Organic & Biomolecular Chemistry Blog

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

The next entry to the series comes from Professor Philip Gale at the University of Technology Sydney who first published with OBC in 2003, the journal’s first year. He has continued to support the journal with 21 articles across the years, most recently in 2023.

About Phil

Phil Gale is the Deputy Dean of Science at the University of Technology Sydney. Phil was born and raised in Woolton, Liverpool (there are an unusually high number of academic chemists who originate from L25) and attended Gateacre Community Comprehensive School. He moved to the University of Oxford in 1988 to study Chemistry and remained there to undertake a DPhil under the supervision of Paul Beer in 1992. He moved as a Fulbright Scholar to the University of Texas at Austin in 1995 to work with Jonathan Sessler and subsequently was awarded a Royal Society University Research Fellowship which he took up at Oxford in 1997. While at Oxford, he co-wrote an Oxford Chemistry Primer on Supramolecular Chemistry with Paul Beer and David Smith which resulted in the Inorganic Editor of that series, Prof. John Evans from the University of Southampton inviting Phil down to give a seminar. Southampton offered Phil a continuing position as a Lecturer and Royal Society University Research Fellow, and he rose through the ranks becoming Professor of Supramolecular Chemistry in 2007 and serving as Head of Chemistry at Southampton between 2010 and 2016.

Phil then moved as Head of Chemistry to the University of Sydney in early 2017. He served as Head from 2017 to 2022 and Associate Dean International from 2020 to 2023. In April 2022 he became interim Dean of Science at Sydney and in February 2023, moved to the University of Technology Sydney as Deputy Dean of Science.

Phil and his research team have won several awards for their work including the RSC Bob Hay Lectureship, the Corday Morgan Medal and Prize, the RSC Supramolecular Chemistry Award and the 2018 Izatt-Christensen Award in Macrocyclic and Supramolecular Chemistry.

First OBC paper: S. Camiolo, P. A. Gale, M. B. Hursthouse & M. E. Light, Nitrophenyl derivatives of 2,5-diamidopyrroles: structural behaviour, anion binding and colour change signaled deprotonation, Org. Biomol. Chem., 2003, 1, 741-744, DOI: 10.1039/b210848h

Most recent OBC paper: M. Fares, X. Wu, D. A. McNaughton, A. M. Gilchrist, W. Lewis, P. A. Keller, A. Arias-Betancur, P. Fontova, R. Pérez-Tomás & P. A. Gale, A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death, Org. Biomol. Chem., 2023, DOI: 10.1039/d3ob00128h

Favourite OBC paper: C. J. E. Haynes, N. Busschaert, I. L. Kirby, J. Herniman, M. E. Light, N. J. Wells, I. Marques, V. Félix & P. A. Gale, Org. Biomol. Chem., 2014, 12, 62-72, DOI: 10.1039/c3ob41522h

How has your research developed over the last 20 years?

When I began my independent career in the late 1990s with my own research group, many anion receptor systems reported in literature were structurally complex, containing macrocyclic components and often carrying a positive charge. We focused on simplifying the structures of these systems and reported a series of acyclic receptors, including 2,5-diamidopyrroles, ortho-phenylene-based bis-ureas, dipyrromethene bis-amides and 1,3-diamidoanthraquinones. We showed that simple acyclic receptors could still retain high affinity and selectivity for particular anions. My first paper in OBC was published in 2003 in the 4^th issue of volume 1. At the time I was a relatively new academic at the University of Southampton in the UK, looking at designing hydrogen bond donor motifs to bind anions. We’d noticed that pyrrole 2,5-dicarboxamides containing electron-withdrawing groups would deprotonate upon addition of fluoride which in some cases would cause a colour change. At that time (and for a while after) there were many examples of colorimetric fluoride sensors reported in the literature – this paper together with contemporaneous work from Thorri Gunnlaugsson’s group at Trinity College Dublin demonstrated that the colour changes observed with these systems may also be due to deprotonation processes. We kept an eye out for these types of acid-base reactions and reported further examples over the following years – including in 2010 an example of a receptor containing multiple hydrogen bonds affecting the pKa of a bound anion resulting in deprotonation of the anionic guest.

Over the last twenty years we have stayed with the theme of anions but moved from designing receptors to designing and testing anionophores to facilitate the transport of anions across lipid bilayer membranes. This has been a collaborative effort with many colleagues including Tony Davis and David Sheppard in Bristol, Jeff Davis in Maryland, Bradley Smith at Notre Dame, Jonathan Sessler in Austin, Roberto Quesada in Burgos, Vitor Félix in Aveiro, Rob Elmes at Maynooth University, Kate Jolliffe at the University of Sydney, Yun-Bao Jiang at Xiamen University, Ricardo Pérez-Tomás at Barcelona, and Injae Shin at Yonsei University. My group has moved during this time, first to the University of Sydney in 2017 and this year to the University of Technology Sydney.

Early work focused on producing analogues of the natural product prodigiosin – one of the most potent HCl co-transporters known. However, as with our work on anion receptors, we simplified the design of anion transporters to understand the factors that govern efficient transport. Work focused both on encapsulating tripodal tris-ureas and -thioureas and planar single ureas, thioureas and squaramides that we demonstrated are very effective transporters when fluorinated. In 2013, we published a quantitative structure activity relationship study, showing that in a series of simple thioureas with one n-hexyl substituent and a phenyl substituent with different groups in the 4-position, the lipophilicity of the receptor is the dominant molecular parameter determining effective transport, with smaller contributions from the receptors’ volume and affinity for chloride.

With our collaborators, we’ve found that anion transport into cells can trigger apoptosis and interfere with autophagy and hence these compounds may potentially have anti-cancer properties. We’ve also demonstrated that our compounds can facilitate the transport of chloride across epithelial cell membranes. This is an interesting result as chloride transport is reduced or stopped across epithelial cell membranes in patients with cystic fibrosis. The development of chloride anionophores offers the prospect of replacing the faulty chloride channels in these cells with small molecules that can perform the same function. Our latest paper in OBC, published in 2023, twenty years after the first, is a collaboration with Ricardo Pérez-Tomás where we investigate where fluorescently tagged versions of one of the most effective anion transport motifs (ortho-phenylene bis-ureas) localise in cells.

How has the field of supramolecular chemistry changed over the last 2 decades?

The field of supramolecular chemistry has grown and developed significantly over the last 20 years. One of the most fascinating areas has been the development of systems chemistry and the study of dissipative self-assembly. The use of fuels to form transient assemblies far from equilibrium resembles processes found in biological systems with complex dynamic behaviour. Of course, one of the highlights of the last two decades has been the award of the Nobel Prize in Chemistry in 2016 to Jean-Pierre Sauvage, Fraser Stoddart and Ben Feringa for the development of molecular machines. Another pioneer in this area is Dave Leigh at the University of Manchester, whose work on molecular knots, synthetic chemically-fuelled molecular motors and molecular robotics is always inspiring with the ingenuity and elegance of his supramolecular creations. Another leader in supramolecular chemistry is Wolf prize winner Makoto Fujita at the University of Tokyo. A standout achievement for me has been Fujita’s development of crystalline sponges which allow micrograms of compounds to be soaked into crystals and subsequent X-ray structural determination. This has allowed single crystal X-ray diffraction structures of liquids and very small quantities of materials to be obtained.

I think importantly recently we have seen a generational shift in the field with many of the first generation of supramolecular chemists approaching retirement or having already retired, a new more diverse cohort of researchers is picking up the mantle. A positive international development has been the establishment of the Women in Supramolecular Chemistry network (www.womeninsuprachem.com) which is providing a support network for women and marginalised groups working in supramolecular chemistry. A growing recognition of the importance of supramolecular chemistry is reflected in the recent decision by the Royal Australian Chemical Institute to form a new division of supramolecular chemistry alongside the more traditional areas of chemistry.

Where do you see the challenges being for this field over the next 20 years?

Obtaining research funding is always challenging and supramolecular chemistry is at its core, a fundamental area of chemistry which requires discovery type support to make progress. However, I think it’s important that we as a field can point to applications of supramolecular chemistry in technological processes and in medicine. This will allow us to illustrate to funders and to our academic colleagues, the cross-cutting nature of supramolecular chemistry and the many real-world problems that can be addressed using supramolecular approaches. A group of us wrote a review¹ in 2021 highlighting some of these which covered medicine, sensors, remediation of chemical warfare agents, hydrometallurgy, separations and extractions, environmental remediation, self-healing materials and coatings, adhesives, and batteries. The continued translation of supramolecular chemistry to technological applications in the real-world is vital for the long-term health of our discipline.

Check out the other entries in our blog series here!

¹G. T. Williams, C. J. E. Haynes, M. Fares, C. Caltagirone, J. R. Hiscock & P. A. Gale, Advances in applied supramolecular technologies, Chem. Soc. Rev., 2021, 50, 2737-2763, DOI: 10.1039/d0cs00948b

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

Our next entry to the series comes from Professor Luis R. Domingo at the University of Valencia who first published with OBC in 2003, the journal’s first year. He has continued to support the journal with 27 articles across the years, most recently in 2021.

About Luis

Luis R. Domingo obtained his PhD in Organic Chemistry in 1987. In 2010 he attained his current position as a Full Professor at the Department of Organic Chemistry of the University of Valencia. In 2014 he was admitted as a Fellow of the Royal Society of Chemistry. His research interest is the study of organic chemical reactivity by using quantum chemical procedures based on the analysis of the molecular electron density. He has published more than 370 articles and 8 book chapters, being reviewer of more than 690 articles. Today, he has reached an h index of 61, receiving more than 16,450 citations.

In 2009, Domingo proposed the mechanism of polar Diels-Alder reactions against the ‘pericyclic mechanism’, which is followed by many of the experimental reactions and in 2019 he established the relationship between the structure and reactivity of the three-atom-components participating in [3+2] cycloaddition reactions, proposing four different reaction mechanisms. In 2014, he proposed a new model for the C-C bond formation based on the quantum chemical topology of electron density. He emphasised the significance of the global electron density transfer (GEDT) in the activation energies of polar reactions. After the study of relevant organic reactions classified in 1969 as pericyclic reactions, in 2019 the corresponding mechanism was rejected. He has introduced several concepts widely used today as non-concerted two-stage one-step mechanisms, which involve high asynchronous transition state structures, pseudoradical centres, which participate in many organic reactions involving the formation of new C-C single bonds, and the GEDT which discards the arrow curves used in many textbooks to explain the electronic displacement in polar reactions.

In the present century, Domingo and co-workers have developed several reactivity indices within the Conceptual Density Functional Theory, such as the local electrophilicity ω_k index in 2002, the empirical nucleophilicity N index in 2008, the reactivity difference index in 2012, and the electrophilic and nucleophilic Parr functions in 2013, commonly used nowadays in the study of polar organic reactions.

After 20 years and more than 250 publications in the field of Theoretical Organic Chemistry, in 2016 Domingo proposed a new reactivity theory named Molecular Electron Density Theory (MEDT), which opposes all theories developed in the past century based on analysis of molecular orbitals such as the Frontier Molecular Orbital (FMO) theory. Domingo’s MEDT proposes the study of organic chemical reactivity based on the analysis of electron density changes during a chemical reaction.

First OBC Paper: A. Manuel & L. R. Domingo, Theozyme for antibody aldolases. Characterization of the transition-state analogue, Org. Biomol. Chem., 2003, 1, 637-643, DOI: 10.1039/b209636f

Most recent OBC Paper: M. Ríos-Gutiérrez, P. Pérez, L. R. Domingo & J. Soto-Delgado, The catalytic effects of a thiazolium salt in oxa-Diels-Alder reaction between benzaldehyde and Danishefsky’s diene: A molecular electron density theory study, Org. Biomol. Chem., 2021, 19, 9306-9317, DOI: 10.1039/d1ob01415c

Favourite OBC Paper: L. R. Domingo & J. A. Sáez, Understanding the mechanisms of polar Diels-Alder reactions, Org. Biomol. Chem., 2009, 7, 3576-3583, DOI: 10.1039/b909611f

How has your research developed over the last 20 years?

The development at the end of the last century of quantum chemistry tools capable of performing molecular electron density analysis has made significant advances in the field of Theoretical Organic Chemistry during the last 20 years.

After the proposal in 1999 of Parr’s electrophilicity ω index, which provides a quantitative measure of an important reactivity concept in organic chemistry in 2002, the first electrophilicity ω scale of organic molecules able to explain the reactivity of experimental Diels-Alder reactions was presented¹. The local electrophilicity ω_k index, proposed in 2002, allowed explaining the chemo and regioselectivity in polar cycloaddition reactions². Later in 2008, the empirical nucleophilicity N index was proposed^3,4. Today, the electrophilicity ω and the nucleophilicity N indices allow the quantitative study of polar reactions. Finally, in 2013, the electrophilic and nucleophilic Parr functions were introduced, allowing the understanding of the local reactivity, i.e., the chemo and regioselectivities, in polar reactions⁵.

After numerous theoretical studies of reaction mechanisms in the period 2002-2014 based on the topological analysis of the molecular electron density, a model for the formation of new C-C single bonds experienced by many organic reactions was proposed in 2014⁶. On the other hand, the recognition of the decisive role of the global electron density transfer (GEDT)⁶ in the activation energies of polar organic reactions provided a new vision of relevant reactions such as the polar Diels-Alder reactions⁷, inadequately classified as a pericyclic reaction in 1969.

[3+2] cycloaddition (32CA) reactions are a class of fascinating organic reactions. After 20 years of studying 32CA reactions, an excellent correlation between the electronic structure of the three-atom-components (TACs) and their reactivity was established in 2019. Unlike the 1,2-dipolar structure proposed by Huisgen, four different electronic structures, which experience four different reactivity types, were characterized⁸. Recent studies have shown that although the electronic structure of the TAC can be modified with substitution, the four types of reactivity can be characterized in most 32CA reactions.

After 20 years of working in the field of Theoretical Organic Chemistry, in 2016, Domingo proposed a new reactivity theory named Molecular Electron Density Theory (MEDT)⁹, which establishes that changes in electron density along an organic reaction, and not molecular orbital interactions, are responsible for the chemical reactivity of organic molecules.

Many recent MEDT studies of relevant organic reactions have allowed us to reinterpret the organic reactivity based on electron density analysis. A recent study of the four reactions classified in 1969 by Woodward and Hofmann as pericyclic reactions has proved that this mechanism does not exist since the bonding changes in organic reactions are sequential and non-concerted¹⁰.

How has the field of theoretical organic chemistry changed over the last 2 decades?

The advances carried out in the last 2 decades in the field of theoretical organic chemistry based on the analysis of the molecular electron density, which is the only physical observable, have allowed us to establish new concepts in organic chemistry. This has caused the rejection of models developed in the past such as the FMO theory, the symmetry rules and energy decomposition analyses based on molecular orbitals, all of them proposed in the past century before the possibility to perform any topological analysis of the molecular electron density obtained from Schrödinger’s wavefunction.

On the other hand, the electrophilicity ω and the nucleophilicity N indices, together with the Parr functions have become easy and powerful tools in studying local reactivity in polar reactions for experimental organic chemists.

Finally, the recent topological analysis of the ELF of the reagents in relevant organic reactions such as 32CA reactions has established a good correlation between the electronic structure and chemical reactivity.

Where do you see the challenges being for this field over the next 20 years?

The establishment of Schrödinger’s equation in 1926 was one of the more relevant advances in the field of theoretical organic chemistry as it provides the molecular electron density distribution, which determines the structure and reactivity of organic molecules. Still unfortunately, it cannot be resolved even for the simplest organic molecules. In 1932, the molecular orbital theory was established as a mathematical approach to the wavefunction, but inappropriately molecular orbitals were taken as a reality, proposing in 1931 the Hückel’s p-bonds in unsaturated compounds and 1956 Fukui’s FMO theory to explain organic chemical reactivity. Many concepts, such as pericyclic reactions or concerted reactions are still used today in many organic chemistry textbooks.

Extensive work developed in the present century, based on the analysis of the molecular electron density, has allowed the understanding of many organic reactions, rejecting those concepts based on molecular orbital analyses. Unfortunately, there is still strong influence by research groups that continue working with molecular orbital theories to study reaction mechanisms. But in the last two decades, they have not introduced any advances in chemical understanding.

MEDT proposed in 2016, suggests that the analysis of the molecular electron density, which is the only physical observable, is accurate for understanding organic molecules’ electronic structure and reactivity. Today, theoretical and experimental organic chemists have a great variety of quantum chemical tools able to perform a rigorous analysis of the molecular electron density obtained by any computational level, thus rejecting any obsolete molecular orbital analysis. Note that molecular orbitals were defined to approach the wavefunction, the square of which provides the molecular electron density.

The relationship of HOMO and LUMO energies with the ionization potential and the electron affinity used in Conceptual Density Functional Theory to attain the reactivity indices and that between molecular orbital coefficients and the Fukui functions used to study the local reactivity allows explaining the good correlations found between experimental data and FMO analyses, but non HUMO-LUMO interactions, but rather nucleophilic/electrophilic interactions between molecules of different electronegativity are responsible for the chemical reactivity in polar reactions.

These similitudes make it that unfortunately, many people continue using models based on the updated FMO theory, but it is essential to remember that Schrödinger’s wavefunction was proposed only to describe the electron distribution in a molecule and that electronic interactions between particles constituting a molecule, i.e., nuclei and electrons are responsible for electronic energies.

Check out the other entries in our blog series here!

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

Our first entry to the series comes from Professor Hirokazu Tamamura at the Tokyo Medical and Dental University who first published with OBC in 2003, the journal’s first year. He has continued to support the journal with 12 articles across the years, most recently in 2021.

About Hirokazu

Prof Hirokazu Tamamura graduated from the Faculty of Pharmaceutical Sciences, Kyoto University in 1988 (Supervisor: Prof Haruaki Yajima), and received his Ph.D. from Kyoto University in 1995. He became an Assistant Professor of the Faculty of Pharmaceutical Sciences, Kyoto University in 1989 (Boss: Prof Nobutaka Fujii), and then a Lecturer of the Graduate School of Pharmaceutical Sciences, Kyoto University in 1997.

He became a Visiting Fellow at the National Cancer Institute/NIH, USA in 1999-2000 (Lab. Medicinal Chemistry, Boss: Dr Victor E. Marquez) before becoming an Associate Professor of the Graduate School of Pharmaceutical Sciences, Kyoto University in 2005, and then a Full Professor at the Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU) in 2005. His research fields extend to peptide & protein chemistry, chemical biology, medicinal chemistry and organic chemistry.

Hirokazu Tamamura

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

First OBC Paper: H. Tamamura, T. Kato, A. Otaka & N. Fujii, Synthesis of Potent β-Secretase Inhibitors Containing a Hydroxyethylamine Dipeptide Isostere and Their Structure-Activity Relationship Studies, Org. Biomol. Chem., 2003, 1, 2468-2473, DOI: 10.1039/b304842j

Most recent OBC paper: K. Tsuji, T. Ishii, T. Kobayakawa, N. Ohashi, W. Nomura & H. Tamamura, Fluorescence resonance energy transfer-based screening for protein kinase C ligands using 6-methoxynaphthalene-labeled 1,2-diacylglycerol-lactones, Org. Biomol. Chem., 2021, 19, 8264-8271, DOI: 10.1039/d1ob00814e

Favourite OBC paper: H. Tamamura, K. Hiramatsu, M. Mizumoto, S. Ueda, S. Kusano, S. Terakubo, M. Akamatsu, N. Yamamoto, J. O. Trent, Z. Wang, S. C. Peiper, H. Nakashima, A. Otaka & N. Fujii, Enhancement of the T140-based Pharmacophores Leads to the Development of More Potent and Bio-stable CXCR4 Antagonists, Org. Biomol. Chem., 2003, 1, 3663-3669, DOI: 10.1039/b306613b

How has your research developed over the last 20 years?

My research has been focused on peptide-based medicinal chemistry over the last 20 years. I started on the development of methodologies for peptide synthesis in 1988 at the Graduate School of Pharmaceutical Sciences, Kyoto University. After receiving my PhD and finishing a postdoctoral fellowship at the National Institutes of Health/National Cancer Institute (NIH/NCI), USA, my research got closer to medicinal chemistry and chemical biology, using peptides and their derivatives. As drug leads for chemotherapy of Alzheimer’s disease, we developed potent beta-secretase inhibitors based on peptide derivatives containing a mimic structure of the enzyme-substrate transition state: a hydroxyethylamine dipeptide isostere. Thus, in 2003, my first paper with OBC on the development of beta-secretase inhibitors was published¹. In addition, we had research for the development of antagonists for the chemokine receptor CXCR4, which is correlated with several diseases such as HIV-1/AIDS, cancer and rheumatoid arthritis. Through structure-activity relationship studies on polyphemusin-related peptides, we developed peptidic CXCR4 antagonists, which were designated as T140 derivatives, with high CXCR4-binding affinity, low cytotoxicity and improved biostability. The lead compound, Motixafortide has been progressing through to Phase III clinical studies. In the finding of these CXCR4 antagonists, we published two consecutive papers in 2003 with OBC^2,3.

In association with this research, we established a fluorescence-based assay system for CXCR4 binding of compounds using a fluorophore-labeled T140 derivative⁴. So far we have developed novel CXCR4 antagonists based on nonpeptides as well as cyclic pentapeptide derivatives, which we published in several journals^5-10, mostly OBC^5,7-10. This target receptor CXCR4 forms dimers in the cell surface because it belongs to the G protein-coupled receptor family. So we developed bivalent CXCR4 ligands with polyproline linkers to catch the dimers in cells¹¹. These bivalent CXCR4 ligands are remarkably more potent than the corresponding monomers. In addition, trivalent CXCR4 ligands highly recognise CXCR4-expressed cells because of accumulation of ligands, which we published with OBC in 2015¹². The concept of multimerised peptides has been applied to HIV-1 envelope proteins related to membrane fusion, hence dimeric C34 derivatives showed much more potent anti-HIV-1 activity compared to the monomer C34 peptide¹³.

In my postdoctoral fellowship at NIH/NCI, I had started to develop ligands of protein kinase C (PKC) based on conformationally constrained gamma-lactone derivatives of 1,2-diacylglycerol (DAG). This led to research on the development of DAG-lactones with potent binding affinity for PKC. Initially, we had adopted a competitive assay using radio isotope tritium-labeled phorbol 12,13-dibutyrate to evaluate PKC-binding activity of synthesised DAG-lactones. But from the point of view of environmental health and safety, radio isotope-based screening has been replaced with fluorescene-based screening. Therefore, we developed a fluorescence resonance energy transfer (FRET)-based screening method for PKC ligands, which we published with OBC in 2021⁴. It was an honour that this paper was chosen as the Inside Front Cover of the issue. Taken together my research has focused on medicinal chemistry and chemical biology using peptides, their derivatives and other functional molecules over the last two decades.

How has the field of Medicinal Chemistry changed over the last 2 decades?

Two decades ago, it was common sense that drugs were mostly low molecular weight (small-size) compounds. Through the progress of organic and synthetic chemistry, small-size drugs based on synthesised compounds have been conventionally developed against several diseases. Small molecules have some useful advantages including oral availability and low immunogenicity but serious drawbacks such as low specificity and high possibility of side effects. In this century, high molecular weight biologics (large-size molecules) including human monoclonal antibodies have been developed. Macromolecules have some merits such as high specificity and low possibility of side effects but critical shortages containing low applicability and possible immunogenicity. Accordingly, both small- and large-size drugs have their mutual advantages and drawbacks. In addition, it has been noticed that there is an important drug-like chemical space in the mid-size region between small- and large-size regions. Middle-size molecules, which are categorised between small- and large-size molecules and designated as mid-size drugs, might avoid drawbacks but contain the above advantages possessed by small- and large-size molecules. Therefore, mid-size drugs are ideal as new drug modalities, which encompasses peptides and their derivatives because of their location in this middle-size region.

Small-size drugs can recognise small regions on targeted proteins and usually bind to active centres of enzymes and pockets of receptors. The interface between the drugs and the targeted proteins is relatively narrow. Recently, the number of newly found proteins relevant to several diseases is decreasing since the whole human genome was disclosed in 2003/04. Thus, it has been difficult to find first-in-class drugs (brand-name drugs), which have novel action mechanisms that give new therapeutic approaches to treat diseases. Generic drugs, which can be presented for sale if the patent protection for a brand-name drug expires, or next-in-drugs, which have similar action mechanisms to existing drugs, have come to the forefront as small-size drugs. The concept of molecular target drugs, which bind to only specific molecules relevant to objective diseases and inhibit their functions has come to the fore over the last 20 years. Large-size drugs including human monoclonal antibodies can recognise broad regions on targeted proteins and usually bind to extracellular regions on cell surface receptors. The interface between the drugs and the targeted proteins is relatively expansive. Due to the expansive interface, large-size drugs can specifically recognise targeted proteins and achieve inhibition of protein-protein interaction, hence reducing off-target binding and side effects.

Mid-size drugs containing mostly peptides and their derivatives can have these broad interface regions with targeted proteins, the same as large-size drugs. In addition, mid-size drugs such as peptide derivatives might penetrate cell membranes if the conformation is constrained, therefore can target not only extracellular regions on cell surface receptors but also molecules inside of cells. Accordingly, mid-size drugs can target protein-protein interaction as well as active centres of enzymes and pockets of receptors. They are the current focus for development of next generation drugs. Altogether, the field of medicinal chemistry has been much changed over the last two decades, with medicinal chemists drawing attention to these mid-size drugs.

Where do you see the challenges being for the Medicinal Chemistry field over the next 20 years?

I think in the next two decades the field of medicinal chemistry will have been changed even more. In the design of small-size and mid-size drugs, computer calculation and artificial intelligence (AI) will be applied to a greater extent. There are still meaningful targets for small-size drug development, such as the central nervous system along with virus-related diseases including emerging and re-emerging infectious diseases. Currently these drugs are designed based on the structures of the lead compounds complexed with their targeted proteins determined by the X-ray structure analysis and/or NMR analysis accompanied with docking simulations. Recently, cryo-electron microscopy (cyro-EM) has been used for structural analysis with great success. In the future, cryo-EM will be used for more structure analysis and other spectroscopies might be adopted. Even though the practical structures of the lead compounds bound to the targeted proteins sometimes are not discoverable, computer calculation and AI can produce the plausible structures. These techniques are now already useful for the design of potent drugs and will advance more in the future, to much greater levels. Based on bioinformatics, including genome information and chemoinformatics of libraries, AI drug discovery will advance more and more with application of big data of lead compounds and in silico screening. AI and robotics, in which data from each working step can be obtained by the robots’ sensors and then judged by the AI to make progress towards the next steps, will also be developed in the near future.

Peptides and new drug modalities will also become more prominent, especially cyclic peptide derivatives, which possess many advantages as drug candidates. Antibody drug conjugates (ADCs) are ideal compounds, which are conjugates of monoclonal antibodies and small drugs tethered by linkers. In ADCs, the monoclonal antibody can specifically recognise targeted extracellular regions on cell surface receptors while the small drug is then able to reach intracellular target molecules to inhibit their functions. Many ADCs will be developed, mainly for the application for cancer chemotherapy.

An alternative to drugs is chemical protein knockdown. In this strategy, molecules containing ligands of targeted proteins and E3 ligase are synthesised to attack the targeted protein and induce degradation of them by the ubiquitin-proteasome system in vivo, based on specific and non-genetic IAP-dependent protein eraser (SNIPER), proteolysis targeting chimeras (PROTAC) and other similar mechanisms. These molecules can access undruggable targets, which cannot be bound by small size drugs. In the future, I think chemical protein knockdown will be applied to many targets.

Nucleic acid medicine, another drug modality, is now very popular. RNA-dependent polymerease RNA inhibitors and mRNA vaccines have been useful for treatment and prevention of COVID-19 respectively. Thus, these drugs will be expected for the treatment and prevention of new infectious diseases. Research on other gene therapies involving small interfering RNA (siRNA) and antisense nucleotides along with genome editing will become a hot area. Concomitantly, development of vectors for nucleic acid and genome medicine will be actively pursued. In addition, regenerative medicine including cell therapy will make progress in close association with embryonic (ES cells) and induced pluripotent stem cells (iPS cells). Chimeric antigen receptor-therapy (CAR-T) will also be another next generation therapy for cancer. Altogether, I believe various drug modalities will be utilised to have the right drugs for the right targets in the future.

Check out the other entries in our blog series here!

This year we are proud to be celebrating the 20 years since the launch of Organic & Biomolecular Chemistry. 

Although the first issue of OBC was published in 2003, the journal is part of a proud history of publications stretching back over 170 years beginning with Journal of the Chemical Society (1849-1965) via Journal of the Chemical Society B and C (1966–1971), and Journal of the Chemical Society, Perkin Transactions 1 and 2 (1972–2002). The vision behind OBC‘s creation was to bring together the synthetic and physical organic strands of Perkin 1 and 2, while incorporating more material relevant to biology. Since that first issue OBC has continued to publish a diverse range of high quality and impactful research in the organic chemistry community. 

We are delighted to announce a range of activities to celebrate the 20th anniversary of OBC. You can find out more about each of these activities below:

20th Anniversary Activities

Introductory Editorial

Editorial Board Chair Anthony Davis and Executive Editor Becky Garton introduce the anniversary celebrations with an Editorial: Celebrating the 20^th anniversary of Organic & Biomolecular Chemistry

20th anniversary collection

We have published an ongoing themed collection featuring work from members of the community who have served on the Editorial and Advisory Boards of OBC across the last two decades. We would like to thank everyone who has been a part of the journal as it would not be where it is today without the support they provided and we appreciate them sharing their latest discoveries with us! Hopefully you enjoy the range of articles featured in the collection.

OBC 20th anniversary collection

Community Spotlight Interviews

We will be publishing a series of blogs featuring interviews with authors who have prominently supported OBC by publishing in the journal from our early volumes through to the present day. These blog posts are an opportunity for our authors to give their thoughts on the past twenty years of their research and the encompassing field alongside their insights towards the next two decades.

Professor Hirokazu Tamamura

Professor Luis Domingo

Professor Philip Gale

Professor Dame Margaret Brimble

Professor Guan-Wu Wang

Professor Dhevalapally B. Ramachary

Professor Lei Wang

Professor Alexandra Slawin

Professor Peter Langer

Keep an eye out on our blogs platform and on our socials for future interviews!