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Harnessing biosynthetic pathways to efficiently derivatize biologically active natural products

11 Jan 2019

Nature is unrivaled in its ability to produce structurally complex molecules with high biological potency. Natural products have been used medicinally for centuries and have provided a profitable source of potential drug leads. Developing efficient strategies for their total synthesis, as well as the production of analogues, has always been challenging.

In a recent OBC publication, Professor Shuangjun Lin of Shanghai Jiao Tong University has identified a key enzyme in the biosynthesis of the natural product, Streptonigrin, a highly fictionalized aminoquinone isolated from the bacterium Streptomyces flocculus.

Streptonigrin has a long history and has attracted considerable attention from both the synthetic and biochemical communities due to its challenging molecular framework and potent antimicrobial and broad-spectrum anticancer activities. In the 1970’s, Streptonigrin reached phase-II clinical trials, though ultimately failed due to high levels of toxicity and side effects. Nevertheless, interest in its medicinal properties still remains, and many studies detailing its chemical and biosynthesis have been reported, with the hopes of enabling the production of Streptonigrin-based analogues, which would mitigate the natural product’s cytotoxicity while harnessing is broad biological capabilities.

Prof. Lin reports that previous genetic and biochemical studies successfully identified a key β-carboline (3) intermediate in the biosynthetic pathway of Streptonigrin. The β-carboline moiety is a common structural feature within a large group of natural and synthetic indole alkaloids however, the enzymes catalyzing their formation have not been well characterized or reported. Lin and coworkers have identified a protein, StnK2, which they propose catalyzes a Pictet-Spengler reaction responsible for β-carboline formation from (2S,3S)-β-methyl tryptophan and erythrose (Figure).

The study focussed on the biochemical characterization of StnK2 as a Pictet-Spenglerase, analyzing in detail its stereoselectivity and substrate specificity. StnK2 exhibited exclusive aldehyde specificity, though was flexible towards various tryptophan analogues. Additionally, StnK2 demonstrated high stereoselectivity, only recognizing S-enantiomers and producing the (R)-C-1 of the β-carboline scaffold.

This study has not only contributed to our knowledge of Pictet-Spenglerase enzymes, but has established a new means through which Streptonigrin analogues can be efficiently generated and their medicinal properties explored.

To find out more see:

StnK2 catalysing a Pictet–Spengler reaction involved in the biosynthesis of the antitumor reagent streptonigrin
Xiaozheng Wang, Dekun Kong, Tingting Huang, Zixin Deng and Shuangjun Lin
DOI:10.1039/C8OB02710B

For more papers from the OBC Biosynthesis Themed Collection

Victoria Corless completed her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research centered on the synthesis of kinetically amphoteric building blocks with particular emphasis on creating novel biologically active molecules. She is passionate science and communicating new discoveries to enhance science literacy.

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

06 Dec 2018

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, Zhengguo Cai, Colby N. Newson and Amanda E. Hargrove
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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Unexpected divergent reactivity in Pt-catalyzed cyclizations of 1,5-bisallenes

19 Oct 2017

As a result of their unique physical and chemical properties, allenes have become key building blocks in modern organic synthesis. The discovery and development of their varied reactivity have been extensively reported on in recent years, however, application to more challenging bisallene systems has been comparatively limited.

In her group’s recent OBC publication, Prof. María Paz Muñoz of the University of East Anglia sought to fill this gap in the bisallene literature. The study discusses the development of an unprecedented Pt-catalyzed cyclization of 1,5-bisallenes in the presence of oxygen nucleophiles to selectively access 6- and 7-membered rings.

After initial screening, it was observed that selectivity was highly sensitive to the reaction conditions and could, therefore, be tuned to yield the desired molecular scaffold. Interestingly, in the presence of nucleophilic alcohols, vinyltetrahydropyridines are formed preferentially while the formation of di- and tetrahydroazepines are favoured when water is used.

Exhaustive mechanistic studies provided insight into this divergent reactivity. It was determined that different mechanisms operate depending on the nucleophile and electronic nature of the bisallene (as a result of its nitrogen tether). It is proposed that, in the presence of nucleophilic alcohols, 6-membered vinyltetrahydropyridines are preferentially formed as a result of a platinum hydride active catalyst—which are known to form from platinum complexes and alcohols. Tetrahydroazepines, on the other hand, are favoured when water is used as the nucleophile, proceeding first through a nucleophilic attack followed by carbocylization to form the 7-membered ring.

Understanding this complex mechanistic behaviour provides important insight into bisallene reactivity and will no doubt enhance the scope of this work’s application in organic and medicinal chemistry.

This communication is part of the OBC themed collection, Mechanistic Aspects of Organic Synthesis. You can read the rest of the collection here.

To find out more see:

Nucleophile dependent formation of 6- and 7-membered N-heterocycles by platinum-catalysed cyclisation of 1,5-bisallenes
María Teresa Quirós,César Hurtado-Rodrigo and María Paz Muñoz
DOI:10.1039/C7OB01469D

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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Self-assembly of bioactive peptides, peptide conjugates, and peptide mimetic materials

06 Sep 2017

Molecular self-assembly has become one of the most prominent fields of nanotechnology in recent years. Inspired by nature, many scientists around the world are attempting to utilize it as a tool to design novel nanostructures with desired biomedical properties.

To achieve this goal, it is necessary to understand how self-assembly works and how molecular forces and other conditions drive this self-assembly and define the structure of a specific supramolecular complex.

In a recent Organic & Biomolecular Chemistry publication, Professor Charlotte J. C. Edwards-Gayle and Professor Ian W. Hamley from the University of Reading, UK, have reviewed some of the most prominent self-assembled peptide amphiphiles and their potential applications. These include tissue scaffolds, antimicrobial peptides and drug transporters.

One of the distinct features of self-assembling amphiphiles, which makes them attractive candidates for many applications, is their diversity to form various structures such as micelles, vesicles, nanotubes, fibrils and sheets (Fig.1). The self-assembly of PAs can also be tuned by several factors including amino acid sequence, peptide length, temperature, pH, and concentration.

These features make them perfect, novel tools to create biomaterials which can be responsive to different environmental cues. However, the review points out that the key question of whether there is a relationship between bioactivity and self-assembly of peptide amphiphiles has still remained unanswered, despite the advancement in the field.

Extending the success in designing various structures, together with distinct applications, have made peptide amphiphile self-assembly a vibrant field in which researchers will continue to develop functional constructs with novel applications.

To find out more please see:

Self-assembly of bioactive peptides, peptide conjugates, and peptide mimetic materials
Charlotte J. C. Edwards-Gayle and Ian W. Hamley
DOI: 10.1039/C7OB01092C

Zahra Bahrami Dizicheh is a PhD candidate in molecular biology with Dr. Giovanna Ghirlanda at Arizona State University. She does research on photo-electrochemical hydrogen production with designing and developing interconnection between conductive materials and redox proteins to develop dye-sensitized photo-electrochemical cells.

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Chemistry in Water

20 Mar 2014

We are delighted to share with you a series of collections of recent books, themed issues and articles on the topic of water. These four collections – one per month – demonstrate different aspects of water: its chemistry, its wide use in reactions and as a solvent, its relationship with energy and sustainability, as well as with human health and the environment.

Image (c) Shutterstock

Here, in our second collection, we have assembled some of the ground-breaking research and transformative reviews related to the chemistry in water – highlighting the importance and versatility of water as a medium in chemistry – from across our journals.

Professor Rafael Luque, winner of the RSC 2013 Environment, Sustainability and Energy Division Early Career Award, welcomes this timely and topical collection. “For a more sustainable future, we need to develop benign chemical protocols,” he notes. “Conducting chemical processes in water is a significant step towards this goal. This high profile collection includes articles from leading scientists in the field with varying topics – from materials synthesis to organocatalysis, synthetic organic chemistry and heterogeneous catalysis – that we hope can provide a starting point for young researchers, as well as key references to stimulate further research in the field.”

“This year, as the IPCC prepares to release the final contributions to their Fifth Assessment Report on climate change, it is timely to consider the role of chemistry in addressing global challenges, such as food, water, raw materials and energy,” remarks Professor Lesley Yellowlees, President of the Royal Society of Chemistry. “This collection from our journals shares the latest research from scientists around the world, aiming to tackle these challenges. Featuring original research and commentary by leaders in the field, we hope that you will find this high-quality collection engaging, inspirational and informative.”

You can read all of these articles for free until 21 April 2014! We truly hope you enjoy this collection.

We have already published an article collection on the chemistry of water. In the next couple of months, we will be publishing collections on water in energy, health and the environment.

Did you know that the RSC has put together a webpage on Water, which brings together information on activities for scientists, policymakers, educators and young people? Take a look today…

Reviews and Perspectives

In water, on water, and by water: mimicking nature’s aldolases with organocatalysis and water
Nobuyuki Mase and Carlos F. Barbas, III
Org. Biomol. Chem., 2010,8, 4043-4050 GA?id=C3CS60025D
DOI: 10.1039/C004970K, Perspective

Benign by design: catalyst-free in-water, on-water green chemical methodologies in organic synthesis
Manoj B. Gawande, Vasco D. B. Bonifácio, Rafael Luque, Paula S. Branco and Rajender S. Varma
Chem. Soc. Rev., 2013,42, 5522-5551
DOI: 10.1039/C3CS60025D, Review Article

Olefin metathesis in aqueous media
Jasmine Tomasek and Jürgen Schatz
Green. Chem., 2013,15, 2317-2338
DOI: 10.1039/C3GC41042K, Critical Review

Green chemistry oriented organic synthesis in water
Marc-Olivier Simon and Chao-Jun Li
Chem. Soc. Rev., 2012,41, 1415-1427
DOI: 10.1039/C1CS15222J, Tutorial Review
From themed collection Green Chemistry

sp2 C–H bond activation in water and catalytic cross-coupling reactions
Bin Li and Pierre H. Dixneuf
Chem. Soc. Rev., 2013,42, 5744-5767 GA?id=C0SM01072C
DOI: 10.1039/C3CS60020C, Review Article

Stimulus responsive core-shell nanoparticles: synthesis and applications of polymer based aqueous systems
Olivier J. Cayre, Nelly Chagneux and Simon Biggs
Soft Matter, 2011,7, 2211-2234
DOI: 10.1039/C0SM01072C, Review Article

Alkynes as an eco-compatible “on-call” functionality orthogonal to biological conditions in water
Nick Uhlig and Chao-Jun Li
Chem. Sci., 2011,2, 1241-1249
DOI: 10.1039/C1SC00164G, Minireview GA?id=C1SC00164G

Anion binding in water at lanthanide centres: from structure and selectivity to signalling and sensing
Stephen J. Butler and David Parker
Chem. Soc. Rev., 2013,42, 1652-1666
DOI: 10.1039/C2CS35144G, Tutorial Review
From themed collection Alfred Werner Nobel Prize 100 year celebration

Prebiotic chemistry in eutectic solutions at the water–ice matrix
César Menor-Salván and Margarita R. Marín-Yaseli
Chem. Soc. Rev., 2012,41, 5404-5415
DOI: 10.1039/C2CS35060B, Tutorial Review
From themed collection Prebiotic Chemistry

Original research articles

An in-water, on-water domino process for synthesis
Philip Norcott, Calan Spielman and Christopher S. P. McErlean
Green. Chem., 2012,14, 605-609
DOI: 10.1039/C2GC16259H, Communication

Highly efficient iron(0) nanoparticle-catalyzed hydrogenation in water in flow
Reuben Hudson, Go Hamasaka, Takao Osako, Yoichi M. A. Yamada, Chao-Jun Li, Yasuhiro Uozumi and Audrey Moores
Green. Chem., 2013,15, 2141-2148
DOI: 10.1039/C3GC40789F, Paper

Water as an additive to enhance the ring opening of naphthalene
Qian Wang, Honglei Fan, Suxiang Wu, Zhaofu Zhang, Peng Zhang and Buxing Han
Green. Chem., 2012,14, 1152-1158 GA?id=C1OB05735A
DOI: 10.1039/C2GC16554F, Paper

Click chemistry from organic halides, diazonium salts and anilines in water catalysed by copper nanoparticles on activated carbon
Francisco Alonso, Yanina Moglie, Gabriel Radivoy and Miguel Yus
Org. Biomol. Chem., 2011,9, 6385-6395
DOI: 10.1039/C1OB05735A, Paper

An organocatalytic highly efficient approach to the direct synthesis of substituted carbazoles in water
Pradeep Kumar Jaiswal, Soumen Biswas, Shivendra Singh and Sampak Samanta
Org. Biomol. Chem., 2013,11, 8410-8418
DOI: 10.1039/C3OB42034E, Paper

GA?id=C1GC15726D

Near-critical water, a cleaner solvent for the synthesis of a metal–organic framework
Ilich A. Ibarra, Peter A. Bayliss, Eduardo Pérez, Sihai Yang, Alexander J. Blake, Harriott Nowell, David R. Allan, Martyn Poliakoff and Martin Schröder Green Chem., 2012,14, 117-122
DOI: 10.1039/C1GC15726D, Paper

Stille couplings in water at room temperature
Guo-ping Lu, Chun Cai and Bruce H. Lipshutz
Green Chem., 2013,15, 105-109
DOI: 10.1039/C2GC36042J, Paper

DNA-based asymmetric organometallic catalysis in water
Jens Oelerich and Gerard Roelfes
Chem. Sci., 2013,4, 2013-2017
DOI: 10.1039/C3SC00100H, Edge Article

Pyridinium-based tripodal chemosensor in visual sensing of AMP in water by indicator displacement assay (IDA)
Kumaresh Ghosh, Sk Sarfaraj Ali, Avik Ranjan Sarkar, Asmita Samadder, Anisur Rahman Khuda-Bukhsh, Ioannis D. Petsalakis and Giannoula Theodorakopoulos
Org. Biomol. Chem. , 2013, 11, 5666-5672
DOI: 10.1039/C3OB40833G, Paper

GA?id=C2GC16240G

Design, synthesis, and solution behaviour of small polyamines as switchable water additives
Sean M. Mercer, Tobias Robert, Daniel V. Dixon, Chien-Shun Chen, Zahra Ghoshouni, Jitendra R. Harjani, Soran Jahangiri, Gilles H. Peslherbe and Philip G. Jessop
Green Chem. , 2012,14, 832-839
DOI: 10.1039/C2GC16240G, Paper

In situ generation of bioreducible and acid labile nanogels/microgels simply via adding water into the polymerization system
Zhong-Kai Wang, Long-Hai Wang, Jiao-Tong Sun, Li-Fen Han and Chun-Yan Hong
Polym. Chem., 2013, 4, 1694-1699
DOI: 10.1039/C2PY21058D, Paper

Template-directed synthesis of multi-component organic cages in water
Artur R. Stefankiewicz, Mark R. Sambrook and Jeremy K. M. Sanders
Chem. Sci., 2012,3, 2326-2329
DOI: 10.1039/C2SC20347B, Edge Article

Tuning the catalytic activity of L-proline functionalized hydrophobic nanogel particles in water
Annhelen Lu, Dafni Moatsou, Deborah A. Longbottom and Rachel K. O’Reilly
Chem. Sci., 2013,4, 965-969
DOI: 10.1039/C2SC21300A, Edge Article

GA?id=C3SC51547H

Gold nanoparticles stabilized by an amphiphilic pillar[5]arene: preparation, self-assembly into composite microtubes in water and application in green catalysis
Yong Yao, Min Xue, Zibin Zhang, Mingming Zhang, Yong Wang and Feihe Huang
Chem. Sci., 2013,4, 3667-3672
DOI: 10.1039/C3SC51547H, Edge Article

Water-controlled synthesis and single-crystal structural transformations of a cyanide-bridged W(IV)–Ni(II) molecular wheel complex and 3D networks
Dao-Peng Zhang, Li-Fang Zhang, Guo-Ling Li and Zhong-Hai Ni
Chem. Comm., 2013,49, 9582-9584
DOI: 10.1039/C3CC46063K, Communication

Oxidation of water by a nonhaem diiron(IV) complex via proton-coupled electron transfer
Dong Wang and Lawrence Que
Chem. Comm., 2013,49, 10682-10684
DOI: 10.1039/C3CC46391E, Communication
From themed collection Biological oxidation reactions: mechanisms and design of new catalysts

Enantioselective Friedel–Crafts reactions in water catalyzed by a human telomeric G-quadruplex DNA metalloenzyme
Changhao Wang, Yinghao Li, Guoqing Jia, Yan Liu, Shengmei Lu and Can Li
Chem. Comm., 2012,48, 6232-6234
DOI: 10.1039/C2CC31320K, Communication

Enhanced imine synthesis in water: from surfactant-mediated catalysis to host–guest mechanisms
Kamel Meguellati, Ali Fallah-Araghi, Jean-Christophe Baret, Abdeslam El Harrak, Thomas Mangeat, Carlos M. Marques, Andrew D. Griffiths and Sylvain Ladame
Chem. Comm., 2013,49, 11332-11334
DOI: 10.1039/C3CC46461J, Communication
Open Access

A method for increasing permeability in O₂/N₂ separation with mixed-matrix membranes made of water-stable MIL-101 and polysulfone
Harold B. Tanh Jeazet, Claudia Staudt and Christoph Janiak
Chem. Comm., 2012,48, 2140-2142
DOI: 10.1039/C2CC16628C, Communication

Cu(OTf)₂-catalysed Ritter reaction: efficient synthesis of amides from nitriles and halohydrocarbons in water
Gui-Rong Qu, Yan-Wei Song, Hong-Ying Niu, Hai-Ming Guo and John S. Fossey
RSC Adv., 2012,2, 6161-6163
DOI: 10.1039/C2RA20941A, Communication

GA?id=C3RA40833G

Recyclable NaHSO₄ catalyzed alkylation of tert-enamides with indoles or amines in water: facile construction of pharmaceutically analogous bis-alkaloid scaffolds
Xue-Qiang Chu, Shun-Yi Wang and Shun-Jun Ji
RSC Adv., 2013,3, 8380-8387
DOI: 10.1039/C3RA40833G, Paper

Efficient microwave-assisted preparation of squaric acid monoamides in water
Carlos López, Manuel Vega, Elena Sanna, Carmen Rotger and Antoni Costa
RSC Adv., 2013,3, 7249-7253
DOI: 10.1039/C3RA41369A, Communication

CuI/TBAB as a novel efficient catalytic system for Heck reaction in water
Yufang Wang, Qichao Yang, Li Yang, Jianxin Shi and Mingjie Zhang
RSC Adv., 2013,3, 21251-21255
DOI: 10.1039/C3RA44819C, Communication

Highly efficient visible-light-induced photocatalytic hydrogenation of nitrobenzene to aniline in water
Weiming Wu, Rui Lin, Lijuan Shen, Ruowen Liang, Rusheng Yuan and Ling Wu
RSC Adv., 2013,3, 10894-10899
DOI: 10.1039/C3RA40935J, Paper

Ruthenium catalysed one-pot synthesis of S-allyl and cinnamyl dithiocarbamates using allyl and cinnamyl acetates in water
Sabir Ahammed, Amit Saha and Brindaban C. Ranu
RSC Adv., 2012,3, 6329-6335
DOI: 10.1039/C2RA20856C, Paper

GA?id=C3SC52357H

Water-soluble multi-cage super tetrahedral uranyl peroxide phosphate clusters
Jie Qiu, Jie Ling, Laurent Jouffret, Rebecca Thomas, Jennifer E. S. Szymanowski and Peter C. Burns
Chem. Sci., 2014,5, 303-310
DOI: 10.1039/C3SC52357H, Edge Article

Mechanistic changes observed in heavy water for nitrate reduction reaction on palladium-modified Pt(hkl) electrodes
J. Souza-Garcia, E. A. Ticianelli, V. Climent and J. M. Feliu
Chem. Sci., 2012,3, 3063-3070
DOI: 10.1039/C2SC20490H, Edge Article

Active and reusable Pd(II) organometallic catalyst covalently bonded to mesoporous silica nanospheres for water-medium organic reactions
Wenhan He, Fang Zhang and Hexing Li
Chem. Sci., 2011,2, 961-966
DOI: 10.1039/C0SC00652A, Edge Article

Selective electrocatalytic reduction of carbon dioxide to formate by a water-soluble iridium pincer catalyst
Peng Kang, Thomas J. Meyer and Maurice Brookhart
Chem. Sci., 2013,4, 3497-3502
DOI: 10.1039/C3SC51339D, Edge Article

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Organic & Biomolecular Chemistry Blog

Archive for the ‘Themed Collections’ Category

Harnessing biosynthetic pathways to efficiently derivatize biologically active natural products

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

Unexpected divergent reactivity in Pt-catalyzed cyclizations of 1,5-bisallenes

Self-assembly of bioactive peptides, peptide conjugates, and peptide mimetic materials

Chemistry in Water

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