Organic & Biomolecular Chemistry Blog

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

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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

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In this HOT article Bräse and co-workers report the synthesis of eight new rhodamine fluorophores with fluorous ‘ponytails’, dubbed rhodamine F dyes. Rhodamine derivatives are widely used as fluorescent labels for biomolecules and characteristically have high absorption coefficients and high absorption and emission maxima in the visible region combined with high chemical and photostability.

The ‘ponytails’ are fluorous alkyl residues that are deliberately not cleaved during synthesis. They facilitate fluorous solid-phase extraction, utilising the strong, specific nature of fluorine-fluorine interactions. During this purification process a fluorous solid phase is used to bind fluorous molecules and separate them from non-fluorous compounds.

The fluorine content of the rhodamine F dyes is below 50% of the total molecular weight, preserving solubility in organic solvents. Conjugation with a peptide mediates cellular uptake may have potential applications in live cell imaging; clear, bright images were obtained in human cervix carcinoma cells incubated with rhodamine F dyes at concentrations as low as 1 µM.

Rhodamine F: a novel class of fluorous ponytailed dyes for bioconjugation
Dominik K. Kölmel, Birgit Rudat, Delia M. Braun, Christin Bednarek, Ute Schepers and Stefan Bräse
DOI: 10.1039/c3ob40267c

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Published on behalf of Steve Moore, Organic & Biomolecular Chemistry web science writer.

In this HOT article, Dave Smith, Sabrina Pricl and co-workers report the synthesis of 4 different RGD-peptide derivatives, which spontaneously self-assemble into nanoscale architectures. They used multiscale modelling to understand the self-assembly of these ligands and they demonstrated that by modifying the building blocks through organic synthesis on the molecular scale, they could control the morphology of the resulting self-assembled nanostructures. The multivalent binding of the assemblies to integrin proteins was shown to be highly dependent on the morphology of the assemblies. The paper elegantly showcases the importance of nanoscale morphology on binding events and highlights the advantages of employing a self-assembly approach. 

Self-assembled multivalent RGD-peptide arrays – morphological control and integrin binding
Daniel J. Welsh, Paola Posocco, Sabrina Pricl and David K. Smith
DOI: 10.1039/c3ob00034f

Free to access for 4 weeks

… and presently in the Top 10 most read articles in OBC –  check the full list here

Copper-catalyzed aromatic C–H bond halogenation with lithium halides under aerobic conditions
Song Mo, Yamin Zhu and Zengming Shen
DOI: 10.1039/c3ob40185e

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Direct acylation of N-benzyltriflamides from the alcohol oxidation level via palladium-catalyzed C–H bond activation
Jihye Park, Aejin Kim, Satyasheel Sharma, Minyoung Kim, Eonjeong Park, Yukyoung Jeon, Youngil Lee, Jong Hwan Kwak, Young Hoon Jung and In Su Kim
DOI: 10.1039/c3ob40140e

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Recent advances in the synthesis of aromatic nitro compounds
Guobing Yan and Minghua Yang
DOI: 10.1039/c3ob27354g  

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Facile dimethylarsenic exchange and pyramidal inversion in its cysteine and glutathione adducts
D. Scott Bohle and Yuxuan Gu
DOI: 10.1039/c3ob40268a 

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PEGylation enables the specific tumor accumulation of a peptide identified by phage display
Walter Mier, Susanne Krämer, Sabine Zitzmann, Annette Altmann, Karin Leotta, Ursula Schierbaum, Martina Schnölzer, Michael Eisenhut and Uwe Haberkorn
DOI: 10.1039/c3ob27475f  

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Synthetic use of the primary kinetic isotope effect in hydrogen atom transfer 2: generation of captodatively stabilised radicals
Mark E. Wood, Sabine Bissiriou, Christopher Lowe and Kim M. Windeatt
DOI: 10.1039/c3ob40275d  

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We are delighted to have received the authors’ comments from Christopher S. P. McErlean on the recently published HOT article “Revitalizing the aromatic aza-Claisen rearrangement: implications for the mechanism of ‘on-water’ catalysis”.

“Chemistry creates. It is the only discipline in which you can design or imagine a new entity and then go away and build it. Of course, it is always easier said than done, so synthetic organic chemists spend a good deal of their time exploring ways to build molecules more efficiently. That’s what the McErlean Research Group does at the University of Sydney. We are primarily focused on making synthesis easier.

Every undergraduate chemist knows that the aromatic Claisen rearrangement is a great way to build functionalized phenols. The reaction is so prevalent in heterocycle synthesis that we tend not to reference the original work – it is assumed knowledge. Our group envisaged that the aromatic aza-Claisen rearrangement would be an equally powerful way to make functionalised anilines, but the known reaction conditions are just too forcing to be useful.

“On-water” reactions rely on interfacial water to catalyze chemical transformations. Exactly how the interfacial water does this has been the source of much recent debate. Most of the protagonists have relied on computationally derived evidence to support one theory or another. We thought that we could kill two birds with one stone by using on-water catalysis to facilitate the aromatic aza-Claisen rearrangement and probe the kinetics of this transformation.

The outcomes of our work are twofold: an easy way to build functionalised naphthylamines and anilines, and experimental evidence that supports the acid-catalyzed nature of on water chemistry.

We hope that chemists employ this operationally simple synthetic tool to build life-changing molecules, and we hope that our results will spur more experimental chemists to provide hard data regarding the on-water phenomenon.”

This Communication is free to access for the next 4 weeks!

Revitalizing the aromatic aza-Claisen rearrangement: implications for the mechanism of ‘on-water’ catalysis
Kaitlin D. Beare and Christopher S. P. McErlean
DOI: 10.1039/C3OB40118A   

Interested in Christopher S. P. McErlean‘s research? Why not also read these recently published articles:

An in-water, on-water domino process for synthesis
Norcott, Philip; Spielman, Calan; McErlean, Christopher S. P.
Green Chem., 2012, 14, 605.
DOI: 10.1039/c2gc16259h

Total synthesis of C-19 lipid diols containing a 2,5-disubstituted-3-oxygenated tetrahydrofuran
Nesbitt, Caroline L.; McErlean, Christopher S. P.
Org. Biomol. Chem., 2011, 9, 2198.
DOI: 10.1039/c0ob00754d