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Understanding the synthesis of analogues and SARs

Andy Parsons introduces the Synthesis of Penicillin Analogues and SARs
Following the discovery and isolation of benzylpenicillin, or penicillin G, a large number of compounds with slightly different structures were then prepared. We call these compounds penicillin analogues. There were several reasons for preparing so many penicillin analogues. This included looking to solve problems associated with using penicillin G. For example, penicillin G cannot be taken orally as it is acid sensitive and so needs to be administered by injection. One such analogue is amoxicillin, which is the most commonly prescribed antibiotic in the UK National Health Service. Varying the structure of penicillins was also needed to find out what features of the penicillin molecule are important to its biological activity - we call this establishing a structure-activity relationship, or SAR.
Finally, several analogues were designed to overcome the problem of increasing antibiotic resistance. Unfortunately, we know that bacteria have proved adept at developing resistance to new antimicrobial agents. Analogues can be created in order to increase the solubility, lifetime or biological effectiveness of a compound. However, they also provide a method through which the active sites of a medicine can be categorised. If the lead compound bound to its target molecule cannot be crystallized and analysed then a structure-activity relationship, or SAR, can be used to identify the most important functional groups within the lead compound. Analogues are synthesised which are lacking one or more functional groups, relative to the lead.
The antimicrobial properties of each analogue are measured and compared in order to identify which groups are necessary for the activity of the molecule. Where there has been a marked reduction in antimicrobial activity it can be assumed that the functional group absent in this analogue was responsible for a portion of the antimicrobial activity of the lead. For example, an imaginary lead compound may contain a phenolic group with two OH groups. These groups could form hydrogen bonds with a complimentary site within the active site of the enzyme. However, if we replace the two -OH groups with two ethers (R-O-R) then we will lose any hydrogen bonding resulting from the OH groups acting as hydrogen bond donors.
If hydrogen bonding at this site is an important part of the binding interaction (between the medicine and enzyme), then the effectiveness of the analogue will be reduced. As such we can deduce that the -OH groups are an important part of the lead molecule and should not be replaced by a group that is not a hydrogen-bonding donor. Once the active functional groups of a lead compound have been identified then other parts of a compound can be modified in a variety of ways. For example, it can be helpful to shield a vulnerable part of a molecule, such as protecting the most reactive site within a medicine. For example, the bulky tertiary-butyl group, Me3C-, makes an excellent steric ‘shield’.
This large, bulky hydrocarbon group can protect areas of the molecule that are vulnerable to, for example, hydrolysis or nucleophilic attack by providing a sterically hindering barrier. This approach can be effective to protect medicines from certain enzymes that may react and degrade them. Another ‘trick of the trade’ is to convert ketones into alcohols as this can increase the solubility of a lead compound in water, whilst retaining the hydrogen bond accepting oxygen atom. An O-H group can act as both a hydrogen bond donor and a hydrogen bond acceptor. Hence the resulting structure is more likely to be soluble in the aqueous environment within the human body.
Interestingly, the protonation or de-protonation of a molecule can be used to increase the ionic bonding attractions between the analogue and target enzyme. For example, a carboxylate ion will have a much greater ionic interaction with a positively charged site within an enzyme active site, compared to the neutral carboxylic acid. It can take years to synthesise the analogues of a single lead compound, involving much trial and error in order to find out the mechanism of action of a medicine (e.g. how medicine interacts with an enzyme). Once the important functional groups have been identified, analogues can be prepared and tested in order to ensure that the final medicine is as effective as possible.
Through increasing affinity to the target enzyme or combating the resistance mechanisms of microorganisms, modification of analogues gives chemists a valuable tool to explore the mechanisms of microbial infection.

Me-Too Medicines

The successful progress in treating several diseases has led to the development of a pharmaceutical industry with an estimated market of around £1 trillion (that is £1,000,000,000,000; to help give a sense of what this number equates to, 1 trillion seconds is 30,000 years!). Marketing pharmaceuticals has become a major business and consequently, it has adopted the rules common to other commercial fields.

The huge market for medicines has lead to a competition among pharmaceutical firms – as soon as a prototype drug becomes available several other similarly active compounds immediately follow, called ‘me-too’ medicines or drugs. Me-too (or ‘copy-cat’) medicines have an identical mechanism of action to the original prototype, and there are only minor differences in the way the medicines work and are processed by the body.

This increasing marketing of me-too drugs has been questioned, so pharmaceutical firms are justifying the development of not-so-innovative medicines. Arguments include: me-too drugs offer an improvement on the effectiveness (efficacy) of the prototype; they show a different profile of adverse effects; they are effective against bacteria resistant to the prototype; they improve compliance in long-term treatment; they are less expensive than the prototype.

But, are me-too medicines justified? Do they diminish the incentives for innovation in pioneering medicines without adding therapeutic value? Or, is increased choice between medicines valuable, keeping prices down, particularly for patients for whom the pioneer medicine is ineffective or entails undesirable side effects?

Drug development – from medicinal chemistry to process chemistry

We have seen that small changes in the structure of a penicillin can have a significant impact on its biological properties i.e. whether groups are electron-donating or withdrawing (we call these electronic effects) or whether the groups are small or large in size (we call these steric effects). In a pharmaceutical company, this work will be undertaken by a medicinal chemist who aims to identify the essential features of a compound that are required for the desired biological activity. Once the structure of the drug is optimised the project passes on to process chemists who make the compound in suitable quantity and quality to allow large scale animal testing and then human clinical trials. So, chemistry plays the most critical role in the drug development process, bolstering the growth of the pharmaceutical industry. (Our MChem students at York have the opportunity to explore sustainable practices in process chemistry, through a miniproject developed with AstraZeneca.)

Film makers and fiction writers have been attracted to the subject of drug discovery – remember Sean Connery in Medicine Man, Harrison Ford in Extraordinary Measures, Will Smith in I am Legend, Anne Hathaway in Love and Other Drugs and/or Robert De Niro in Awakenings? What are you favourite science-based movies, television shows or fiction books?

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Exploring Everyday Chemistry

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