Organic & Biomolecular Chemistry Blog

For years, radiotherapy has been an essential mode of noninvasive cancer therapy and advancements have led to life saving treatments for patients. In contrast to other conventional radiotherapies, boron neutron capture therapy (BNCT) is unique in its selective destruction of cancerous cells. BNCT is based on nuclear capture and fission reactions when nonradioactive ¹⁰B is irradiated with neutrons to yield excited ¹¹B* which decays into high energy alpha particles and ⁷Li nuclei. Boron is preferentially accumulated into tumour cells though non-toxic carriers and the short length of the generated neutron beams (5-9 µm) destroys nearby cells leaving the surrounding healthy tissue intact.

The development of carrier systems that deliver sufficient amounts of boron to carry out effective destruction of all vicinal tumour cells has been a significant area of BNCT research for many years. A recent breakthrough made by Professors Atsushi Ikeda of Hiroshima University, Takeshi Nagasaki of Osaka City University and Kazuya Koumoto of Konan University has led to the development of a novel method for incorporating boron-containing moieties within hydrophobic lipid membranes.

Liposomes have been studied extensively as boron carriers and are promising candidates for BNCT as lipids display low toxicity. In the past, boron-containing liposomes have been prepared by dissolution of boron compounds in an internal water phase (Figure, A) or by using amphiphilic boron compounds embedded in the liposomal bilayer such that boron coats the outer surface of the lipid membrane (Figure, B). Unfortunately, even when these two methods are used in conjunction, the concentration of boron within the liposome is insufficient for effective BNCT and increasing liposomal dosing is problematic as high concentrations of lipids interfere with uptake mechanisms in the liver.

A novel method for boron transport is therefore of high value and in their recent OBC publication, the first example of boron incoporation into liposomal lipid membranes was successfully demonstrated. Key was the preparation of aryl pinacolato boronate esters bearing methyl groups at both ortho positions (Figure, R¹ positions) of the phenyl rings which helped in stabilizing the boronate esters against hydrolysis.

While the concentration of boron within the lipid membrane was not particularly high, this study has unlocked yet another avenue through which non-toxic liposomal boron carrier concentrations can be improved and when used with previous boron loading methods, produces liposomes with sufficient boron concentrations to carry out BCNT. This result will no doubt enhance BNCT and lead to critical, life saving therapies for cancer patients.

To find out more see:

Lipid-membrane-incorporated arylboronate esters as agents for boron neutron capture therapy
Masafumi Ueda, Kengo Ashizawa, Kouta Sugikawa, Kazuya Koumoto, Takeshi Nagasaki and Atsushi Ikeda
DOI:10.1039/C6OB02142E

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

The importance of natural products in health and medicine is enormous owing to their diverse biological activities and their role as a basis for drug development. Endeavours in total synthesis have attracted some of the most talented organic chemists–providing intellectual and creative outlets–and have been central to the evolution and technical development of organic synthesis.

In the early 1990’s, Professor Hideo Kigoshi of the University of Tsukuba reported the first total synthesis of the marine macrolide Aplyronine A which is still a highly desirable synthetic target due to its potent and unique biological properties.

In collaboration with Professor Ichiro Hayakawa of Okayama University, the group has recently published a highly efficient second-generation total synthesis of Aplyronine A which requires fewer synthetic steps and boasts an improved overall yield. Issues with poor stereoselectivity, regioselectivity and isomerization were overcome through the optimization of a Ni/Cr-mediated coupling.

As shown in the retrosynthetic pathway below, Aplyronine A was obtained from 10, the same intermediate used in the first generation synthesis however, instead of the Julia coupling between ketone and sulfone-containing fragments, the macrolactone 11 was cyclized via an intramolecular Ni/Cr-mediated coupling. This modification drastically reduced the number of unwanted byproducts obtained from the Julia coupling and eliminated the need to employ a modified Yamaguchi lactonization which had resulted in the formation of an undesired 26-membered lactone that required an additional isomerization to yield the desired product. Precursor 11 was constructed through an intermolecular esterification between carboxylic acid 12 and alcohol 13 which were each prepared through asymmetric Ni/Cr-mediated couplings. In the case of the carboxylic acid, route efficiency was further enhanced as this strategy resulted in the simultaneous formation of the C14–C15 (E)-trisubstituted double bond and the C13 stereogenic center through the use of a chiral ligand.

In addition to establishing an efficient synthetic pathway to Aplyronine A, the Ni/Cr-mediated coupling has significant potential in the preparation of structurally diverse derivatives which may result in enhanced biological activity and the discovery of a novel lead.

The popularity of natural products as synthetic targets will continue as they provide unparalleled inspiration for drug leads and the synthesis of non-natural compounds. Strategies to develop concise and efficient synthetic routes are significantly important not only in terms of their utility in medicine but in the downstream application of novel synthetic methodologies developed during the process of their total synthesis.

To find out more see:

Second generation total synthesis of aplyronine A featuring Ni/Cr-mediated coupling reactions
Ichiro Hayakawa, Keita Saito, Sachiko Matsumoto, Shinichi Kobayashi, Ayaka Taniguchi, Kenichi Kobayashi, Yusuke Fujii, Takahiro Kanekob and Hideo Kigoshi
DOI: 10.1039/C6OB02241C

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

As part of an ongoing research programme in host-guest supramolecular chemistry, Professor Paul Beer of Oxford University has been developing methods for the synthesis of interlocking molecular architectures based on halogen bond donor motifs.

Halogen bonding interactions—the noncovalent, attractive interaction between an electron deficient halogen (X) and a Lewis base (B)—are slowly becoming more prevalent as a complimentary alternative to more commonly used binding interactions. Since its discovery in the late 1960’s, anion recognition chemistry has developed from an interesting area of academic research to a pillar of supramolecular chemistry. In recent years, there has been dramatic advancements within the field that have resulted in a number of practical applications such as organocatalysis involving ion complexation, ion extraction from mixtures and the development of sensory devices and molecular switches.

Anions play fundamental roles in a large number of biological, chemical, medicinal and environmental processes and nature’s binders typically complex anions through intricate networks of electrostatic interactions. The ability to mimic the selectivity of biological systems in artificial settings has been a longstanding challenge in this field.

In a recent OBC publication, the Beer group successfully synthesized two mono-cationic and two dicationic halogen and hydrogen bonding rotaxane anion recognition systems (see figure) and successfully demonstrated the enhanced binding affinity and selectivity of the dicationic halogen bonding analogue relative to its hydrogen bond-containing counterpart. In addition, the dicationic halogen bonding system displayed an enhanced preference for binding to bromine anions over other halides, nitrate and dihydrogen phosphate oxoanions. NMR binding studies reveal that the enhanced strength and selectivity of halide recognition is the result of chelated charge assisted halogen bonding interactions in the dicationic system. This study elegantly demonstrates efforts in exploiting the XB chelate effect to improve anion binding affinity and selectivity. Halogen bonding is still an emerging area of research however, examples such as this highlight its utility as a complementary mode of binding when compared to other more established interactions and will no doubt lead to an evolution in anion receptor design.


To find out more see:

Chelated charge assisted halogen bonding enhanced halide recognition by a pyridinium-iodotriazolium axle containing [2]rotaxane
Alexander E. Hess and Paul D. Beer
DOI: 10.1039/C6OB01851C

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

Nature uses a cooperative interplay of noncovalent interactions to control complex self-assembly of organized nanostructures with extreme precision. Taking this as inspiration, the field of structural DNA nanotechnology has been working toward the development of programmable, self-assembling nanomaterials and motion control at the nanoscale level by exploiting the remarkable molecular recognition properties of DNA. A number of basic structural motifs using branched DNA have been designed and are key elements for the construction of supramolecular arrays, molecular scaffolds and mechanical and logical nanodevices.

The paranemic crossover (PX) motif, as described in a recent OBC publication, has been of particular interest due to its unique ability to behave as both a self-assembling building block or tile and cohesive linker. Its application, until now, has been limited to 1D arrays as the level of flexibility within PX tiles needed to be controlled in order to access well-defined 2D and 3D DNA structures.

PX DNA arises from the fusion of two parallel double helices through strand cross-overs wherever the two strands come in contact. The component double strands are not linked and can hypothetically pair with each other indefinitely in a manner similar to the pairing of a buldged double helix. Advantageously, the PX structural motif reduces the need for sticky end cohesion, traditionally used in DNA-based self-assembly, which leads to an overall increase in nanostructure stability as sticky ends are susceptible to enzymatic degradation. In addition, complex DNA nanostructures made solely from PX motifs reduce topological problems during self-assembly thus minimizing error.

Researchers from the National Centre for NanoScience and Technology in Beijing, Anhui Normal University in China and Purdue University in the United States have collaboratively studied various structural parameters in order to optimize PX DNA’s ability to participate in the assembly of highly desirable 2D nanostructures. By varying the number of base pairs that make up the major (wide, W) and minor (narrow, N) grooves of the bulged double helix, several versions of PX tiles were prepared. Optimal parameters were observed when T₆₅ (according to the formula T_WN), which assembled into an extended, flat and regular 2D array (see image). Any deviation from this number of base pairs resulted in the tile becomes stressed and twisted leading to random aggregates.

This discovery has made possible the application of the highly desirable PX motif in 2D nanoconstruction which will no doubt lead to the synthesis of more stable and structurally and functionally intricate DNA self-assembling nanostructures.

To find out more see:

Synthetic methodologies to control the selectivity and specificity of catalytic reactions remain the subject of intense research due to the importance of chiral compounds in pharmaceuticals, agrochemicals and functional materials. Homogenous catalysis takes advantage of weak interactions between the substrate, catalyst and groups distal to the active site to impart selectivity. Such features are ubiquitous in enzymes which display exceptionally high levels of stereochemical control and activity. In order to exploit the advanced capabilities of such enzymes for selective catalytic transformations, researchers have linked transition metal catalysts with different biological scaffolds–proteins, peptides, DNA–to create artificial metalloenzymes.

Since their inception in the late 1970’s, artificial metalloenzymes have emerged as a vibrant area of research with numerous examples of a variety of catalytic transformations reported alongside creative methods for incorporating the transition metal complex into the biomolecular scaffold. Key to their design is the ‘second coordination sphere’ provided by the biological scaffold where supramolecular interactions within the active site contribute to the rate and enantioselectivity of the system.

Prof. Thomas Ward and Prof. Oliver Wenger of the University of Basel have recently reported a novel biotin-streptavidin system equipped with an anchored photosensitizer capable of undergoing electron transfers between the biotinylated electron donor and ruthenium(II)-labeled streptavidin.

In the past, studies of the luminescent properties of biotinylated d⁶ metal complexes, common in photoredox catalysis, have been carried out for the purposes of cell imaging and ruthenium and rhenium complexes have been employed in the elucidation of electron tunneling pathways of various proteins. The application of phototriggered electron transfers to ruthenium photosensitizers, up until this point, had not yet been realized and this recent discovery demonstrates a significant advancement within this field.

This new biotin-streptavidin artificial metalloenzyme contains a ruthenium catalyst and photosensitizers embedded within the biotin binding pocket of streptavidin through covalent interactions with non-native cysteine residues. Their performance in various electron transfer studies demonstrates their potential to behave as advanced photoredox catalysts and given the diversity of reactions amenable to photoredox processes, these novel artificial metalloenzymes will provide unique opportunities within selective catalysis.

To find out more see:

Light-driven electron injection from a biotinylated triarylamine donor to [Ru(diimine)₃]²⁺-labeled streptavidin
Sascha G. Keller, Andrea Pannwitz, Fabian Schwizer, Juliane Klehr, Oliver S. Wenger and Thomas R. Ward
DOI: 10.1039/C6OB01273F

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

The ubiquity of radioisotope-based bioprobes is being challenged by their nonradioactive counterparts. In recent years, they have gained significant popularity in life sciences due to major advances in available detection methods and enhanced analytical performance. Many would argue that radioactive labels offer superior results in experiments that require high sensitivity and resolution but their safe handling, stability and the proper disposal of radioactive materials limit speed and convenience of use.

The newest generation of fluorescent and chemifluorescent probes promise greater flexibility and versatility for a range of applications and the development of fully automated instrumentations and powerful imaging systems provide high throughput solutions to meet the increasing demands of the modern lab.

Unique photophysical properties can be incorporated into small biomolecules to generate fluorescent bioprobes. Fluorescently labeled nucleosides have distinct advantages over other synthetic molecules due to inherent fluorescence and minimal steric disruptions, and they can be tuned e.g. to form unusual base-pair preferences. They form noncovalent, highly specific duplexes with a complementary nucleic acid strand and are used to detect a defined DNA or RNA target sequence.

In a recent publication from the group of Yoshio Saito of Nihon University, the development of a novel nucleoside-based bioprobe containing a 3-deaza-2’-deoxyadenosine skeleton was reported. It behaves as an indicator for adenosine-cytosine base pair formation in oligodeoxynucleotide (ODN) duplexes by monitoring base-pair induced protonation. The probe displays distinct changes in its absorption and fluorescence activity as a result of its protonation state. In this way, the group is able to clearly discriminate cytosine from other bases on complementary strands based on absorption and fluorescence spectra.

The development of new biomarkers is providing insight to various genetic disorders, disease susceptibility, cancer predisposition and medication response. When fluorescent bioprobe imaging is coupled with genetic analytical techniques, such as single nucleoside polymorphism (SNP)-typing, the two synergize and provide a much more complete view than either one alone.

To find out more see:

Design and synthesis of a novel fluorescent benzo[g]imidazo[4,5-c]quinoline nucleoside for monitoring base-pair-induced protonation with cytosine: distinguishing cytosine via changes in the intensity and wavelength of fluorescence
Shogo Siraiwa, Azusa Suzuki, Ryuzi Katoh and Yoshio Saito
DOI:10.1039/C6OB00494F

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

In their search to solve complex biological problems by bridging gaps between protein synthesis and biological application, Prof. Jennifer Ottesen and her group at Ohio State University have been successfully developing what they term a ‘chemical toolbox’ for histone protein synthesis.

Within the field of epigenetics, heritable changes in gene expression outside of the DNA sequence are tightly regulated by post-translational modifications (PTMs) of DNA and histone proteins–the proteins that package DNA. Known PTMs of histone proteins include methylation, acetlyation, phosphorylation, sulfonylation and ubiquitination and fall under a hypothesized “histone code” which suggests that combinations of these markers alter DNA accessibility through chromatin restructuring and ultimately regulate gene expression.

In building synthetic histone proteins with distinct combinations of chemical modifications, the role of a specific sequence of PTMs in gene expression and the molecular mechanisms by which they function can be elucidated and targeted. This is of particular interest as epigenetics has become a hot topic in recent years due to an ever-growing understanding of these markers and their potential to act as selective entry points for disease intervention.

Ottesen’s recent publication in Organic and Biomolecular Chemistry outlines a new hybrid phase ligation approach for the synthesis of modified histone proteins which overcomes some long standing issues inherent in histone total synthesis. This method combines both solid and solution-phase ligation chemistry to improve process efficiency and overall yield. The group even demonstrates its ability to produce previously challenging CpA-K12ac histone protein which could not be synthesized with standard approaches.

Key to their success is the application of a dual-linker strategy which led to an efficient, sequence-independent resin attachment that liberates the desired native carboxy terminus of the protein which had been previously difficult to accomplish. Below is a scheme describing the solid-phase native chemical ligation of one of their desired targets, histone H4. A single coupling cycle includes deprotection followed by ligation and cleavage from the resin may be accomplished at either the Rink linker (black), or at the HMBA linker (red) to generate the native terminus.

Studies such as Prof. Ottesen’s are crucial as mechanisms by which certain genes are regulated must first be determined before developing targeted therapeutic approaches. Histone deacetylase (HDAC) inhibitors for example, interfere with histone deacetylase and have shown activity against various cancers, neurological diseases and immune disorders. The utility of this class of compound depends on their ability to target and modulate a subset of genes without causing global biological changes. Presently, additional work is required to define the human epigenome, its role in disease development and the processes that regulate it. Progress in the synthesis of highly desirable modified histone proteins brings us ever closer.

To find out more see:

Hybrid phase ligation for efficient synthesis of histone proteins
Ruixuan R. Yu, Santosh K. Mahto, Kurt Justus, Mallory M. Alexander, Cecil J. Howard, and Jennifer J. Ottesen
DOI: 10.1039/C5OB02195B

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

Computational chemistry is a powerful tool for understanding real-world chemical problems. The gap between experiment and computational models is growing ever smaller. Calculated results for isolated molecules are becoming more relevant and reliable calculations for larger and larger molecular systems are becoming more accessible.

A computational study of enantioselective spiroacetalization catalyzed by phosphoric acids carried out by researchers at the Universidad de Salamanca and Oxford University effectively demonstrates the ability of advanced computational methods to elucidate key and often subtle factors that lead to different reaction outcomes.

The study uses a hybrid quantum mechanics (QM)/molecular mechanics (MM) method which makes computational simulations of large systems feasible by combining an accurate quantum mechanical description of the ‘interesting’ part of the system (i.e. the catalyst active site) with the computational efficiency of molecular mechanics applied to the surroundings. This way, one can assess the importance of environmental effects while avoiding a high computational cost. This is accomplished by partitioning the system’s total energy into inner (or active) and outer parts. The interactions within the inner part are then treated with the computationally higher quantum mechanics level and the outer parts are described using less expensive, lower level molecular mechanics methods.

The origin of greater enantioselectivity for the imidodiphosphoric acid (Figure, cat-II) over the binol phorophoric acid (Figure, cat-I) was determined through exhaustive analysis of transition state conformers using the QM/MM method. Ultimately,  it was determined that the source of chiral discrimination in catalyst II comes from a unique, bifunctional hydrogen bonding interaction between the catalyst and substrate. This confining interaction ends up limiting the accessible area to the imidodiphosphoric oxygen, resulting in an enantioselective outcome.

The significance of this work lies in the utility of theoretical models in explaining important empirical results. The ability to dissect a mechanism and identify the influential factors that determine a selective reaction outcome could not have been so easily accomplished without the use of computational analysis and will no doubt aid in the design of future organocatalysts for small, non-sterically demanding molecules.

To find out more see:

QM/MM study on the enantioselectivity of spiroacetalization catalysed by an imidodiphosphoric acid catalyst: how confinment works
Luis Simón and Robert S. Paton
DOI: 10.1039/C6OB00045B

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.