José’s comment on: Intelligent, Biodegradable, and Self-Healing Hydrogels Utilizing DNA Quadruplexes

By José M. Martinez

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This paper is about making of a water based gel made from the supramolecular interactions of guanosine rich oligonucleotides. They attached these oligonucleotides symmetrically into the ends of PEG chains of variable lengths and conformations. This was made through High Efficiency Liquid Phase (HELP) synthesis. This synthetic strategy, as its name says, occurs in a liquid phase instead of the usual solid phase synthesis. The purpose of this is to allow them to obtain greater quantities of product more easily without risking the effectiveness. These DNA-PEG-DNA monomers have the ability, when diluted and presented with a cation (K+ or Na+), to self-assemble its DNA moieties through non-covalent interactions to for G-quadruplexes. Those strong interactions change the physical properties of the solution by forming a hydrogel. In the study, it was proven that the concentration of the cation required to trigger the self-assembly is relatively small. It is even compared to the concentration of salts found in body-related fluids like sweat, saliva, and tears. The hydrogel also has the capability to heal itself and interact by diffusion with another of the same kind. Finally, it was found that by adding a few extra nucleotides to the DNA moiety of the monomer and a matching strand for that part, the G-quadruplexes could be disassembled, returning the gel back to its liquid phase. All the previously stated properties indicate potential uses of this hydrogel for biomedical purposes.
Regarding myself, I learned mostly about the molecular aspect of gels and how they are formed. It was very interesting seeing the role that the supramolecular interactions played in the formation of this particular gel and the experiments made to investigate further into its properties.

JMM: Tanaka, 2017. Intelligent, Biodegradable, and Self-Healing Hydrogels Utilizing DNA Quadruplexes

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.