Year Four ChemistryLearning Centre: Medicinal Chemistry

The discipline of medicinal chemistry is concerned with research into new agents for curing illnesses. It is naturally very related to organic chemistry by virtue that these medicinal compounds tend to have biological activity, thus containing a substantial number of carbon compounds.

Medicinal chemistry has various links with organic chemistry. Firstly, it acts as the bridge between traditional and modern chemistry, by identifying the compounds in natural cures such as the fruit of Ascelus Punduanda Wall. (which was found to be a steroid glucoside) and subsequently, it is necessary to understand their drug action mechanisms and plausible side effects due to interactions with other compounds in the body. Finally, medicinal chemistry has many relations with synthesis in organic chemistry as these compounds need to be subsequently synthesised into commercial drugs for use. We will be covering mainly synthesis for now.

Elucidation of CompoundsThere are various means of elucidating the structure of a natural compound, and more often than note it is necessary to use a variety of these methods in order to determine the final structure of a certain compound.

However, it would be necessary to separate the product in order to obtain a single pure compound rather than a mixture of several compounds, which would not give the desired results. Methods of doing this include High Performance Liquid Chromatography (HPLC), gas chromatography, as well as simply dissolving in polar and non-polar solutions, followed by filtration or decanting.

Following that, we can then use various types of spectroscopy to determine the compound such as mass spectroscopy (taught in Y3 RA), UV spectroscopy, IR spectroscopy and Nuclear Magnetic Resonance (NMR).

Ultra-Violet/Visible Spectroscopy

It measures the absorption of light by a certain molecule, and from this is able to tell the identity of transistion metals, organic compounds with a high level of conjugation and charged complexes. The absorption can be processed by Beer-Lamberts Law, which calculates the absorption.

Infrared Spectroscopy

IR Spectroscopy is able to tell us the types of functional groups in a certain molecule. It is able to detct the stretching and bending of bonds as these would absorb IR radiation of a certain wavelength but not others. Generally, stronger and lighter bonds would vibrate faster. Generally, a C-H bond would have a value of about 3000 cm-1, C-D 2200 cm-1, C-O 1100 cm-1 and C-Cl 700 cm-1.

Nuclear Magnetic Resonance NMR makes use of a very strong electromagnet is a machine in order to tell us about the atoms in a molecule by means of understanding the spin of the electrons which in turn tells us the nature of the atoms. Currently, the main types of NMR are 13C and 1H. In 13C NMR, there are various regions which are able to tell us the type of bond the carbon is attached to as well as to a certain extent which atom it is attached to in the case of oxygen.

HNMR Spectroscopy

Although at this stage it may not exactly be clear what are the uses of spectroscopy in medicinal chemistry, it has many uses indeed. In fact, all the diagrams from this previous section have been taken from a research paper entitled Isolation and Identification of Biologically Active Compounds in Aesculus Punduanda Wall. which was able to identify compounds and elucidate a structure in a fruit commonly used in traditional medicine in Myanmar.

Things to Watch Out ForIt is important to note that when dealing with the human body, it is not as simple as finding any compound with the required functional group for curing an illness. It is necessary to consider various other factors as well, which as mainly physical and chemical barriers to a drug meeting its intended receptor as well as possible side effects it may have on the body.

Maintaining an Equilibrium

It is necessary to maintain an equilibrium, when put simply being the . It is advantageous to be able to have a drug that is able to bind on to the receptor complex well, in order to allow it to take effect. However, it is also necessary for the drug to dissociate from the receptor be excreted from the system subsequently so that allergies can be contained and once the patient has recovered, he does not suffer from any side-effects. There are exceptions however to this, as certain pharmacological agents form covalent bonds with the receptor, and as we know it is difficult to break a covalent bond. These include acetylcholineterase and exemestene. In this case, it is necessary for the receptor to be able to naturally break down the drug after use.

Exemestane is used to treat breast cancer in post-menopausal women. By reducing estrogen levels, it slows the growth of breast tumours which require estrogen to grow.

Physical and Chemical Barriers

For most commercial drugs, they are administered by oral means. As a result, there are several barriers that have to be overcame before reaching the target site. The drug will most likely be absorbed in the intestines, hence it has to be able to first overcome the acidic stomach followed by the alkaline intenstinal tract. Furthermore, it also needs to be soluble, which is dependent on its size, surface area, tablet coating and nature of crystal form. We can modify the properties of a drug, for example when mesalamine was found ineffective by virtue of being metabolized before reaching the colon, mesalamine was used instead as it had similar medicinal properties.

Drug MetabolismIt is important for a drug to be able to be metabolized without taking too much of a toll on the liver. Moreover, it is possible for the drug to be metabolized during its initial trip to the liver, before it has reached most of the target cells. This is termed as the first-pass effect, and thus requires a different form to avoid this effect [Note the carbon furthest from the benzene ring]. For example, lidocaine is not usually used as it has a half-life of only 2 hours, instead tocainide is used as it has a longer half-life of 15 hours.

pH Dependence

In certain drugs such as aspirin, its properties are pH dependent. Although aspirin is not soluble, its sodium salt is much more soluble. Thus, if the pH is lowered, the more acidic form of aspirin is more likely to be favoured compared to the sodium salt, thus the seemingly soluble aspirin may be converted into the less soluble form at places such as the stomach and be precipitated out of the solution.

This pH may be calculated from the Henderson-Hasselbach equation .

Isomerism

Although isomers may seem rather similar, in a biological sense they are very different from each other as proteins tend to be folded in such a way that they are asymmetrical in nature and thus their interactions with such isomers will also be different. For instance, ephedrine melts at 79 oC and is soluble in water, whiclest pseudoephedrine melts at 118 oC and is only sparingly soluble in water. Thus, drugs such as (-)-epinephrine has 10 to 15 times more vasoconstrictor activity than (+)-epinephrine. [Diagram: Left is ephedrine, Right is pseudoephedrine]

SynthesisAspirin

Aspirin is formed from the synthesis of salicylic acid and acetic anhydride in the prescence of a phosphoric acid catalyst. This is a form of an esterification process, with the H+ from the acid being able to cause the aceti anhydride to possess an alcohol functional group which would then take part in a reaction with the salicyclic acid.

Mechanism

Metronidazole

Metronidazole is an antibiotic used against anaerobic bacteria and protozoa. Although the synthesis may seem rather complicated, we may see certain understandable parts. For instance, from 1 to 2, it is very similar to the nitration of benzene or toluene that has been taught, whereas for 2 to 3 we can think of it as the chlorinated alcohol and 2 undergoing an alkylation reaction.

Mechanism

Caffeine

Believe it or not, caffeine can actually be synthesised from uric acid through several steps as depicted over here. Although obviously commercially coffee is derived from natural origins, it is interesting to see how a waste product can become an edible compound through careful manipulation. In the first step, we basically use formamide, derived from formic acid, as a reducing agent to remove a ketone group, and subsequently we add methyl groups to three parts of xantine to get caffeine.

Mechanism

Physiological Action

There are generally two types of biological hormones, lipid-soluble and water-soluble ones. The lipid soluble ones would enter the target cell whereas the water soluble hormones would be detected by a receptor on the cell membrane. This has to do with the phospholipid bilayer making up the cell membrance, however we shall not be elaborating further.

In the case of cocaine, it is a weak base, which may be converted into an acid salt. Cocaine is not only lipid soluble, in the acid salt form it is charged and this allows it to enter the cell membrane through small pores as well as through the phospholipid bilayer. Hence, this makes it most penetrating to brain cells, the same for nicotine, marijuana and heroine. As a result, it is harmful to a persons physiological and psychological state.

However, there are nonetheless certain drugs which face difficult crossing the blood-brain barrier if intended. This can be solved by means of a technique to invent a special form called prodrugs, which improves the bioavalability of a drug, in other words makes it easier to cross blood-organ barriers by masking it with lipid-soluble substances. An example would be fexofenadine, which replaced terfenadine over the small risk of a serious side effect. Terfenadine was in fact the first non-sedating antihistamine to be commercially made available.

Hands-On KitFor the purpose of demonstrating how we can relate to the chemistry of compounds which once seems so alien to us, we will be performing the hydrolysis of aspirin which you have just learnt the synthesis process in order to get back its original reactants.

In the hands-on kit, you will find two cups, an aspirin tablet as well as solutions of both an acid and acetone.

Add the tablets to the acetone and crush them well. Decant the clear liquid away allow it to evaporate for possibly a few days. You may stop once you observe crystals of aspirin.

Next, add the water and HCl in approximately equal volumes. Cover the cup with the lid provided and place some ice over it. [This is to prevent loss of vapour by causing it to re-condense.] Heat the solution for sufficient amount of time at about 60oC. A white precipitate should be evolved. Allow the solution to dry for a few more days, and after filtering one should get salicylic acid. Please do note however that this is a rather crude means of hydrolysis and may not result i n fine results, however do it for the experience, maybe?

Aspirin Crystals White precipitate Salicylic Acid Crystals

Reaction [Without Catalyst, which may be a base or acid] :Essentially, aspirin acts as an ester with its functional group attached to the benzene ring. This produces salicylic acid as a product.

[Source: crscientific.com]

Questions:1. What is the mass of salicylic acid required to produce 30 mg of aspirin?2. What is the ratio of ephiderine to ephiderine HCl (pKa 9.6) in the intestinal tract at pH 8.0? [Ephiderine may be regarded as conjugate base]

3. Thalidomide is a drug displaying optical isomerism, with one isomer having medicinal value and the other harmful to the body. However, the issue is that both isomers can be converted in-vitro from one enantiomer to another. Identify the chiral atom and draw its enantiomer.

4. Complete the following reaction for the synthesis of paracetamol. [Hint: 1 and 2 are isomers]

1223

5. Histamine is a bodily compound with the following chemical structure. However, there are several other bodily compounds which act as competitive inhibitors to its action. Given that the following structure is an antihistamine, explain via its chemical structure why it is useful in reducing the action of histamine. [Left Histamine, Right Antihistamine]

6. DOXP is one of the compounds produced in a series of synthesis reactions to produce antimalarials. It is produced from pyruvic acid and glyceraldehyde-3- phosphate with only CO2 as a by-product. [Hint: DOXP has a 5-carbon chain.] Pyruvic AcidGlyceraldehyde-3-phosphate

Answers:

1. [Simple Question] From learning centre, molecular formula of aspirin is C9H8O4. Its molar mass is 180 g mol-1, thus 0.167 mmol of aspirin and salicylic acid each is needed. Salicylic acid is of the formula C7H8O3, with molar mass 138 g mol-1, hence 23.0 mg of salicylic acid is needed.

2. [Simple Question] By Henderson-Hasselbach equation,

3. [Moderate Question]

The carbon attached to the nitrogen but not oxygen is chiral. [(R)-thalidomide is a sedative whilst (S)-thalidomide causes birth defects.]

4.

[Moderate/Hard Question] The students should be expected to know this as for the first step, it is a commo`n nitration step and since the OH group is electron withdrawing, the NO2+ group would be more likely substituted into the 1,3 positions. They can infer from the final product that 2 is the 3 substituted product. As NaBH4 is a source of hydride ions and a reducing agent, it will reduce the NO2 group to an NH2 group.

5. [Hard Question] Both the histamine and antihistamine have a particular similar structure, namely the C CH2 CH2 N group which interacts with the same receptor as histamine. As a result, when both are present near a receptor, they will compete to interact with the receptor and this competition results in reduced interaction between histamine and receptor.

6. [Hard Question]

Requires knowledge that if CO2 is a by-product, it would mean that there the bonding site be such that it is possible for one atom to lose a C and O atom while the other an O.

[Note: Error in glyceraldehyde-3-phosphate as carbon numbered 4 should have an OH group attached]