issue will be greatly appreciated.

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.

Topics and schedule for this semester’s GMs

Our research lies primarily in the field of supramolecular chemistry, specifically, in self-assembly. We are, however, working with supramolecular G-quadruplexes (SGQs) and have also a strong interest in oligomeric G-quadruplexes (OGQs; e.g., DNA, RNA). The former requires us to stay up do date in areas such as synthesis, organic mechanisms, self-assembly studies, and host-guest chemistry, among others. The latter requires us to keep up to date with many aspects of OGQs: structure/dynamics studies; relevance in cells and whole organisms (biological relevance in genomes, RNA structures, regulatory elements); as pharmacological targets (anticancer agents); applications in various areas such as sensors (aptamers); materials/nanotech (G-wires), etc. This makes keeping a balanced assortment of topics/articles a bit of a challenge. Thus, in this preliminary GM schedule you’ll find the dates and corresponding articles up until mid April. Each title has some tags (key words) next to it to help keep track of the subjects being covered during the semester. The missing articles (“TBA”) will be added later at which point I’ll update the schedule.

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…