Author Archive

Novel application of fluorescent peptide displacement for small molecule screens against RNA targets

Recent advances in our understanding of RNA have expanded its role beyond just a carrier of genetic information. Modern views of RNA encompass a diverse range of molecules, which play a central role in modulating a number of important biological processes, including the progression of various cancers and nontumorigenic diseases.

In her recent OBC publication, Professor Amanda Hargrove of Duke University has created a general, high throughput screening technique for the identification of small molecule inhibitors of different RNA proteins using a fluorescence indicator displacement (FID) assay.

Small molecule RNA inhibitors offer advantages such as enhanced absorption, distribution, and oral bioavailability over commonly employed oligonucleotides used in antisense technologies. Fluorescence-based assays are widely used techniques used to screen small molecule libraries, however, the incorporation of fluorescent tags can lead to alterations in the RNA’s native structure and often pose synthetic challenges. FID, on the other hand, is a ‘tagless’ approach in which the indicator displays different fluorescent properties in the presence or absence of an oligonucleotide.

The Hargrove group implemented the Tat FID assay in order to simultaneously screen a library of small molecules against multiple RNA targets. This provides an efficient means of measuring binding affinity as well as evaluating specificity. The Tat FID assay requires a Tat peptide construct labeled with a Förster Resonance Enhancement Transfer (FRET) pair—a 5-carboxyfluorescein (FAM) at the N-terminus and 5-carboxytetramethylrhodamine (TAMRA) at the C-terminus (see figure). When the peptide is bound to RNA, the distance between fluorophores allows for excitation of FAM and emission detection from TAMRA. Displacement of the Tat peptide results in quenching of the fluorescent signal, which can be used to quantify binding affinity.

A library of 30 small molecules (including known RNA binding small molecules) was screened against four select RNA structures. The assay was successful in identifying hits for all four RNA molecules and identified indiscriminate and differential binding of individual small molecules. Binding results correlated with known literature results and statistical analysis was used to clarify the relationship between small molecule structures/RNA based on their binding affinity and selectivity.

As with any fluorescence-based assay, the Tat FID assay possesses inherent limitations. However, it has been shown to be a powerful high throughput technique as a result of its ease of operation, low concentration requirement for both ligand and target, and its ability to rapidly assess small molecule/RNA binding interactions.

To find out more see:

Fluorescent peptide displacement as a general assay for screening small molecule libraries against RNA
Neeraj N. Patwardhan, 
DOI:10.1039/C8OB02467G


Victoria Corless has recently completed her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centered on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules. She is passionate about communicating new discoveries to enhance science literacy.

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Sustainable fertilisers derived from canola oil and elemental sulfur

Developing efficient crop fertilisation has become an ever-growing concern given the increasing demand for global food production. Slow-release fertilisers have been developed as a strategy to increase the efficiency of crop production while minimizing nutrient waste, reducing negative environmental impacts and enhancing crop yield. Mechanisms for controlled nutrient diffusion include semi-soluble or complex forms of the nutrient, slow hydrolysis of water-soluble compounds, and encapsulation of the nutrient within semipermeable or permeable coatings for controlled solubility/release (among many others). While slow-release strategies are promising, technical limitations such as the brittle nature of inorganic coatings and composites or the imperishable nature of synthetic polymer coatings hinder their industrial utility.

In a collaborative study published by Professor Justin Chalker of Flinders University, the group sought to develop an efficient and durable slow-release fertiliser derived from canola oil and elemental sulfur. Sulfur is highly appealing given its low cost, abundance, and that it is a secondary plant nutrient and fungicide. Numerous studies and years of research, however, have demonstrated that a persistent limitation of sulfur-coated fertilizers is their brittle nature. The present study, therefore, focused on converting sulfur to a more durable polymer form to be used as a composite with or encapsulate NPK (nitrogen, phosphorous, and potassium) nutrients.

Inverse vulcanisation was used to prepare the sulfur polymer. In this process, elemental sulfur is heated to promote the production of thiyl radicals which can react with an unsaturated small-molecule cross-linker. In this case, canola oil was used as the cross-linker to form a polysulfide polymer capable of encapsulating NPK nutrients.

Elution studies in which fertiliser is placed in a soil column and conductivity of the outflow is measured demonstrated the superior capabilities of the sulfur-encapsulated NPK fertiliser in controlling NPK nutrient release relative to free NPK. A small-scale plant growth study also found that plants treated with the composites were significantly healthier and produced more fruit relative to other groups. What’s even more exciting is the fact that the canola oil polysulfide can be made from recycled cooking oil, converting food waste into valuable fertilisers.

With the rising challenge of feeding a rapidly growing population while also mitigating damaging environmental impacts, studies such as this that make significant strides toward efficient and sustainable agricultural practices are more important than ever.

To find out more see:

Sulfur polymer composites as controlled-release fertilisers 
Maximilian Mann, 
DOI:10.1039/C8OB02130A


Victoria Corless has recently completed her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centered on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules. She is passionate about communicating new discoveries to enhance science literacy.

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Peptide anchors for water-resistant sunscreen

The risks associated with excessive exposure to ultraviolet (UV) radiation are well studied and many national healthcare initiatives have been pushing for large-scale sun protection programs. Despite this drive for a broader public awareness, recent studies have disclosed that skin cancers, such as melanoma, basal cell carcinoma, and squamous cell carcinoma, have become the most common form of cancer worldwide, with more new cases of skin cancer diagnosed in the U.S. than breast, prostate, lung and colon cancer combined.

In a recent OBC study by Professor Ronald Raines of MIT, the researchers identify that although the risk of skin cancer and visible signs of aging can be minimized by using sunscreen, there is still a need to develop more durable, non-greasy sunscreens that are not readily washed away with water or sweat.

Sunscreens typically form a protective barrier on the skin and protect against various types of UV radiation by either absorbing or reflecting UV light before it can reach DNA. Typical absorbing filters are small aromatic compounds, such as salicylates, cinnamates, benzophenones, or derivatives of p-aminobenzoic acid.

Previous studies have been carried out wherein small molecule UV filters have been attached to lipophilic moieties to minimize the amount of sunscreen washed away during physical activity. However, such compounds have not been shown to effectively withstand ‘washing’ and are often undesirably greasy, which according to the authors diminishes public compliance to use them.

Raines and coworkers propose that collagen mimic peptides (CMPs) could be used to effectively anchor pendent UV-filters to the skin. Natural collagen contains loops and interruptions in its overall 3D structure which provide numerous binding sites for CMPs (as demonstrated in the Raines group’s previous work). Since collagen is the primary component of skin, this would provide a means for efficiently tethering UV filters to the skin in order to create an effective, water-resistant sunscreen. Raines and coworkers showed the successful anchoring of a salicylic acid bound CMP and its retention on collagen-containing skin surrogates after repeated water washes. This strategy is highly modular and provides an excellent proof-of-concept for the development of more effective and durable sunscreens to address a worldwide concern.

To find out more see:

A pendant peptide endows a sunscreen with water-resistance
Aubrey J. Ellison and 
DOI:10.1039/C8OB01773E


Victoria Corless has recently completed her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centered on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules. She is passionate about communicating new discoveries to enhance science literacy.

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Harnessing ring strain to drive the classically forbidden thermal [2+2] addition of cycloalkenes

The cyclobutane ring is a unique structural element found in a wide variety of biologically active natural products and synthetic molecules. Although cyclobutanes have been known for centuries, as a result of inherent ring strain, their application in synthesis has only become more popular in the last 40-50 years.

The photochemical [2+2] cycloaddition of alkenes represents a powerful strategy for the synthesis of cyclobutane rings. However, direct irradiation of cycloalkenes with UV light often leads to unwanted and difficult to control rearrangement pathways.

Professor Jimmie Weaver of Oklahoma State University proposes an alternative to direct irradiation of cycloalkenes by instead capturing energy in the form of ring strain. The Weaver group has applied their mild and efficient methodology toward the synthesis of cyclobutane rings imbedded within a C2-symmetric tricyclic framework.

It is well known that thermal [2+2] cycloadditions are ‘forbidden’ processes due to unfavourable orbital overlap of the reaction partners during the transition state. However, a common exception to this is the [π2s+π2a] addition of alkenes and ketenes. The Weaver group proposes that a thermal [π2s+π2a] cycloaddition could take place for ground state alkenes by generating a high energy intermediate, which would result in a decreased relative energy barrier for the thermal cycloaddition.

This method uses an iridium-based photocatalyst to generate the highly strained trans-cycloheptene intermediate—which possesses 27-36 kcal/mol of ring strain—in order to drive the thermal [2+2] cycloaddition of cycloheptenes and various cycloalkene substrates. Interestingly, the reaction results in four new stereocenters which are generated with excellent stereoselectivity and regioselectivity. An added advantage of using light within the visible spectrum to activate the photocatalyst minimizes competitive photochemical [2+2] addition pathways.

This study is an excellent example of the application of basic principles to drive previously inaccessible mechanistic pathways. The authors hope that their study will encourage other applications of visible light energy to drive unfavourable endergonic reactions.

To find out more see:

An elusive thermal [2+2] cycloaddition driven by visible light photocatalysis: tapping into strain to access C2-symmetric tricyclic rings
Kamaljeet Singh, 


Victoria Corless has recently completed 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 building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules. She is passionate about communicating new discoveries to enhance science literacy.

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Creating a platform for the development of photoswitchable ligand libraries

Photoswitchable small molecules have become important tools for analyzing biological systems. The discovery of light-tuneable molecules has enabled the study of intricate physiological responses within cells through precise spatial and temporal control to modulate their function. Although powerful tools, de novo design is often challenging as it requires detailed information about the structure of both the ligand and the receptor.

In a recent OBC publication, the group of Professor Ratmir Derda of the University of Alberta discusses a strategy to develop libraries of light-responsive (LR) ligands, which can be produced by grafting known LR structures, such as azobenzene, onto molecules with established biological activity. In this way, the challenges of identifying novel LR ligands can be addressed by selecting from a library of tagged LR-compounds that are already known to possess desired biological function.

Their study outlines a proof-of-concept for such a library using the synthesis of LR-bicyclic peptides, which contain a hydroxyl amine and di-chlorobenzene containing azobenzene (HADCAz) linker.

HADCAz behaves as a 3-point linchpin and can be used in the bicyclization of peptides through its orthogonally reactive ‘thiol-reactive’ and ‘aldehyde-reactive’ attachment points. The authors successfully demonstrated the synthesis of a small library of bicyclic peptides from linear, unprotected peptides (~20 amino acids in length) in a one-pot, two step reaction involving double intramolecular nucleophilic addition and oxime formation to form the two loops. The peptide-bound HADCAz linkers were shown to reversibly switch to their cis-conformers after irradiation with 365 nm light and molecular dynamic (MD) simulation was used to assess conformational changes, the properties of which were seemingly dependent on the peptide’s length.

While optimizations are still required for broad application, this work provides a versatile platform from which numerous avenues within the realms of optochemical genetics and photo-pharmacology can be explored.

To find out more see:

Light-responsive bicyclic peptides
Mohammad R. Jafari, 
DOI:10.1039/C7OB03178E


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 building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Novel route to the [7-5-5] tricyclic core of Daphniphyllum alkaloids

To date, more than 320 new alkaloids have been isolated from the evergreen plants of the Daphniphyllum genus. In ancient times, extracts of the bark and leaves of Daphniphyllum plants were used in Chinese herbal medicines to cure minor ailments and treat pain. Recent studies have discerned that the Daphniphyllum class of alkaloid displays significant and varying biological activity, including anticancer, antioxidant and vasorelaxant activities. However, their unique polycyclic architectures containing multiple quaternary stereocenters render these alkaloids synthetically challenging.

A recent OBC publication by Tohru Fukuyama and Satoshi Yokoshima of Nagoya University reports on the synthesis of a common structural core prevalent among the Daphniphyllum alkaloids. The common [7-5-5] tricyclic core features a quaternary carbon centre, two contiguous stereogenic centres and a tetrasubstituted C-C double bond.

The study began with the synthesis of the adjacent stereogenic centres, which was ultimately achieved through a Claisen-Ireland rearrangement with a 73% isolated yield (1 step) and dr = 6.3:1.

The challenging tetrasubstituted C-C double bond was tackled next. Limited procedures for the installation of the tetrasubstituted C-C alkene have been reported for the [7-5-5] tricyclic core. The highly congested nature of such substituted double bonds results in destabilizing eclipsing interactions, which are mirrored in the transition states leading to them. The tetrasubstituted C-C double bond of the [7-5-5] tricyclic core was therefore carried out using an E1cB-elimination of intermediate 28 to generate the a,b-unsaturated ketone 29 with a 78% isolated yield.
Extensive investigations revealed that the quaternary carbon centre could be accessed through a 2,3-Wittig rearrangement, which occurred stereoselectively on the less hindered face of the bicyclic intermediate. Quite efficiently, this transformation yielded intermediate 36 which contained a vinyl group that was to be used in the construction of the 7-membered ring. Final steps included a ring-closing metathesis and an intramolecular carbonyl ene reaction to complete the [7-5-5] ring system.

This creative study provides an excellent platform for the total synthesis of Daphniphyllum alkaloids that have the [7-5-5] tricyclic core.

To find out more see:

Synthesis of the [7-5-5] tricyclic core of Daphniphyllum alkaloids
Yusuke Kitabayashi, Tohru Fukuyama and Satoshi Yokoshima
DOI: 10.1039/C8OB00859K


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 building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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New class of synthetic antibody mimics for improved therapeutics

Molecules capable of mimicking the binding and/or functional sites of proteins represent a promising avenue for the development of potential drug candidates. This strategy allows for the incorporation of key structural features into simpler scaffolds and opens a wide range of opportunities for developing molecules with enhanced and modular biological activities.

A recent OBC publication by Professor Rob Liskamp of Glasgow University addresses a current challenge in the development and application of complementarity determining region (CDR) mimics, which have recently been shown to successfully behave as synthetic antibody mimics.

 

The concept of simplifying large proteins into simpler structures requires the synthesis of preorganized molecular scaffolds, which function as the core structural unit for attaching the biologically active CDR component. Such analogues have been shown to possess increased bioavailability, proteolytic stability and exhibit reduced immunogenic responses.

The group had previously reported the synthesis of a CTV-derived scaffold (Figure, compound 2), onto which different peptide segments could be incorporated, essentially generating synthetic CDRs with novel and tuneable physico-chemical properties. Poor solubulity however, has limited the progress of this class of compound in the drug discovery process.

Their current study focuses on the development of a scalable, one-pot synthesis of water soluble CTV-derived scaffolds (Figure, compounds 3, 4), which incorporate mono or diethylene glycol spacers. Late-stage diversification of the CTV-derived scaffolds is ammenable through Cu(I)-catalyzed azide-alkyne cycloaddition. This allows for the generation of a diverse series of synthetic antibodies, which were shown to mimic the antigen binding site of monoclonal antibody (mAb) infliximab (Remicade)—used for the treatment of human tumour necrosis factor alpha (hTNFa) mediated autoimmune diseases. SPR binding studies against the hTNFa receptor identified 5 leads with KD’s measured between 11 and 66 mM. While further modifications are required to improve solubility for evaluation in vitro, this study demonstrates the potential of this work to extend beyond antibody mimics. As any azide handle can be linked to the CTV-derived scaffold, one can envision the application of this methodology toward alternative protein mimics.

To find out more see:

Synthetic antibody protein mimics of infliximab by molecular scaffolding on novel CycloTriVeratrilene (CTV) derivatives
Ondřej Longin, 
DOI:10.1039/C8OB01104D


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 building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Reactivity Caging Strategy for Controlling Bioorthogonal Reactivity

Bioorthogonal reactions offer a unique and highly effective means of studying biological molecules in their native environment. Classical examples include native chemical ligations, Staudinger ligation, and click chemistry though numerous examples have been reported in the literature over the past several decades.

The majority of studies centred around the development of bioorthogonal reagents have focused on improving kinetics and selectivity in vivo. However, less explored are reagents in which their reactivity in biological settings is modulated through controlled activation by light or a specific enzyme.

In their recent OBC publication, Professor Scott Laughlin and coworkers describe the modular control of novel cyclopropane-tetrazine ligation. Previous reports have demonstrated the poor reactivity of C3 disubstituted cyclopropene in these types of reactions due to unfavourable steric interactions between the C3 substituents and the tetrazine during the transition state (Figure A). To this end, 3-N-substituted spirocyclopropenes were designed to control ligation through a “reactivity caging strategy” in which the introduction of a removable bulky N-protecting group sterically inhibits premature reaction with the tetrazine partner (Figure B and C).

The novel cyclopropene scaffold was synthesized from commercially available starting materials in good overall yields and applied successfully to the labelling of a tetrazine-modified protein. Given the widespread use of light-removable nitrogen protecting groups, the group predicts their activatable cyclopropene scaffold will be amenable to control at multiple wavelengths. While optimization of reaction kinetics is still required, this study provides interesting opportunities for the application of diverse caging groups in modulating reactivity for specific biological systems and applications.

To find out more see:

Caged cyclopropenes for controlling bioorthogonal reactivity
Pratik Kumar, 
DOI:10.1039/C8OB01076E


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 building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Novel bis-urea anionophores facilitate ion transport in live cell environments

The development of synthetic molecules capable of facilitating the transport of ions across cell membranes has become a prominent and active field of research. These compounds mimic the activity of natural ionophores and have found broad application in materials sciences, chemical biology and medicine.

The majority of known synthetic ionophores facilitate the transport of cations. However, there is mounting evidence to support the ability of anion selective ionophores (anionophores) to act as anticancer agents and novel leads in the treatment of channelopathies—diseases, such as cystic fibrosis, caused by dysfunctional ion channels or related regulatory proteins. The ultimate hope is that they can be used to restore ion channel function in such cases.

An important step toward practical application is to demonstrate the activity of anionophores not only in synthetic vesicle assays but in live cell environments. In a collaborative study between Prof. Phillip Gale of the University of Sydney, Prof. Anthony Davis and Prof. David Sheppard of the University of Bristol, the biological activity of a series of ortho-phenylene bis-urea (OPBU) anionophores was explored using a biological anion transport assay employing Fischer rat thyroid cells. This family of anionophores is readily prepared from commercially available starting materials using simple chemistry which allows for facile structural variation and the study of structure-activity relationships.

It was shown that activity was dependent on both the electronic nature and lipophilicity of the bis-urea anionophore. Interestingly, while lipophilicity was shown to promote intrinsic activity it also had a contrary effect on deliverability which hampered the anionophore’s effectiveness in living cells. Bis-urea 4a (Figure) was shown to be the most effective in all assays and is based on a difluorinated central scaffold.

This study provides interesting insight into the biological activity of this class of anionophores and is a promising first step toward their potential application in medicine.

To find out more see:

Anion transport by ortho-phenylene bis-ureas across cell and vesicle membranes
Christopher M. Dias, Hongyu Li, Hennie Valkenier, Louise E. Karagiannidis,  
DOI:
10.1039/C7OB02787G


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 building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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New rigid spin-labels for enhanced EPR studies of RNA

Electron paramagnetic resonance (EPR) is powerful technique for studying chemical species containing unpaired electrons. It has far reaching applications in a number of fields as it can be used to elucidate structural, electronic and conformational dynamic features in a given system. 

In biological settings, paramagnetic probes have been developed to ‘spin-label’ desired biomolecules using a technique called site-directed spin labelling (SDSL). In combination with other methods, EPR has emerged as an efficient means of studying proteins close to their native physiological states and can be used to glean information regarding the immediate environment of the spin-labeled side-chain as well as measure intra- and intermolecular distances within the protein. A challenge has been in developing rigid spin-labels to improve the accuracy of distance measurements as the most reliable information is attained if the distance between spin-labels is unchanged by conformational flexibility.

In their most recent OBC publication, Prof. Snorri Sigurdsson of the University of Iceland and Prof. Thomas Prisner of Goethe University describe the development of an enhanced isoindoline-nitroxide derivative of uridine (ImUm), the first example of a conformationally constrained spin label for RNA.

Limited mobility of ImUM is a result of the nitroxide N-O bond lying in the same axis as the bond used to link it to the uridine base. As a result, bond rotation does not drastically alter the position of the nitroxide. Additionally, ImUm was shown to bind specifically and with high affinity to abasic sites in duplex RNAs. Here, rigidity is further enhanced through intramolecular hydrogen bonding between the nitroxide probe and the orphaned uracil base. ImUm is a promising label for EPR studies of RNA, providing highly useful and dynamic structural information unbiased by conformational flexibility.

To find out more see:

A semi-rigid isoindoline-derived nitroxide spin label for RNA
Dnyaneshwar B. Gophane,  
DOI: 10.1039/C7OB02870A


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 building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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