New and effective drugs?Yes, please, but where from?

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Where can we begin?Disease will always be with us although the criticaldiseases will differ from place to place and time totime. There will therefore always be a demand fornew and effective drugs but it has become muchmore difficult to bring them to market in recentdecades. There’s been a lot written about the slow-down in the marketing of new drugs in the last 20years from the point of view of the internationalpharmaceutical industry establishment. But if youasked an Indian physician what is needed to discovera new drug he or she might say, “Very little, actually.We’ve have plenty of good drugs from Mother Naturein our traditional Ayurvedic medicine”. Neverthelessfrom industrial pharma the slow-down is a fact andvarious reasons have been noted as contributorsincluding an increasingly challenging regulatoryenvironment, a lack of good druggable targets (all the easy ones having been done), increasinglydemanding disease states associated with agingpopulations, a lack of good quality new chemicalentities, and so on. Overall an intrinsically riskybusiness has become riskier. What’s to be done? It’s entirely appropriate and understandable thatcompanies should take serious steps to mitigate therisks and thereby increase profitability. It’s also veryclear that companies have to make choices aboutwhat to develop from the many opportunities arisingfrom their own research. Nevertheless, the demandremains and scientific research, much of it academic,has the responsibility to create opportunities tosatisfy the demand.

This E-Book is about how we have approachedmeeting this responsibility at the University ofStrathclyde in Glasgow, Scotland. To expand on thebackground to what we do it is worth recalling that

some of the most outstanding achievements in drugdiscovery have been recognized by the award of NobelPrizes. Nobel Prizes normally go to scientists whosefundamental discoveries have had a major impact overa number of years in the particular field of scientificresearch. Just occasionally a Nobel Prize recognizes adiscovery that has come directly to the consumer. Fromthe point of view of a medicinal chemist it’s notablethat two good examples of this concern the NobelPrize for Physiology or Medicine, not for chemistry, andare associated with drug discovery.

In 1988 the Nobel Prize was awarded jointly to Sir James Black, and Drs Gertrude Elion, and GeorgeHitchings for their establishing ‘important principlesfor drug treatment’, which in practice meant thediscovery of ß-blockers (Black) and antibacterialagents (Elion and Hitchings). The important principleshere were to do with the scientific approaches thatcan lead to effective medicines. These scientists were outstanding in demonstrating the connectionbetween a biological mechanism and a successfuldrug, in this way bringing chemistry and biologycloser together than ever before to the benefit ofmillions of people.

As I write the news has come through that this yearthe Nobel Prize for Physiology or Medicine has beenawarded to William C. Campbell and Satoshi Omurafor their discovery of the antiparasitic drug, avermectin,and to Youyou Tu for her discovery of the antimalarialdrug, artemisinin. Avermectin was isolated by Omurafrom a soil bacterium, Streptomyces avermitilis. Tudiscovered her active compound in a plant that figuresin Chinese traditional medicine, Artemesia annua. In both cases, the clinically used products today arederivatives of the naturally occurring compounds that

Heterocyclic Chemistry in Drug Discoveryat the University of Strathclyde

New and effective drugs? Yes, please, but where from?

the Nobel Laureates discovered. They are tellingexamples of a tradition of drug discovery based uponcompounds isolated from plants and microorganismsthat has been one of the main sources of drugs for centuries.

Translating this to the range of opportunities forchemistry available today in drug discovery there isthe combination of chemical and biological mechanisms(following Black, Elion, and Hitchings) on the onehand, and the identification and modification ofnaturally occurring compounds (following Campbell,Omura, and Tu) on the other. Drug discovery isintrinsically multidisciplinary but chemistry is always at its heart because chemistry creates thevast majority molecules that become drugs. AnotherNobel Laureate, the Lord Todd of Trumpington, a manof many honours including Nobel Laureate, Order ofMerit, Past President of the Royal Society, had strongviews on the importance of chemistry. He declared inan after dinner speech at a meeting I had organised,“Chemistry is the Queen of Sciences. Get your chemistryright and everything else follows.” Lord Todd’s scientificcontribution that led to his great distinction was atthe border of chemistry and biology, in his time, asnow, an area of science with great intrinsic interestand potential for useful, translatable discoveries and inventions. He was an organic chemist who laidthe chemical foundations upon which much of thechemistry of the components of DNA was built. Andderived from this we have the synthesis of genes(first demonstrated by Ghobind Khorana) andultimately much of modern chemical biology. In the following pages I want to show how several of our drug discovery projects at the University ofStrathclyde have learned from these outstandingcontributions.

The Special Properties of the compounds we call 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 which are,simply stated, compounds with rings of atoms builtfrom carbon together with other elements, nitrogen,oxygen, and sulfur, being the most relevant tobiological chemistry. Whilst not always the mostchallenging class of compounds for academic organicchemical synthesis, heterocyclic compounds areespecially rich in their biological importance, a factthat has a lot to do with their ability to interact with 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 we commonlyuse are also heterocyclic compounds.

Before introducing my topics let’s consider theessentials of how heterocyclic chemistry works in avery conceptual way. Whatever application we’reinterested 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 heterocycliccompounds have such interesting and diverseapplications using a few simple ideas.

Most applications of heterocyclic compounds inmedicinal chemistry or in materials chemistry do not depend upon reactions of the compounds butupon the way in which molecules stick together orassociate. Association can be strong or weak, long orshort lived but whatever its type, the fundamentalinteractions are based upon the same three things,molecular size, shape, and electrostatic charge. It’snot necessary to understand the detail of how chargesarise but Figure 1 shows the consequences step bystep. The basic rules of electrostatics apply to atomsand molecules: like charges repel and opposite

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charges attract (Figure 1A). All this assumes that the interacting parts of molecules can actually gettogether, in other words that their shapes match.Even if there are attracting charges, if the moleculescan’t get close together because there are other atomsin the way, we won’t see any chemical interaction andwon’t be able to create a useful application, particularlyin medicinal chemistry (Figure 1B). Given the rightcharge, shape, and size, some molecules are able toassociate in stacks or rods or other arrangements. Suchmultimolecular aggregates are the basis of materialsthat are important in many electronic applications(Figure 1C).

So in discovering new drugs, we’re chiefly concernedwith finding compounds that act in a specific way in abiological 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 to normal. Inall these things we require selective action to minimiseside effects and we need subtle and selective chemistryto provide it. That’s where the refined application ofheterocyclic chemistry comes in. Using heterocycliccompounds we can find compounds that engagethrough their charge and shape with a specificcomponent of biology, typically a protein or DNAmolecule, and modify the biological function which, if taken through to a medicine, will benefit the patient.In fact all of the medicines deriving from the NobelPrize winning work mentioned in the introductioncontain heterocyclic components.

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 pharmaceutical industryitself has made it clear for many years that despite its size it cannot do everything worth doing orinteresting. It has a challenging regulatory andcommercial framework in which to work and thesechallenges have led to systematisation of research

processes and decision-making. All of this isunderstandable in their context but, if I am beingcritical, it has industrialised thinking and therebycircumscribed creativity. Both for reasons of coverageand creativity, therefore, 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 pointof view, other people do specialised organic synthesisbetter than me. The need that my colleagues and Ihave tried to satisfy is to create new compounds withspecific biological effects, either to treat disease(which is medicinal chemistry) or to investigate howbiology works (which is chemical biology). In my viewand experience, medicinal chemistry and chemicalbiology go hand in hand. To make a significantcontribution, we’ve had to make choices about what tostudy but we’ve also been able to take opportunitiesas they have arisen; then with the flexibility thatgood academic teamwork can bring, one thing leadscreatively to another. Chemical and biologicalmechanisms and naturally occurring compounds all take part and we can look to all of the NobelLaureates mentioned above for inspiration.

I’ll present three examples of our projects. The firstbegins with the chemistry of a class of heterocycliccompound known as pteridines, so called becausethey were first discovered as pigments in the wingsof butterflies. It leads little by little to a new class ofcompound discovered by our teams at Strathclydeprimarily for the treatment of challenging cancerssuch as prostate and pancreatic cancer. The secondconcerns an opportunity brought to us by colleaguebiologists based upon some intriguing properties of a protein secreted by a parasitic worm that affectssome Asian rodents. Following this line of research,we have obtained new compounds with proven

potential for treating inflammatory diseases such asasthma and rheumatoid arthritis; we call it ‘The WormsProject’. Finally, I shall describe our most advancedproject, which concerns a group of compounds knownas minor groove binders because they bind to a part of the structure of DNA known as the minor groove.Most, but not all of the applications of thesecompounds, are as treatments for infectious diseases.One compound has entered clinical trials for thetreatment of Clostridium difficile infections and wehave good evidence that others can be developed totreat parasitic diseases such as sleeping sickness and Leishmaniasis.

Now we in this Department can’t do it all either andeach of these projects has required contributionsfrom willing colleagues and effective collaborators in other institutions. What I am about to describe is ateam effort. There’s a lot of chemistry and I’m goingto try to deal with it without using detailed chemicalstructures. Instead, I’ve drawn abstracted cartoonswith which I can show not only the essential shape of our molecules but also how they work to controlbiology beneficially. Even getting one compound toclinical trials is good going for an academic laboratory.We hope and that more will progress and we’reworking hard at it with our partners.

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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

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1B

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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.

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 availability of 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 someinteresting biology and useful chemical compoundsin this field.

Some of the secrets of medicinal chemists: How we come up with new compoundsPteridines consist of two six-membered ringscomposed of carbon and nitrogen fused togetheralong one side (Figure 2). Whilst the rings themselvesare significant in the chemical and biological properties,the atoms and groups of atoms attached to the ringsprovide the diversity, interest, and significance intheir chemistry. As suggested by Figure 2, if a newmolecule is invented with a different structure on theright, it should still bind to the biological machinery,most commonly enzymes, but might do differentthings from the naturally occurring pteridine. Thedifferences could in principle be either to block a

naturally occurring reaction (an inhibitor or antagonist)or to promote it (an activator or agonist). Dependingupon the application and desired outcome one or the other might be required. This logically simpleconcept of modifying part of a molecule to control its function in the desired way is at the heart of much medicinal chemistry design as will be seenbelow. Whilst it is a simple concept, the challenge isconverting the concept into new chemistry and usefulapplications. In the case of our work with pteridinesand their relatives, we have been interested in bothactivators and inhibitors.

If we just take our starting pteridine template, we’vebeen able to vary and add substituents to obtaincompounds that stimulate the production one of thesmallest naturally synthesised molecules, nitric oxide (Figure 2B). Nitric oxide acts as a signallingagent in several biological systems includingstimulating the relaxation of muscle in arteries and our new compounds can indeed promote suchmuscle relaxation. This could have benefit forexample in treating the symptoms of high bloodpressure such as occurs in diabetes.

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 and

A. ParentPteridine

B. Add substituentsMuscle relaxants

C. Change ring sizeNew synthesis

Figure 2. A. Cartoon representation of a pteridine, two fused six membered rings. B. In nature, pteridines have additional atomsof groups of atoms attached (substituents). The naturally occurring pattern of substituents is fixed but we can vary them usingsynthetic 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 includea variety of substituents we had to develop new synthetic methods.

bind 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.

develop new synthetic methods. When the newcompounds became available, with the help ofcolleagues, they were screened to find significantbiological activity. In fact two new substantial projectswere seeded in this way, the first to treat sleepingsickness, a disease caused by parasites known asTrypanosomes, and the second to treat cancers such asprostate and pancreatic cancer. Different modifications(Figure 2D and E) were required for the two differentdiseases. Every project at this stage is not takenforward. In these cases, the compounds designed totreat sleeping sickness were too toxic. On the otherhand, the anti-cancer compounds are actively beingrefined and developed in a project led by mycolleague, Professor Simon Mackay.

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 showna 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 compounds

Figure 3. A representation of the molecular target of the antitrypanosome 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.

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D. Add substituentsTarget sleeping sickness

E. Different substituents,Different placesAnti-cancer drugs

B

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 beingfurther developed.

The Worms ProjectParasites that cause sleeping sickness, a largelyuntreatable disease, were a target one of thepteridine-related projects. But in the Worms Project, aparasite has suggested to us how to create compoundsthat modulate the immune system beneficially. Thisis a good example of a drug intended to restore thebalance that has been disturbed in a disease. A husbandand wife team of professors from the University ofStrathclyde and the University of Glasgow, respectivelyBilly and Maggie Harnett, have made their careersfrom the study of a protein known as ES-62, which is secreted by a worm Acanthocheilonema viteae(Figure 4) that is a parasite of gerbils. Billy and Maggieisolated and purified ES-62 and showed that itlowered the activity of the immune system so thatthe parasite was not attacked by its host but not somuch that the host was killed by bacterial or viralinfections. Obviously the parasite needs its host toreproduce and survive so the immunomodulation byES-62 was very important. Billy and Maggie wereconvinced that there could be a useful drug somewhererelated to this biology. However the protein itself wasnot suitable: it was too big a molecule to be formulatedeasily as a medicine. Moreover, because it is not ahuman protein, the human immune system wouldmost probably be stimulated and ES-62 destroyed.Lastly, if given orally, it would be destroyed by

digestion. What was needed was a small, drug-likemolecule that could reproduce the potentiallybeneficial immunomodulatory properties of ES-62. An interesting ethnological and philosophical aspect of this opportunity is that it considers theimmunological balance in a person to be importantfor their health and the success of their treatment. It thus connects with eastern medicinal traditions,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-62were. To put it another way, we did not know thechemistry by which ES-62 worked. And to make iteven more challenging, there was no crystal structureof ES-62 available from which we could build a model;there still isn’t. So none of the usual starting pointsfor a medicinal chemistry project was present; we’reworking from a naturally occurring compound but we don’t have any information about its detailedstructure. In this situation, we fell back on the basicprinciples of chemical structure and reactivityapplying them to the biological context.

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

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.

Fortunately, one small aspect of the structure of ES-62 that was important to its function had beenidentified by the biologists. Attached to the surface of 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. However withone or two other clues from PC-containing moleculesthat the Harnetts had studied, it was possible todesign some compounds that would be worth testing.Figure 5 illustrates how this was done.

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, one positive and one negative. To create asmall molecule analogue (SMA) of ES-62 we neededto include 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 assays that would lead us in the right direction. By carryingout a wide range of assays using cultured cellsimportant in the immune system, the Harnettsidentified compounds that stimulated or depressedthe immune response or did nothing at all. From the

very first set of compounds that we tested two werefound that had strong and similar effects to those ofES-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 project we have compounds with thepotential to be beneficial in a wide range of diseasesin which the balance of the immune system is important. 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 partnership with 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 and opportunities and to undertake their initial develop-ment. The pharmaceutical industry is no charity nordoes it sometimes appear to be philanthropic but isthe balance right now?

Anti-infective drugs from DNA minor groove bindersTurning now to our most advance 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 of thesetests because there were some interesting challengesto design novel, tight-binding compounds togetherwith the expectation of significant exploitablebiological activity if new compounds could bediscovered. There is, however, a really critical

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challenge for the development of new drugs fromthis field which arises as follows. Our compounds will be designed to bind tightly to DNA which willlead 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 this projectbegan, Roger Waigh and I, who led the team, believedthat it was sufficiently important to look for newopportunities in this field that we would deal withthis question later. What guided us were the resultsfrom biological assay in which we compared thebehaviour of our compounds in bacterial cells andhuman cells; we followed the trail shown by toxicityto bacterial cells 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. The

larger, 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 the minor groove. Two molecules of our compoundsbind side by side causing the minor groove to expand.This in 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 else hadyet investigated. We had a starting point for chemicaldesign in the form of a compound made by Streptomycesspp called distamycin. Distamycin was known to bean MGB but it was non-selective in its biologicalactivity and also too toxic to be a useful drug. By ‘thinking out of the box’ Roger and I designed afamily of compounds that were apparently non-toxicto cells but very toxic (at least 1,000 fold greater) tothe cells of one of the major classes of bacteria,Gram-positive bacteria. This class includes organismswell known for causing infections that are difficult totreat, typically hospital acquired infections such ascause by Staphylococcus aureus and Clostridiumdifficile. So we were on the track to deal with a majortherapeutic need. I’ll describe the developmentleading 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 curvature of thehelix of DNA so that it can fit to the minor groove.There are several classes of compound that do thisincluding some dyestuffs, known in the field asHoechst after the company that discovered them, and some naturally occurring compounds, the so-called anthramycins, that have been developed asanticancer drugs at the School of Pharmacy, Universityof London. These are all heterocyclic compounds witha curve. The prototype for our discoveries, distamycin,was discovered by Arcamone in Italy in the 1960s. It

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.

has the necessary curved structure and the beauty ofit from 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 buildingblocks 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 theearly synthesis of minor groove binders and in fact toall of the subsequent work. 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 further biologists to investigate theiractivity. This research team included Mike Barrett fromthe University of Glasgow to look at trypanosomiasisin animals. 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 inan animal model of trypanosomiasis. A further studyin antiparasitic activity is led by Dr Chris Carter hereat Strathclyde; she has found that a different groupof our compounds is affective against Leishmaniaspp., parasites that cause both skin and visceraldisease. Again, we have proof of concept that suchcompounds might be developed as medicines throughin vivo activity in an animal model. Lastly in oursurvey of possible applications to infectious diseases,collaborating with Dr Arvind Patel of the University of Glasgow, yet another sub-class of compounds hasshown up with significant activity against virallyinfected cells (hepatitis C virus) but this project has

really 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 to researchand manage a development project. So it was necessaryto find a way to bring our antibacterial compounds

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.

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through to clinical trials and it took some time to workout. This part of the story is not heterocyclic chemistryitself but belongs very much to the theme of this articlebecause it deals with the important steps in translatinga discovery into a medicine. The solution has involvedteamwork but in a different way from the scientificteams 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, MGBBiopharma. The initiative to form this company camefrom Dr Miroslav Ravic, who is medically qualifiedand has great experience in the development ofcompounds and of clinical trials. Together with others,he worked with the Scottish financial community toraise funds to carry out the necessary developmentwork to GLP standards acceptable to internationalmedicines regulators. A key player in the financialarrangements is John Waddell who is Chief Executiveof Archangels, the syndicate that has played themajor role in supporting the development of MGBBiopharma. It is notable in what he says that gettinginvolved in a drug development project was not aneasy decision. John writes:

“Chief Medical Officer for England Prof Dame SallyDavies recently described the threat of antimicrobial

resistance as a “ticking time bomb” and said the dangersit posed should be ranked along with terrorism. Newantibiotics made by the biotech and pharmaceuticalindustry will be central to resolving this crisis, but therehas 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 and drug 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.”

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 being recognisedas a serious global public health concern. Nevertheless,the number of new classes of antibacterial drugs underdevelopment remains very small…

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…

MGB-BP-3 has a truly novel mechanism of action, and is the first of an entirely new class of antibacterials.MGB-BP-3 is being developed against a broad range of Gram-positive hospital acquired infections.”

In this development project, MGB Biopharma activelymanages the project and recruits contributions fromsuitably skilled, qualified, and equipped contractresearch organizations to undertake specificcomponents of the work plan. The University, with its

Left: Capsules of MGB-BP-3 formulated for use in thetreatment of Clostridium difficile infections.

Right: A freeze-dried sample of MGB-BP-3 formulated afterreconstitution for intravenous administration.

expertise in heterocyclic chemistry, medicinalchemistry, and microbiology provides underpinningresearch and consultancy. The scientific andintellectual standing of the University of Strathclydeadds greatly to the strength of MGB Biopharma as hasbeen shown by the recent award of over £1M incompetitive public funding from the UK’s TechnologyStrategy Board to support the Phase 1 clinical trial ofMGB BP3 for the treatment of Clostridium difficileinfections. Further applications for approval for clinicaltrial using other formulations of our most advancedcompound will follow in the next year. Moreover, weare able to pursue in partnership a number of theother compounds for anti-infective indications that Ihave described above some of which are particularlyimportant in developing countries.

Where heterocyclic chemistry has taken us.In addition to quoting Lord Todd’s remark ‘Chemistryis the Queen of Sciences’, two of the most importantlearned societies in the world have promoted similarviews: ‘Chemistry is central to everything’ (AmericanChemical Society), and ‘Better living through chemistry’(Royal Society of Chemistry). One of the satisfactionsfor me looking back at the research in heterocyclicchemistry carried out at the University of Strathclydeover the past 40 years is that we’ve been able tojustify within our research and its applications thesegrand statements of an august person and of majorinternational scientific societies. I think it fortunatethat my University and I were in tune with each other in the balance of research and development. In particular, the systems and internal workings ofthe University’s administration actively supportedscientific creativity and translational research. Keymembers of this team have included Dr David McBethand Dr Catherine Breslin; Catherine has been mostimportant in getting all of the teams to function andto link the research outcomes to the commercialexternal environment. We think we’ve been able todo something special at Strathclyde in recent yearsand we’re working hard to get the best possiblechances for outcomes that will benefit health care for millions of people world-wide.

“Drug development opportunitiesfor new antibiotics have improveddramatically in the past few years,with antimicrobal drug resistanceincreasingly being recognised as aserious global public healthconcern. Nevertheless, the numberof new classes of antibacterialdrugs under development remainsvery small…”

www.strath.ac.uk/chemistry

Professor Colin J SucklingResearch Professor of Chemistry

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