Analogs: Adenosine, Deoxycytidine, Guanosine/Deoxyguanosine, Thymidine, Deoxyuridine

by Kevin Ahern, PhD

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    00:00 Adenosine is, of course, the molecule that is the rival version of deoxyadenosine. You see the difference here. In the position number 2, there’s a hydroxyl instead of a hydrogen. This compound here, BCX4430, with its elaborate name, is a derivative of adenosine. We can see the slight change that’s happened in the structure of the base that’s attached to the ribose ring. This difference being shown right here in the green squares. The BCX4430 is a competitive inhibitor of ATP when it gets phosphorylated, and as a competitive inhibitor of the ATP, it can do a couple of things. One is it can stop the synthesis of an RNA and it can also interfere with the ability of cells to use that molecule as a triphosphate for energy. This BCX4430 is a powerful antiviral agent and it's used to treat people who are infected with the Ebola virus. Deoxycytidine is shown here and derivatives of it, ara-C as shown here, have similar things as we saw before. So like the ara-A which had an arabinose at that position, cytarabine has an arabinose as the sugar in its place as shown here. This molecule is used in chemotherapy because it interferes with the ability of cells to use this as a cytidine nucleotide in the building of a nucleic acid. Zalcitabine or ddC is shown here and we start to see some similarity of pattern that’s happening now among these derivatives. This compound is lacking again a hydroxyl group at position number 3 and like we saw earlier, the lack of hydroxyl at position number 3 means that this molecule will be a chain terminator during the synthesis of DNA. Zalcitabine is also known as ddC and ddC is an antiviral agent and commonly used in the 3-drug cocktails used to treat HIV. Now here’s an odd one, emtricitabine has the structure that you can see here and you see that there’s not even a lot of things that you recognize relative to the deoxycytidine. However, that’s the way that the infective agents see it. We see, first of all, the fluorine that is different here and we see the sugar being upside down amazingly enough but this agent does have some effective antiviral activity and it’s also used in anti-HIV treatments. Another odd sugar derivative is lamivudine which is known as 3TC. 3TC has a modified sugar as shown here and it’s also a powerful antiviral and anti-HIV agent. It’s also used in the 3-drug cocktails used to treat HIV patients. Guanosine and deoxyguanosine derivatives are also powerful compounds used as treatments against these infective agents. Abacavir is shown here and we see it has a couple of odd things about it.

    03:08 First of all, it’s lacking that position number 3 hydroxyl and second, you may not notice, but it has a double bond to that position at the bottom as well, meaning this is a very unusual sugar-type structure. In addition, we see at the very top of this guanosine derivative is that this has a cyclopropane, which is a very reactive and very odd structure to have on its base at that point.

    03:33 Abacavir is used primarily as an anti-HIV treatment. Acyclovir has a very odd structure because it’s lacking the lower part of that sugar. You don’t see the lower part of the sugar at all but it’s used to treat herpes and other viruses. Entecavir has, again, a couple of oddities to its structure. You can see, first of all, it has a double-bonded carbon at the position at the top of the ring and it’s used to treat hepatitis B. Thymidine derivatives are also important. Here is one called stavudine which, also, is like one of the previous slide that lacks the hydroxyl at position 3 and had that double bond at the bottom. You can see that difference here, and stavudine is used to treat as an anti-HIV agent and also is an antiviral agent to prevent the growth of certain viruses. Telbivudine is shown here and we see now that there’s really some mixing and matching that’s occurring because everything is flipped. The base is on the wrong side of the sugar and the hydroxyl is essentially flipped in the wrong direction as well. We can see that difference there and we can see that difference there. This compound is used to treat hepatitis B. Zidovudine also known as AZT, is used to treat HIV and it has an odd structure at position number 3. It’s not completely lacking something there but it has this group of nitrogens that are linked there and this is used partly as a substrate by the HIV virus but again it cannot extend once it’s been built into a growing DNA chain. It’s an anti-HIV agent as I noted. Deoxyuridine is also a strategy for making derivatives to stop some of these infective agents from functioning. One of these molecules made from it based on deoxyuridine is idoxuridine, and it has the same uracil base as deoxyuridine except for it has an iodine attached to the ring as you can see here. This molecule is used to treat herpes simplex keratitis. The last molecule that I’ll talk about here is trifluridine and again, like uracil, it has a similar structure but in this case it has a 3-fluorine derivative that is attached to it at the very top. Now, all these various molecules that I’m talking about are quite varied in their structures. They do have some similarity to the nucleosides that are natural that appear in the nucleic acids. The secret to the way in which each of these functions is that they typically have some selective advantage in inhibiting the polymerases of the viral or the bacterial agents that they’re designed to work against. That means that the polymerases of these various agents preferentially are recognizing these agents in contrast to the cellular polymerase, which is rather ignoring them. So the more the derivatives can be designed to affect only the polymerases of the infective agents, the more effective these modified agents will be and the less side effects will be observed as a result of them. We’ll spend a lot of time in this lecture going through nucleotide metabolism, how the purines are made, how the pyrimidines are made, how the de novo pathways work, how the salvage pathways work, how the deoxyribonucleotides are made, how the thymidine nucleotides are made, and then finally wrapping it all up, how our knowledge of all these different nucleotides are used to make medications to stop the infective agents that affect human health.

    About the Lecture

    The lecture Analogs: Adenosine, Deoxycytidine, Guanosine/Deoxyguanosine, Thymidine, Deoxyuridine by Kevin Ahern, PhD is from the course Purine and Pyrimidine Metabolism.

    Author of lecture Analogs: Adenosine, Deoxycytidine, Guanosine/Deoxyguanosine, Thymidine, Deoxyuridine

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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