Organic & Biomolecular Chemistry Blog

Acylthioureas that can act as ion transporters across cell membranes may lead to novel treatments for cystic fibrosis and associated conditions.

Inorganic anions such as chloride play a crucial role in biological systems, and the mechanisms behind their transport and regulation are still to be fully understood. Proteins embedded in the lipid bilayer regulate these transport processes and carry anions across cell membranes. When these processes are defective, then channelopathic diseases such as cystic fibrosis can develop.

Synthetic anion transporters based on small molecules may serve as replacements for faulty transport proteins, and may therefore find use in the treatment of such diseases.

Professor Philip Gale and his research group at the University of Southampton have been looking into synthetic membrane transporters for anions based on thiourea scaffolds.

In this HOT Article, Prof. Gale and co-workers discuss the synthesis of a series of acylthioureas and their potential as anion transporters in POPC lipid bilayers. They have discovered that these molecules function effectively as anion antiporters, but that the incorporation of lipophilic moieties leads to a reduction in their efficiency. This is due to an intramolecular hydrogen bond that forms and shields the binding site from interactions with water.

It is clear from these results that striking a balance between hydro- and lipo-philicity of the anion transporter is of crucial consideration in their efficiency. Furthermore, the intramolecular hydrogen bonding behaviour of these molecules may be of use in enabling more hydrophilic moieties to be incorporated in future transporter design. It is hoped that this information will eventually lead to the development of new transporters for medicinal applications.

Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding
Cally J. E. Haynes, Nathalie Busschaert, Isabelle L. Kirby, Julie Herniman, Mark E. Light, Neil J. Wells, Igor Marques, Vítor Félix and Philip A. Gale
Org. Biomol. Chem., 2013, DOI: 10.1039/C3OB41522H

In this HOT paper, Peter Kündig’s research team have developed a new mode of copper-mediated oxidative coupling allowing access to racemic (aza)oxindole structure in an efficient and atom-economic fashion.

Oxindoles are useful structures in organic chemistry as they are found ubiquitously in nature. Molecules bearing this motif have a range of interesting biological properties and new methods of their construction are always useful to the organic chemist.

Peter Kündig and his team at the University of Geneva have been looking into the asymmetric synthesis of these structures, employing palladium-catalysed intramolecular α-arylations of amide substrates.[1] During these studies, they discovered a novel and efficient route to access racemic 3,3,-disubstituted oxindoles which employed a copper-mediated radical reaction.[2] This reaction has also been applied to the racemic synthesis of aza-oxindoles.[3]

In this excellent account from Prof. Kündig, this methodology has been further explored. The substrate scope has been expanded leading to a range of oxindoles bearing a variety of aromatic, hetero- aromatic, allyl and heteroatom substituents in the 3-position. The reaction was also successfully performed on a large scale, with excellent yield and regioselectivity. In addition to this, some nifty DFT and computational studies confirm the proposed mechanism and regioselectivity.

Read the full article here.

Copper(II) chloride mediated (aza)oxindole synthesis by oxidative coupling of Csp2–H and Csp3–H centers: substrate scope and DFT study
Chandan Dey, Evgeny Larionov and E. Peter Kündig
Org. Biomol. Chem., 2013,  DOI: 10.1039/c3ob41254g

---

[1] E. P. Kündig, T. M. Seidel, Y. X. Jia and G. Bernardinelli, Angew. Chem., Int. Ed., 2007, 46, 8484; Y. X. Jia, J. M. Hillgren, E. L. Watson, S. P. Marsden and E. P. Kündig, Chem. Commun., 2008, 4040.

[2] Y. X. Jia and E. P. Kündig, Angew. Chem., Int. Ed., 2009, 48, 1636.

[3] C. Dey and E. P. Kündig, Chem. Commun., 2012, 48, 3064.

In this HOT paper, K. C. Nicolaou and co-workers have developed a series of taxol analogues which show potent activity against several cancerous cell lines.

The fight against cancer is one of the hottest areas of drug discovery. Despite this, there is still a shortfall in treatment options and the disease is on the rise. The development of safer and more selective drugs is therefore required.

Paclitaxel (taxol) and docetaxel are two of the most highly successful anti-cancer drugs and much research has been performed focused on their synthesis and structure. K C Nicolaou and his group at Scripps are well-versed in the construction of paclitaxel; the group published one of the first total syntheses of this complex molecule in 1994.

10-Deacetylbaccatin III is an advanced synthetic precursor to paclitaxel and shares many its core structural features. Thanks to the synthetic efforts of recent years, it’s also readily accessible and therefore it provides an interesting starting point for further structure-activity relationship studies. Nicolaou and Valiulin have found that, upon treatment with diethylaminosulfur trifluoride (DAST), 10-deacetylbaccatin III undergoes a nifty vinylogous pinacolpinacolone rearrangement leading to a new enone structure and its fluorinated analogue.

Nicolaou and Valiulin have capitalised on this discovery and have prepared an small library of structurally analogous taxoids using this reaction. The library of analogues was submitted to screening program run by the National Cancer Institute (NCI) where the compounds were evaluated against 60 different cancerous cells lines. Several of the taxoids showed significant potency against numerous tumour cell lines. This study has revealed important information regarding the structure-activity relationship of the taxoid family of molecules. It has also produced some promising potential leads for new anti-cancer drugs.

Synthesis and Biological Evaluation of New Paclitaxel Analogs and Discovery of Potent Antitumor Agents
Kyriacos C. Nicolaou and Roman A. Valiulin
DOI: 10.1039/C3OB40654G

Free to access for 4 weeks

In this HOT paper, John Pezacki and co-workers report novel rearrangement and addition reactions of biarylazacyclooctynone (BARAC) leading to tetracyclic products. This behaviour may limit the practical applications of azacyclooctynones as bioorthogonal probes for biological systems.

Bioorthogonal reactions, i.e. reactions which can occur inside of a living system without interfering with native chemical processes, allow for the study of molecules such as proteins and lipids in vivo and in real time. The 1,3-dipolar cycloaddition between azides and octynes is an example of such a reaction. This copper-free variant of the Huisgen cycloaddition (better known as the click reaction) has been applied within cultured cells, live zebrafish and mice.

John Paul Pezacki and his research group at National Research Council Canada have been looking into these reactions and their application in biological probes and sensors. During their studies into the cycloaddition of azacyclooctynones such as BARAC (biarylazacyclooctynone), they noticed some interesting and unexpected results.

These molecules are able to undergo novel intramolecular cyclisation reactions which lead to the formation of tetracyclic products. Pezacki has performed some neat kinetics studies and computer-modelling, which have revealed that this rearrangement is accelerated by the presence of acid and that the linker side-chain also influences the rate of rearrangement.

This elegant, but rather unhelpful, reaction may limit the effectiveness of these molecules in biological systems, and this fascinating study illustrates how challenging it is to design effective bioorthogonal reactions.

Rearrangements and addition reactions of biarylazacyclooctynones and the implications to copper-free click chemistry
Mariya Chigrinova, Craig S. McKay, Louis-Philippe B. Beaulieu, Konstantin A. Udachin, André M. Beauchemin and John Paul Pezacki.
DOI: 10.1039/C3OB40683K

Free to access for 4 weeks

Synthesis and binding studies of novel di-substituted phenanthroline compounds with genomic promoter and human telomeric DNA G-quadruplexes
Chunying Wei, Yanbo Wang, Meiying Zhang
DOI: 10.1039/C3OB27426H

Researchers in China have developed a series of phenanthroline molecules that interact with human telomeric DNA G-quadruplexes, which are promising targets in anti-cancer drug discovery.

G-quadruplexes are guanine-rich nucleic acid sequences. The guanine bases can hydrogen bond to form tetrads, and these tetrads can then stack up to form a G-quadruplex. They are significant in telomeres as their formation inhibits the telomerase enzyme, which is implicated in the onset of around 85% of cancers.

G-quadruplexes are also increasingly being found in non-telomeric parts of the chromatid, such as genomic promoter regions. Their presence and purpose is still not fully understood although they have also been implicated in cell aging and the formation of cancerous cells. For these reasons, G-quadruplexes are pretty promising targets for drug discovery.

Phenanthrolines can stabilise telomeric G-quadruplexes, and some have shown excellent inhibition of the telomerase enzyme. Before now, interactions between phenanthrolines and promoter G-quadruplexes have been relatively unstudied.

In this HOT article, Chunying Wei and co-workers at the Key Laboratory of Chemical Biology and Molecular Engineering at Shanxi University have synthesised six novel di-substituted phenanthroline molecules. They have also probed their interaction with human telomere and promoter G-quadruplexes. They have found that the compounds significantly inhibit the telomerase enzyme at low micromolar concentrations.

It is hoped that these molecules will aid and inspire the design of new anti-cancer drugs.

Annabella Newton is an organic chemist based in Melbourne, Australia. Until recently, she was a postdoctoral researcher and she has just started work as a trainee patent attorney with Phillips Ormonde Fitzpatrick.