Chemistry –the Queen of Sciences

www.strath.ac.uk/chemistry

Some years ago the Royal Society of Chemistrypromoted a slogan ‘Better Living through Chemistry’.It seems to have been lost in the passage of time butremains fully valid today. The American ChemicalSociety puts it differently: ‘Chemistry at the Centre ofEverything.’ But for the title of this paper, I mustacknowledge the first Chancellor of the University,the Lord Todd of Trumpington, a man of manyhonours including Nobel Laureate, Order of Merit,Past President of the Royal Society, who declared inan after dinner speech at a meeting I had organised;“Chemistry is the Queen of Sciences. Get yourchemistry right and everything else follows.” LordTodd’s scientific contribution that led to his greatdistinction was at the border of chemistry and biology,which in his time as now is an area of science withgreat intrinsic interest and potential for useful,translatable discoveries and inventions. He was anorganic chemist who laid the chemical foundationsupon which much of the chemistry of the componentsof DNA were built. Derived from this we have thesynthesis of genes first by another Nobel LaureateGhobind Khorana and ultimately much of modernchemical biology. However, before anyone reads toofar, it’s important for me to emphasise that this paperdeals with my own projects and experiences. There areother ways of discovering drugs and other aspects ofheterocyclic chemistry. I’ve described some of thosein Special Reports and in other short paperspublished by Adjacent Digital Politics Limited.

The Chemistry of HeterocyclesTodd worked in the field of compounds known asnucleosides and nucleotides, which are componentsof DNA and many other compounds of biologicalmachinery, referred to as cofactors or coenzymes.All of these compounds contain heterocycles whichare, simply stated, compounds with rings of atomsbuilt from carbon together with other elements,nitrogen, oxygen, and sulfur, being the most relevantto biological chemistry. Whilst not always the mostchallenging class of compounds for academic organicchemical synthesis, heterocyclic compounds areespecially rich in their biological importance, a fact

that has a lot to do with their ability to interactwith each other. A very large part of the molecularmachinery of biology involves one heterocycliccompound bonding with another. So it is no surprisethat when we want to manipulate biology, to treatdisease for example, the compounds that wecommonly use are also heterocyclic compounds.My research has been concerned with many aspectsof these compounds, mostly in recent years withmedicinal chemistry. It is interesting and significantthat the Royal Society of Chemistry identifies two ofmy fields of interest, anti-cancer compounds andantibacterial drugs, in the accompanying editorial tothis document.

Before introducing my topics and teams, I’d like toexplain a little of the background chemistry ofheterocyclic compounds in a very conceptual way forthose of you who are not scientists. Whatever applicationwe’re interested in it’s the sheer diversity of compoundsthat can be made in the laboratory that makesheterocyclic chemistry so important. As chemists, wehave our detailed structural formulae to representcompounds and the ways in which they react; it’s avery powerful means of international communicationand very arcane to the non-chemist. But if we leavethe synthetic chemistry on one side and assume thatwe can make the compounds we want (an assumption)it is possible to understand why heterocyclic compoundshave such interesting and diverse applications usinga few basic rules of chemistry.

Most applications of heterocyclic compounds inmedicinal chemistry or in materials chemistry do notdepend upon reactions of the compounds but upon theway in which molecules stick together or associate.Association can be strong or weak, long or short lived,but whatever its type, the fundamental interactions arebased upon the same three things – molecular size,shape, and electrostatic charge. It’s not necessary tounderstand the detail of how charges arise but I’vedrawn sketches to illustrate the consequences. Thebasic rules of electrostatics then apply: like chargesrepel and opposite charges attract (Figure 1A). All this

Heterocyclic Chemistry in Drug Discovery at the University of Strathclyde

Chemistry – the Queen of Sciences

assumes that the interacting parts of molecules canactually get together, in other words that their shapesmatch. Even if there are attracting charges, if themolecules can’t get close together because there areother atoms in the way, we won’t see any chemicalinteraction and won’t be able to create a usefulapplication, particularly in medicinal chemistry (Figure1B). Given the right charge, shape, and size, somemolecules are able to associate in stacks or rods orother arangements. Such multimolecular aggregatesare the basis of materials that are important in manyelectronic applications (Figure 1C).

So in discovering new drugs, we’re chiefly concernedwith finding compounds that act in a specific way in a

biological system. If there’s an infection, we want tokill the infectious agent but not the patient. If there’san imbalance in a person’s function, such as highblood pressure or a psychiatric problem, we want amedicine that will restore the balance. In all thesethings we require selective action to minimise sideeffects and we need subtle and selective chemistry toprovide it. That’s where the refined application ofheterocyclic chemistry comes in. Using heterocycliccompounds we can very often find compounds thatengage through their charge and shape with aspecific component of biology, typically a protein orDNA molecule, and modify the biological functionwhich, if taken through to a medicine, will benefitthe patient.

++ ++

+

+-+

+-

--

-

++

--+

+--

++

--

++

- -+

+- -

++

- -

+- + -

- -

Molecules attract

Orange molecule fits into yellow molecule’s cavity and the charges match

Molecules align with opposite charges attracting, forming chains that may further associate into stacks

Orange molecule is too big for the yellow molecule’s cavity although the charges match

Molecules repel

1A

1B

1C

Figure 1A. Cartoon of two heterocyclic molecules with opposite charges at each end showing how they interact with each otheras charges approach. B. A cartoon of how a drug molecule can be understood to fit its biological target molecule by having theright charge and shape. If the molecule is too big, it will not bind and have an effect, even if the charges attract. C. An illustrationof how charge and shape in heterocyclic molecules can lead to association of molecules in rows and in stacks. Such structuresoccur in molecular materials.

New Drugs from Academic ResearchIt’s not uncommon for people to ask why academicscientists should be involved in medicinal chemistrywhen globally we have such a well-developedpharmaceutical industry. The pharmaceuticalindustry itself has made it clear for many years thatdespite its size it cannot do everything worth doingor interesting. It has a challenging regulatory andcommercial framework in which to work and thesechallenges have led to systematisation of researchprocesses and decision-making. All of this isunderstandable in their context but, if I am beingcritical, it has industrialised thinking and therebycircumscribed creativity. I’ll come back to this pointin the context of our experience in translatingacademic research into commercial value later. Fornow it is enough to recognise that both for reasonsof coverage and creativity there is a real place foracademic teams in drug discovery. It boils downsimply to the academic sector fulfilling one of itsprime roles, namely to create opportunity.

Well if the industry cannot do it all, in what fields ofchemistry should one choose to work? These daysindustry is replete with highly skilled syntheticchemists so it is not in synthetic chemistry itself thatnew things are most wanted. Anyway, from my point ofview, other people do specialised organic synthesisbetter than me. The need that my colleagues and I havetried to satisfy is to create new compounds with specificbiological effects, either to treat disease (which ismedicinal chemistry) or to investigate how biology

works (which is chemical biology). In my view andexperience, medicinal chemistry and chemical biologygo hand in hand. To make a significant contribution,we’ve had to make choices about what to study butwe’ve also been able to take opportunities as they havearisen added to which, with the flexibility that goodacademic teamwork can bring, one thing leads toanother. I want to illustrate these points with 3 storiesof projects to which I have contributed. The first beginswith the chemistry of a class of heterocyclic compoundsknown as pteridines, so named because they were firstdiscovered as pigments in the wings of butterflies. Itleads little by little to a new class of compounddiscovered by our teams at Strathclyde primarily for thetreatment of challenging cancers such as prostate andpancreatic cancer. The second concerns an opportunitybrought to us by colleague biologists based upon someintriguing properties of a protein secreted by a parasiticworm that affects some Asian rodents. Following thisline of research, we have obtained new compoundswith the potential for treating inflammatory diseasessuch as asthma and rheumatoid arthritis; we call it‘The Worms Project”. Finally, I shall describe our mostadvanced project, which concerns a group of compoundsknown as minor groove binders because they bind toa part of the structure of DNA known as the minorgroove. Many, but not all of the applications of thesecompounds, are as treatments for infectious diseases.One compound will shortly enter clinical trials forthe treatment of Clostridium difficile infections andwe have good evidence that others can be developedto treat parasitic diseases such as sleeping sickness

A. Parent

B. Add substituents C. Change ring size

Figure 2. A. Cartoon representation of a pteridine, two fused six membered rings. B. In nature, pteridines have additional atoms ofgroups of atoms attached (substituents). The naturally occurring pattern of substituents is fixed but we can vary them using

synthetic chemistry to obtain compounds with different properties such as artery relaxation. C. We can also create families ofrelated compounds by changing the shape a little, for example changing a six to a five-membered ring. To do this and include a

variety of substituents we had to develop new synthetic methods.

and Leishmaniasis. In every case, we’ve neededflexible, specialised teams to make progress so I’veidentified each project with a team number in thefollowing discussion.

Now, we can’t do it all either and each of theseprojects has required contributions from willingcolleagues and effective collaborators in otherinstitutions. What I am about to describe is a teameffort. There’s a lot of chemistry and I’m going to tryto deal with it without using detailed chemicalstructures. Instead, I’ve drawn abstracted cartoonswith which I can show not only the essential shapeof our molecules but also how they work to controlbiology beneficially. Even getting one compound toclinical trials is good going for an academiclaboratory. We hope that more will progress andwe’re working hard at it with our partners.

From pteridine chemistry to anticancer drugsLooking back, choosing to continue a tradition ofwork in pteridine chemistry was an importantstrategic decision. My late colleague, ProfessorHamish Wood, introduced me to the field and it hasbeen taken forward working closely with my currentcolleague, Dr Colin Gibson. Pteridines are significantin biology because as parts of biological syntheticprocesses in vivo they contribute to the availabilityof essential components for life, in particular theheterocyclic components of nucleic acids includingDNA and certain essential amino acids. Thereforethere was a good chance that we would find some

interesting biology and useful chemical compoundsin this field.

Some of the secrets of medicinal chemists: How we come up with new structures.Pteridines consist of two 6-membered rings composedof carbon and nitrogen fused together along one side(Figure 2). Whilst the rings themselves are significantin the chemical and biological properties it is theatoms and groups of atoms attached to the rings thatprovide the diversity, interest, and significance intheir chemistry. As suggested by Figure 2B and C, if anew molecule is invented with a different structureas on the right, it should still bind to the biologicalmachinery, most commonly enzymes, but might dodifferent things from the naturally occurringpteridine. The differences could in principle be eitherto block a naturally occurring reaction (an inhibitor orantagonist) or to promote it (an activator or agonist).Depending upon the application and desiredoutcome one or the other might be required. Thislogically simple concept of modifying part of amolecule to control its function in the desired way isat the heart of much medicinal chemistry design aswill be seen below. Whilst it is a simple concept, thechallenge is converting the concept into newchemistry and useful applications. In the case of ourwork with pteridines and their relatives, we havebeen interested in both activators and inhibitors.

If we just take our starting pteridine template (2A),we’ve been able to vary and add substituents to

D. Add substituentsTarget sleeping sickness

E. Different substituents,Different placesB

D. Adding substituents to this new structure, we obtained potential compounds to treat sleeping sickness. E. Adding differentsubstituents in different places, we obtained compounds effective in models of prostate cancer; these compounds are being

further developed.

obtain compounds that stimulate the production oneof the smallest naturally synthesised molecules, nitricoxide (Figure 2B). This compound acts as a signallingagent in several biological systems includingstimulating the relaxation of muscle in arteries. Thiscould have benefit for example in treating thesymptoms of high blood pressure such as occurs indiabetes… Project Team 1

Modification of the pteridine can become morecomplex (Figure 2C). We can change size of one ringwhilst keeping much of the rest of the compound,including the substituents on the 6-membered ring,the same. To do this flexibly we had to design anddevelop new synthetic methods. When the newcompounds became available, with the help ofcolleagues, they were screened to find significantbiological activity. In fact two new substantialprojects were seeded in this way, the first to treatsleeping sickness, a disease caused by parasites knownas Trypanosomes, and the second to treat cancerssuch as prostate and pancreatic cancer. Differentmodifications (Figure 2D and E) were required forthe two different diseases. Every project at this stageis not taken forward. In these cases, the compoundsdesigned to treat sleeping sickness were too toxic.On the other hand, the anti-cancer compounds areactively being refined and developed in a projectled by my colleague, Professor Simon Mackay…Project Team 2

We have sophisticated tools to help design ourcompounds. Figure 3 shows the fit of one of our moreactive anti-trypanosomal compounds to its moleculartarget, an enzyme known as pteridine reductase 1.The connection between the green frameworkstructure and the cartoon 2D is clear. In red is shown

a piece of the molecular machinery, the cofactor, NAD,which is one of the compounds that Todd worked onleading to his Nobel Prize. The largely grey surfacewith patches of blue and red represents the surfaceof the target enzyme itself with red showing regionsof positive electrostatic potential and blue negativepotential. The interpretation of the surfaces andcharges allows us to understand how our compoundsbind to their target and hence to design new candidatesfor synthesis and evaluation. Such so-called structurebased design is a common feature of many medicinalchemistry projects. This study was made possible bycollaboration with Prof Mike Barrett, a parasitologistat the University of Glasgow, and Prof Bill Hunter, acrystallographer and enzymologist at the Universityof Dundee… Project Team 3

Figure 3. A representation of the molecular target of theantitrypanosome compounds derived from X-raycrystallography. Interpretation of the image allows us tounderstand how the inhibitor binds to its target and todesign new structures for synthesis and evaluation. The‘drug’ is shown in green. The red framework shows one ofthe compounds that Todd worked on, the coenzyme NAD,which is also a heterocyclic compound.

Compound class Team Disease Effective in vivo? Current Status

Pteridine 1 Pulmonary disease, diabetes Yes Full evaluation needed

Pteridine relative 2 Cancer Probably Full evaluation underway

Pteridine relative 3 Sleeping sickness Yes Toxic, discontinued

Table 1. Score sheet for drug discoveries at Strathclyde.

The Worms ProjectParasites that cause largely untreatable diseases werea target one of the pteridine related projects. But inthe Worms project, a parasite suggested to us how tocreate compounds that modulate the immunesystem… Project Team ‘4’ A husband and wife team ofprofessors from the University of Strathclyde and theUniversity of Glasgow, respectively Billy and MaggieHarnett, have made their careers from the study of aprotein known as ES-62, which is secreted by a wormAcanthocheilonema viteae (Figure 4) that is a parasiteof gerbils. Billy and Maggie isolated and purifiedES-62 and showed that it lowered the activity of theimmune system so that the parasite was not attackedby its host but not so much that the host was killedby bacterial or viral infections. Obviously the parasiteneeds its host to reproduce and survive so theimmunomodulation by ES-62 was very important. Billyand Maggie were convinced that there could be auseful drug somewhere related to this biology.However the protein itself was not suitable: it was toobig a molecule to be formulated easily as a medicine.Moreover, because it is not a human protein, thehuman immune system would most probably bestimulated and ES-62 destroyed. What was neededwas a small, drug-like molecule that could reproducethe potentially beneficial immunomodulatoryproperties of ES-62. An interesting ethnological andphilosophical aspect of this opportunity is that itconsiders the immunological balance in a person tobe important for their health and the success of theirtreatment. It thus connects with eastern medicinaltraditions, including the Ayurvedic medicine of India.

Transforming biology into manageable chemistryIn the pteridine-related projects we had somewhereobvious to start designing compounds, namely thestructures of the naturally occurring pteridines. Here,however, there were no such templates. Moreover in afurther contrast to the pteridine projects, we had noidea what the molecular target or targets for ES-62 are.To put it another way, we did not know the chemistryby which ES-62 worked. And to make it even morechallenging, there was no crystal structure of ES-62available; there still isn’t. So none of the usual startingpoints for a medicinal chemistry project was present.

Fortunately, one small aspect of the structure ofES-62 that was important to its function had beenidentified by the biologists. Attached to the surfaceof ES-62 were many small molecules known asphosphoryl choline (PC) and through a number ofexperiments it had been shown that these PCcomponents were important in the biological activityof ES-62. That gives a starting point, but PC is socommon in biology that simple analogues of it aspotential drugs would be unlikely to be selectiveenough to be developed as medicines. Howeverwith one or two other clues from PC-containingmolecules that the Harnetts had studied, it waspossible to design some compounds that wouldbe worth testing. Figure 5 illustrates how this was done.

Figure 5. A cartoon representation of the design of thesmall molecule analogues (SMAs) of ES-62. A. A represent -ation of the ES-62 protein with many surface groups. B. The phosphorylcholine (PC) component to be mimicked.C. Cartoon of the SMA in which there is a carrier part of themolecule (oval) linked by a flexible chain to the PC-likehead group. The heterocyclic chemistry component is foundin the positively charged head group of the SMA or in thecarrier component.

Figure 4. The parasite Acanthocheilonema viteae thatsecretes ES-62 to maintain its balance with its gerbil host.

If you look at a chemical structure with the eyes of achemist, you can identify those parts of the moleculemost likely to be important in determining thechemical and biological properties of the compoundrepresented. In the case of the PC component of ES-62, the most important feature was electrostaticcharge, both positive and negative. To create a smallmolecule analogue (SMA) of ES-62 we needed toinclude positive and negative charge in the rightrelative positions to each other and with the rightshape. In this way we should obtain a compound thatwill interact with the biological systems that lead toimmunomodulation in a manner similar to that of ES-62. We can also build into the design features ofchemical stability and variability so that an optimiseddrug can be obtained in due course from the samemolecular template.

Having solved the conceptual chemistry designproblem we had to test the compounds that we madeto see if they could replicate the functions of ES-62.This relied upon the skill of the biologists, Billy andMaggie Harnett, and their teams to devise assaysthat would lead us in the right direction. By carryingout a wide range of assays using cultured humancells important in the immune system, the Harnettsidentified compounds that stimulated or depressedthe immune response or did nothing at all. From thevery first set of compounds that we tested, two werefound that had strong and similar effects to thoseof ES-62. That success was just lucky, but still moresurprising was that when these compounds weretested in animal models for the treatment ofinflammatory diseases including asthma, rheumatoidarthritis, and lupus they were found to be safe (non-toxic) and effective both curatively andprophylactically.

So from this team we have compounds with thepotential to be beneficial in a wide range of diseasesin which the balance of the immune system isimportant. The task now is to fund an optimisationand development programme. This is proving difficultbecause despite the demonstrated efficacy of theSMAs, industry is reluctant to form a partnershipwith us because the biological mechanism of actionof the SMAs has not been established. We understandas academics the wish of industry to minimise risksbut wonder whether it is appropriate to expect theacademic world both to discover new drugs andopportunities and to undertake their initial development.The pharmaceutical industry is no charity nor does itsometimes appear to be philanthropic but is thebalance right? I’ll have more to say about this later.

Anti-infective drugs from DNA minor groove bindersI now turn to our most advanced project area inwhich one compound has reached clinical trials. As Isaid earlier, we could not do it on our own but beforeI come to the commercial development partnership,I’ll explain how we came to discover a class ofcompounds with wide ranging biological activities,especially in infectious diseases. When choosing afield of study, it’s a good idea to consider its potentialimpact as well as its intrinsic scientific interest. Thefield of DNA binding compounds passed both ofthese tests because there were some interestingchallenges to design novel, tight-binding compoundstogether with the expectation of significantexploitable biological activity if new compoundscould be discovered. There is, however, a really criticalchallenge for the development of new drugs fromthis field which arises as follows. Our compoundswill be designed to bind tightly to DNA which will

Compound class Team Disease Effective in vivo? Current Status

Pteridine 1 Pulmonary disease, diabetes Yes Full evaluation needed

Pteridine relative 2 Cancer Probably Full evaluation underway

Pteridine relative 3 Sleeping sickness Somewhat Toxic, discontinued

Phosphorylcholineanalogue (SMA) 4 Inflammatory diseases Yes, very Optimisation of SMA

and development

lead to some sort of biological activity. But all livingorganisms use DNA to contain their basic biologicalinformation so that they can function and reproduceeffectively. So how can we arrange for our newcompounds to be selective and affect only pathologicalconditions such as cancer and infections but not doany damage to healthy cells and healthy people? To be honest, we did not know. When Team 5 beganwork, Roger Waigh and I, who led the team, believedthat it was sufficiently important to look for newopportunities in this field and would deal with thisquestion later. What guided us were the results frombiological assay in which we compared the behaviourof our compounds in bacterial cells and human cells;we followed the trail shown by toxicity to bacterialcells but lack of effect on human cells.

As everyone knows, the DNA molecule existsprincipally as a double helix. What’s less well knownis that the two chains wind round each other suchthat the grooves created are different sizes. Thelarger, the major groove, is principally where proteinsbind to control the operation of DNA and the smaller,the minor groove, is the molecular target for ourdrugs. Figure 6 shows how our compounds fit into theminor groove. Two molecules of our compounds bindside by side causing the minor groove to expand. Thisin turn changes the shape of DNA preventing itsproper biological function ultimately leading to celldeath. Roger Waigh and I thought that if we couldincrease the strength of binding of our MGBs to DNAby strengthening the interactions between the MGBand the non-charged patches on the DNA surface(grey in figure 6) we would increase binding andpotentially selectivity in a way that no-one elsehad yet investigated. We had a starting point forchemical design in the form of a compound made byStreptomyces spp called distamycin. Distamycin wasknown to be an MGB but it was non-selective in itsbiological activity and also too toxic to be a usefuldrug. By ‘thinking out of the box’ Roger and I designeda family of compounds that were apparently non-toxic to human cells but very toxic (at least 1,000fold greater) to the cells of one of the major classesof bacteria, Gram positive bacteria. This class includesorganisms well known for causing infections that aredifficult to treat, typically hospital acquired infectionssuch as caused by Staphylococcus aureus and

Clostridium difficile. So we were on the track to dealwith a major therapeutic need. I’ll describe thedevelopment leading to clinical trial in a moment.

The design of Minor Groove BindersThe key characteristic of a minor groove binder forDNA is that its structure matches the helix of DNA sothat it can fit to the minor groove. There are severalclasses of compound that do this including somedyestuffs, known in the field as Hoechst after thecompany that discovered them, and some naturallyoccurring compounds, the so-called anthramycins,that have been developed as anticancer drugs at theSchool of Pharmacy, University of London. These areall heterocyclic compounds with a curve. Theprototype for our discoveries, distamycin, wasdiscovered by Arcamone in Italy in the 1960s. It hasthe necessary curved structure and the beauty of itfrom the point of view of drug discovery is that it ismade up of a series of heterocycles called pyrrolesthat are linked in a chain in the same way that aminoacids are linked in proteins. This gives a very variablestarting structure into which we can incorporate anenormous range of different heterocycles so that wecan obtain the required selectivity for a drug and therequired properties for a medicine. To achieve this wehave to be able to synthesise the necessary building

Figure 6. A minor groove binder (MGB) fitting into DNA.With the Strathclyde drugs and related compounds, twomolecules of MGB bind side by side into the minor groovewhich is forced to expand a little. This changes the shapeof DNA sufficiently to prevent its normal biologicaloperation, a situation that can lead to many functionalchanges, including ultimately cell death.

blocks and to have reliable methods of linking them.All of this is solid, standard synthetic heterocyclicchemistry, some of which is necessary for every project.Figure 7 shows the architecture of the molecules.

A wide range of therapeutic opportunitiesDr Abedawn Khalaf was the main contributor to thesynthesis of compounds in Team 5 and in fact to allof the subsequent teams. With some contributionsfrom others he made about 300 compounds in thesame family but with substantial detailed variations.From this library we selected a subset that includedall the major characteristic details of structure andworked with more biologists to investigate theiractivity. Team 6 included Mike Barrett from theUniversity of Glasgow to look at trypanosomiasis inanimals. This disease, the animal equivalent ofhuman sleeping sickness, is a serious economicproblem in sub-Saharan Africa affecting the cattleupon which the human populations depend. Mike’sgroup has found that one of our MGBs is curative in

an animal model of trypanosomiasis. The biology inTeam 7 is led by Dr Chris Carter here at Strathclyde;she has found that a different group of our compoundsis affective against Leishmania spp. , parasites thatcause both skin and visceral disease. Again, we haveproof of concept that such compounds might bedeveloped as medicines through in vivo activity inan animal model. Lastly in our survey of possibleapplications to infectious diseases, in Team 8,collaborating with Dr Arvind Patel of the Universityof Glasgow, yet another sub-class of compounds hasshown up with significant activity against virallyinfected cells (hepatitis C virus) but this project hasreally only reached the screening stage. So far, atleast in discovery terms, Roger’s and my hunch haspaid off: we have found compounds with substantialand selective activity. What now has to be done is todevelop the optimised compounds ready for the clinicand to optimise the others ready for development.

The development of MGB BP3I’ve mentioned several times that there is a realproblem in translating a good drug opportunity, newcompounds with new mechanism of action, into amedicine ready for clinical trial. The way in which themultinational pharmaceutical industry has developedessentially precludes the large companies (so-called‘big pharma’) from taking up such opportunities.Smaller companies often lack the resource toresearch and manage a development project. So itwas necessary to find a way to bring our antibacterialcompounds through to clinical trials and it tooksome time to work out. This part of the story is notheterocyclic chemistry itself but belongs very muchto the theme of this article because it deals with theimportant steps in translating a discovery into amedicine. The solution has involved teamwork,Project Team 9, but in a different way from thescientific teams that I have mentioned already.

In a traditional big-pharma company there would beresearch and development arms that could interact.In our development of MGB BP3 a new model hasbeen developed around a new Scottish company,MGB Biopharma. The initiative to form this companycame from Dr Miroslav Ravic, who is medicallyqualified and has great experience in the development

Head Group

Tail Group

Figure 7. Components of a typical Strathclyde MGB. Thefilled circle, hexagons and pentagons represent differentheterocyclic building blocks and the precise choice ofheterocycle and its position in the molecule determinesthat MGBs chemical and biological properties. The arrowsindicate positions at which the MGBs contact the grey partsof the DNA molecule (Figure 6); these are points ofstructural variety also. Biological selectivity so far seems tobe principally determined by the nature of the head groupand tail group; details of this selectivity are a topic ofactive research.

of compounds and of clinical trials. Together withothers, he worked with the Scottish financialcommunity to raise funds to carry out the necessarydevelopment work to GLP standards acceptable tointernational medicines regulators. A key player inthe financial arrangements is John Waddell who isChief Executive of Archangels, the syndicate that hasplayed the major role in supporting the developmentof MGB Biopharma. It is notable in what he says thatgetting involved in a drug development project wasnot an easy decision.

John writes:“Chief Medical Officer forEngland Prof Dame SallyDavies recently describedthe threat of antimicrobialresistance as a "tickingtime bomb" and said thedangers it posed shouldbe ranked along withterrorism. New antibioticsmade by the biotech andpharmaceutical industry

will be central to resolving this crisis, but there has

been a market failure; no new classes of antibioticshave been identified for more than twenty-five years.The issue is now high on the government and globalagenda and as a result there is a growing focus on theopportunities and challenges of funding biotech anddrug development. Archangels had to face thesechallenges when the possibility of investing in MGBBiopharma came up in 2009. Archangels is a long-established Edinburgh-based, business angel syndicatewith a track record of successful investments in lifescience companies but it took some time to getcomfortable with the scenario of backing a drugdevelopment project. From Archangels’ point of viewthe key challenges to overcome were the quantum offunding required and an understanding of the likelyvalue inflection points for the business; a key driverwas the opportunity to back the first new class ofantibacterial to be developed in Scotland sincePenicillin was discovered in 1928. That said, it is veryunlikely that we would have chosen to proceed if theexperienced and commercially-focused, MGB Biopharmamanagement team had not been in place; as angelinvestors we are backing these individuals to delivercommercial success and an equity return for ourmembers and partners.”

Compound class Team Disease Effective in vivo? Current Status

Pteridine 1 Pulmonary disease, diabetes Yes Full evaluation needed

Pteridine relative 2 Cancer Probably Full evaluation underway

Pteridine relative 3 Sleeping sickness Somewhat Toxic, discontinued

Phosphorylcholineanalogue (SMA) 4 Inflammatory diseases Yes, very Optimisation of SMA

and development

Minor groove binder 5 Antibacterial Yes, very Optimised and developed

Minor groove binder 6 Animal trypanosomiasis Yes Optimisation of MGB and development

Minor groove binder 7 Leishmaniasis Yes Optimisation of MGBand development

Minor groove binder 8 Viral disease Not known ‘Hits’ found but furtherscreening to be done

Minor groove binder 9 Antibacterial Yes, in severalanimal models Phase 1 clinical trial

As a company, MGB Biopharma describes theopportunity and the development like this:

“Drug development opportunities for new antibioticshave improved dramatically in the past few years, withantimicrobal drug resistance increasingly beingrecognised as a serious global public health concern.Nevertheless, the number of new classes of antibacterialdrugs under development remains very small.International health authorities have introducedinitiatives to facilitate faster and more effective ways ofbringing novel antibacterial agents to market. Theseinclude the GAIN act (Generating Antibiotic IncentivesNow) in the US and the Innovative Medicines Initiativein the EU.

MGB Biopharma Limited, a biotechnology company withheadquarters in Glasgow, is developing a truly novelclass of antibiotics based on the minor-groove binder(MGB) platform technology developed by the Universityof Strathclyde. It is backed by a syndicate of Scotland’sleading angel investor groups, including ArchangelInformal Investment, together with Scottish Enterprise.

MGB-BP-3 has a truly novel mechanism of action, andis the first of an entirely new class of antibacterials.MGB-BP-3 is being developed against a broad range ofGram-positive hospital acquired infections. The oralformulation, for the treatment of Clostridium difficileinfections, is being manufactured for a Phase I clinicalsafety trial. C.diff is one of the most common, yetresistant and difficult-to-treat Gram-positive infections.In addition, the Company is completing the pre-clinicaldevelopment of an I.V. formulation for systemichospital-acquired Gram-positive infections, such asmethicillin-resistant and susceptible Staphylococcusspecies, pathogenic Streptococcus species andvancomycin-resistant and susceptible Enterococcus.”

In this development project, MGB Biopharma activelymanages the project and recruits contributions fromsuitably skilled, qualified, and equipped contractresearch organizations to undertake specific componentsof the work plan. The University, with its expertise inheterocyclic chemistry, medicinal chemistry, andmicrobiology provides underpinning research andconsultancy. The scientific and intellectual standingof the University of Strathclyde adds greatly to thestrength of MGB Biopharma as has been shown bythe recent award of over £1M in competitive publicfunding from the UK’s Technology Strategy Board tosupport the Phase 1 clinical trial of MGB BP3 for thetreatment of Clostridium difficile infections. Furtherapplications for approval for clinical trial using otherformulations of our most advanced compound willfollow in the next year. Moreover, we are able topursue in partnership a number of the other compoundsfor anti-infective indications that I have describedabove some of which are particularly important indeveloping countries.

Where heterocyclic chemistry has taken us?I took 3 quotations to start this article: ‘Chemistry isthe Queen of Sciences’ (Lord Todd), ‘Chemistry iscentral to everything’ (American Chemical Society),and ‘Better living through chemistry’ (Royal Society ofChemistry). One of the satisfactions for me lookingback at the research in heterocyclic chemistry carriedout at the University of Strathclyde over the past 40years is that we’ve been able to stand up to thesegrand statements of an august person and of majorinternational scientific societies. I think it fortunatethat my University and I were in tune with each otherin the balance of research and development. Inparticular, the systems and internal workings of theUniversity’s administration actively supportedscientific creativity and translational research. Keymembers of this team have included Dr DavidMcBeth and Dr Catherine Breslin; Catherine has beenmost important in getting all of the teams tofunction and to link the research outcomes to thecommercial external environment. We think we’vebeen able to do something special at Strathclyde inrecent years and we’re working hard to get the bestpossible chances for outcomes that will benefithealth care for millions of people world-wide.

Improving healthcarethrough chemistryImproving healthcarethrough chemistryAdjacent Government highlights the work ofthe Royal Society of Chemistry (RSC) and howit supports chemistry’s contribution to tacklingmajor health challenges…

EDITORIAL FEATURE

Chemical sciences play a major role in everyday lifeand are crucial to economic development. One areawhere they are key is the healthcare sector. Chemistryis vital in order to develop new treatments and drugsfor major healthcare challenges such as cancer.Chemical sciences are also crucial in improvinghealthcare and helping doctors to understand theunderlying disease, developing better diagnoses andtreatments.

Cancer is a leading cause of death worldwide, andaccording to the World Health Organisation (WHO)accounted for 8.2 million deaths in 2012, with themost common causes being, lung, liver, and stomachcancer.

The Royal Society of Chemistry (RSC) is committed toensuring that chemical sciences contributes its fullpotential to tackling the major global challenges oftoday and tomorrow. The RSC has been working withdoctors, academics, and manufacturers since 1841 tohelp advance excellence in the chemical sciences.

As the world’s leading sources of reliable chemicalscience knowledge, the RSC’s global chemistrycommunity contains the expertise of hundreds ofthousands of people, and have over 170 years’worth of top-quality chemical science researchpublications, data, and reports stored in a cutting-edgeonline platform.

The goal of the RSC is to connect people withchemical science knowledge by harnessing theirinformation and expertise and making it easilyaccessible. In order to help support the importanceof tackling major healthcare challenges, the RSCunderstands the importance of drug discovery andnew treatment methods for all areas of healthcare.

At the RSC they support the vital contribution thatchemistry plays in medical research and drugdevelopment in the UK. The RSC believes that overrecent years there has been an increasingacknowledgement that the pharmaceutical sectorneeds to change. (1)

Speaking at a seminar at the RSC in May 2014, Dr Mike Waring from AstraZeneca discussed therelevance of chemistry to the real world andexplained how he believed chemistry plays a bigrole in the treatment of cancer.

“Cancer research is often considered the realm ofbiology and medicine – but chemistry is an equalplayer in that arena. History – a lot of people thinkof cancer as a modern diseases but earliest reportsgo back to Egyptian scientists – Imhotep – to myknowledge that’s the earliest written knowledge ofcancer – under the therapy section he wrote ‘thereis none’ which remained true for many years and ofsome cancers even now,” he explained.

EDITORIAL FEATURE

“One of the big problems is a number of peoplehave said, it’s a disease that has been encoded intoour own DNA, so inevitable for some people really. I guess as I say in many cases you may say there isno adequate treatment.

“I hope and believe that one day we will beat cancerand certainly see great advances over the next fewdecades, but I also feel the solution to this lies firmlyin the discipline of chemistry. The great advantageof chemical treatments is you can treat the wholebody and target the cancer cells wherever it is. “

As well as treatments for cancer, chemistry alsoplays a crucial role in developing antibiotics forbacterial infections that not only create healthcarechallenges in the UK, but worldwide. The RoyalSociety of Chemistry also supports the developmentof antimicrobial resistance through chemistry. It isestimate that around 25,000 people a year die fromdrug resistant microbial infections in Europe alone.

The UK government have a five year antimicrobialstrategy in place (2013-2015), which aims to accelerateprogress made and build upon previous work done inthe UK to tackle antimicrobial resistance.

UK Chief Medical Officer, Dame Sally Daviessupports the strategy and has raised issues in herown annual report.

“There are few public health issues of greaterimportance than antimicrobial resistance (AMR) interms of impact on society,” she said in the Forewordto the Strategy.

“Many existing antimicrobials are becoming lesseffective. Bacteria, viruses and fungi are adaptingnaturally and becoming increasingly resistant tomedicines used to treat the infections they care.Inappropriate use of these valuable medicines hasadded to the problem.

“Coupled to this, the development pipeline for newantibiotics is at an all-time low. We must thereforeconserve the antibiotics we have left by using themoptimally. The process of developing new antimicrobialsand new technologies to allow quicker diagnosis andfacilitate targeted treatment must be accelerated,”Dame Sally Davies added. (2)

1 http://www.rsc.org/campaigning-outreach/global-

challenges/health/

2 https://www.gov.uk/government/uploads/system/uploads/attach

ment_data/file/244058/20130902_UK_5_year_AMR_strategy.pdf

Adjacent Governmenteditorial@adjacentgovernment.co.ukwww.adjacentgovernment.co.uk

The Royal Society of Chemistry(RSC) is committed to ensuring

that chemical sciences contributesits full potential to tackling the

major global challenges of todayand tomorrow.

EDITORIAL FEATURE

Professor Colin J Suckling OBE DSc FRSEResearch Professor of Chemistry

Department of Pure & Applied ChemistryUniversity of Strathclyde

295 Cathedral StreetGlasgow G1 1XL

Tel: 0141 548 2271Fax: 0141 548 5743

www.strath.ac.uk/chemistry