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Ion-Dipole Bonds – Biological Interactions

by Adam Le Gresley, PhD
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    00:01 Now, let’s quickly have a look at ion-dipole bonds. Many drugs, sorry, many drug molecules will be... have ionised functional groups. Now, why you say? Because if we’re looking, for example, at things like amines and carboxylic acids, we already know that they have the potential to either gain a proton or lose a proton.

    00:23 And we also showed in the previous module about amino-acids and their pI idea, indeed, at what pH they are zwitterionic or mostly negatively charged or mostly positively charged. And this relates to this as well because if you look at a secondary amine and you were to put it into water at physiological pH, you’d find that a good portion of that would exist as its ammonium salt.

    00:50 And this means that you’ve now got a positive charge formerly on a nitrogen. And here you can see in the diagram, we have here a phenylethylamine shown here or phenylethylammonium salt interacting its ion with the delta negative of the oxygen or water. And this type of bonding plays a key role in the water solubility of a drug.

    01:16 Question: a salt of weak base in a weak acid is not necessarily very water soluble. Why is this? And now, let’s just have a quick recap about ionic bonding. Obviously in Module II, we actually discussed this in considerable depth. However, in the context of drug-receptor interactions, it’s important to make sure you’re clear on this.

    01:42 Ionic bonds are formed between species that have opposite charges, as you can see here, where we have a carboxylate anion interacting in an ionic fashion with a ammonium cation.

    01:53 And it’s possible for these forces to act over long distances. Indeed, the force between two electrostatic charges falls off as a proportion of 1/r2. Drugs are often ionised and the active sites in receptors contain charge groups such as carboxylic acids, for example, in the case of a glutamic-acid amino-acid, and also lysine, in the case of the amine-containing amino-acid.

    02:22 So, that brings us onto the final type of bonding, covalent bonding, which you should already be familiar with in terms of the concept back from Module I.

    02:32 The majority of the bonds within drugs and their targets will be covalent. And a small number of the drugs can also make covalent bonds with their targets.

    02:41 I used the example of aspirin, salicylic acid, making a covalent bond with COX-1, cyclooxygenase-1.

    02:50 Covalent bonds are strong and hence, drugs forming them will usually be permanently bound to their target unless, of course, a further reaction to cleave that covalent bond takes place.

    03:04 As you’ll see in the next slide, some anti-cancer drugs alkylate DNA in tumour cells. These are drugs such as chlorambucil and other mustard-based drugs. The alkylated DNA cannot function and hence, the cell dies. An example of this would be mechlorethamine, which is shown on the following slide.

    03:27 So, here we have a methyl-based mustard. The reason it’s called this is from the original origins of mustard gas in fairness. If we look here at the structure, you can see that we have a chloroethylamine type of structure. So, here, we have a chloro group and an ethyl group which is bound to a nitrogen group. And it’s indeed the reactivity of this that makes it most useful in terms of DNA, but also highly toxic to everything else. And hence, it’s used as a weapon of war.

    04:00 So, let’s, for example, have a look at what’s happening here.

    04:04 Remember what we said about the lone pair on the nitrogen. The lone pair on the nitrogen is very nucleophilic. And we know that, under normal circumstances, it can react with a molecule of haloalkane and then form a second alkylated version of itself.

    04:19 Now, what happens in this scenario is that an intramolecular reaction occurs. The lone pair of the nitrogen attacks the delta positive on the chloroethyl group, kicks off the chloride.

    04:33 But, of course, it doesn’t have a hydrogen to lose because, as you can see, that amine is a tertiary amine. There are no further hydrogens to be lost as H+. And so, what you end up with is a positively-charged species shown in the right hand side known as an aziridinium ring... aziridinium ring.

    04:52 And what happens in this scenario is that the rather nucleophilic part of one of the bases in DNA such as, for example, the nitrogen 7 on guanine actually can attack this aziridinium ring and open it up. What this results in is a covalently-linked piece of DNA to our mustard, our mechlorethamine. And this is known as alkylation. So, whenever we are forming a covalent bond between a heteroatom and an alkyl group, this is also termed alkylation.

    05:28 Now, if you can imagine what I showed you before in terms of DNA and its strands and how the bases were held together, they’re held together by hydrogen bonds. But, the idea behind that is that, when, for example, DNA needs to be transcribed and that mRNA needs to be translated, of course, the DNA must unzip. If, as you can see here, it is possible to covalently link two sets of bases together from opposite strands, it means that the DNA can itself not unzip and therefore, you cannot get transcription. Thus, in the case of, for example, cancer cells, where cancer is... results in the rapid division of cells as a consequence of the rapid replication of DNA, this type of drug actually stops that from happening, thus leading to cell death because the DNA itself becomes non-viable.

    06:24 Now, let’s bring on the role of water.


    About the Lecture

    The lecture Ion-Dipole Bonds – Biological Interactions by Adam Le Gresley, PhD is from the course Medical Chemistry.


    Included Quiz Questions

    1. …determines its water solubility and interaction with the target receptor molecule.
    2. …determines its water insolubility.
    3. …do not play any crucial role in drug-receptor interactions.
    4. …react with each other to nullify the drug side-effects.
    5. …must be removed before their introduction to patient’s body.
    1. Covalent bond ---- r
    2. Ionic interactions ---- 1/r
    3. Ion-dipole interactions ---- 1/r2
    4. Dipole-dipole interactions ---- 1/r3
    5. London forces ---- 1/r6
    1. …irreversible covalent bonds with their target receptor molecules.
    2. …irreversible ionic bonds with their target receptor molecules.
    3. …reversible covalent bonds with their target receptor molecules.
    4. …reversible ionic bonds with their target receptor molecules.
    5. …irreversible ionic-dipole bonds with their target receptor molecules.
    1. … alkylation of DNA.
    2. …alkylation of RNA.
    3. …alkylation of proteins.
    4. …alkylation of DNA polymerase.
    5. …alkylation of RNA polymerase.
    1. The alkylation of DNA by aziridinium ring attack which formed during the elimination of Cl- due to the intramolecular substitution of the mustard gas molecule.
    2. The alkylation of protein by aziridinium ring attack which formed during the eradication of Cl- due to the intramolecular substitution of the mustard gas molecule.
    3. The alkylation of protein by Cl- ion attack which formed during the intramolecular substitution of the mustard gas molecule.
    4. The alkylation of protein by H+ ion attack which formed during the intramolecular substitution of the mustard gas molecule.
    5. The alkylation of DNA by Cl- ion attack which formed during the intramolecular substitution of the mustard gas molecule.

    Author of lecture Ion-Dipole Bonds – Biological Interactions

     Adam Le Gresley, PhD

    Adam Le Gresley, PhD


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