L11. NA as drug targets Flashcards
Intercalating agents contain what ring systems?
Planar aromatic or heteroaromatic rings
True or False?
Intercalation only prevents replication, not transcription.
False.
Intercalation prevents replication and transcription, finally leading to cell death
How does the mechanism of intercalating agents work?
- Planar systems slip between the base-pair layers and disrupt the shape of the helix
- The aromatic/heteroaromatic rings are held there by van der Waals interactions with the base pairs above and below
- Ionized groups of some drugs can interact with the charged phosphate groups of the DNA backbone, thus strengthening the interaction
Define Proflavine and its structure.
Proflavine is an intercalating agent with a Planar tricyclic system
- The amino substituents are protonated and charged at pH7
- Targets bacterial DNA
What is the mechanism of Proflavine?
- Flat tricyclic ring intercalates between the DNA base pairs and interacts with them via van der Waals forces.
- Aminium cations form ionic bonds with the negatively charged phosphate groups
- This deforms the DNA double helix and prevents replication and transcription
True or False?
Some intercalating agents prefer to approach the helix from the major groove while others prefer the minor groove.
True
Proflavine is an antibacterial compound, part of the group called ________ that were used in the World Wars to treat deep surface wounds.
Aminoacridines
This type of antibacterial drug was proved highly effective at preventing infection and reduced the number of fatalities from deep surface wounds during both World Wars.
Aminoacridines
Define dactinomycin and its structure
Dactinomycin is an intercalating agent that contains Cyclic pentapeptides that position themselves on the outside of the helix
- Naturally occurring in antibiotics and was isolated from Streptomyces parvullis
- The complex is very stable and prevents unwinding of DNA double helix
- Prevent DNA-dependent RNA polymerase from catalysing the synthesis of mRNA and transcription
Dactinomycin favors interactions with what base pairs?
Guanine - cytosine base pairs.
Particularly between 2 adjacent guanine pairs on alternative strands of the helix
What is dactinomycin mechanism of action?
It’s planar tricyclic systems intercalates via the minor groove and H-bonds with G-C base pairs.
The charged amino group forms ionic bond with sugar phosphate backbone
Dactinomycin is an effective anticancer treatment for what age group?
Children
Define an Alkylating agent
Highly electrophilic compounds that form covalent bonds to nucleophilic groups in DNA, N-7 of guanine in particular.
These compounds result in miscoding and ultimately prevent replication and transcription
_______ is the transfer of an alkyl group.
Alkylation
What is miscoding?
Miscoding leads to an alteration in the amino acid sequence of proteins, which, in turn, can lead to disruption of protein structure and function
How do alkylating agents result in miscoding?
Guanine normally exists mainly as a keto tautomer and readily makes base-pair with cytosine by H-bonding.
When the N-7 of guanine is alkylated, the guanine residue becomes more acidic, and an the keto tautomer is turned to an enol tautomer which is more favored and more likely to base pair with thymine, resulting in a miscoding.
How do alkylating agents prevent replication and transcription?
They cause interstrand and intrastrand crosslinking if two electrophilic groups present. This masks that portion of DNA from the enzymes required for replication and transcription.
Define Chlormethine
An alkylating agent where the N displaces Cl intramolecularly to form the highly electrophilic aziridinium ion that will bind to DNA forming a crosslink.
- The N replacing the Cl is an example of the neighboring group effect, called anchimeric assistance
_________ was the first alkylating agent to be used medically.
Chlormethine
Define Mitomycin C
It is a Prodrug, activated in the body to form an alkylating agent that inhibits DNA synthesis by producing DNA cross-links which halt cell replication and eventually cause cell death.
• One of the most toxic anticancer drugs in clinical use
An improved version of Chlormethine is called _________.
Cyclophosphamide
What is a Prodrug?
A prodrug is a medication or compound that remains inactive until administered into the body, where it is metabolized (i.e., converted within the body) into a pharmacologically active drug
How is Mitomycin C formed?
It is formed from the enzyme-catalyized reduction of quinone to form hydroquinone
True or False?
Prodrugs are not drugs until they enter the body because they are achiral outside the body
True
________ is an antitumor antibiotic that is made from a soil fungus called Streptomyces caespitosus.
Mitomycin
What is Mitomycin C mechanism of action?
Intiated by enzyme-cataylized reduction of quinone to hydroquinone.
Guanine residues on DNA are then alkylated, leading to intrastrand crosslinking and inhibition of DNA replication and cell division
Because a reduction step is involved in Mitomycin C mechanism of action, it has been proposed that this drug would be more effective in what type of environment?
a hypoxic (O2 starved) environment. i.e. the center of solid tumor masses
The following agent is used for the treatment of testicular and ovarian cancers.
What is the name of this drug?
Which of the following statements is untrue regarding the structure?
a) The chlorine groups are displaced before the drug becomes active.
b) Intrastrand cross linking of DNA results from the action of the agent.
c) Base pairing between adenine and thymine is disrupted by the agent.
d) The compound acts as a metallating agent
Cisplatin
c) Base pairing between adenine and thymine is disrupted by the agent.
* This drug binds to DNA in regions rich in guanine units
What term is used to describe the strategy where an oligonucleotide is designed such that it base pairs with a segment of messenger RNA and blocks protein translation?
Antisense Therapy
This structure is a prodrug which is converted in the body to the active compound. What is the name of this structure and what is the initial step in its activation process?
a. Ring opening of the aziridine ring.
b. Hydrolysis of the urethane group.
c. Alkylation of the primary amino group.
d. Reduction of the quinone ring system.
Mitomycin C
d. Reduction of the quinone ring system.
The what drug is used as an anticancer drug against a variety of cancers.
mitomycin C
Which drug is used for the treatment of Hodgkin’s lymphoma as part of a multi-drug regime?
Chlormethine
What is the name of this drug?
What is the name of the activated species which is formed from this structure and that acts as the actual alkylating agent?
Chlormethine
An aziridinium ion
What is this drug?
Which region of the molecule is chiefly responsible for its ability to intercalate into DNA?
Dactinomycin
The tricyclic system
Which region of the Dactinomycin molecule interacts with the sugar phosphate backbone of DNA?
The amine groups
How does metallation work in synthesis?
In synthesis, metallated reagents are typically involved in nucleophilic substitution, single-electron-transfer (SET), and redox chemistry with functional groups on other molecules (including but not limited to ketones, aldehydes and alkyl halides).
Metallated molecules may also participate in acid-base chemistry, with one organometallic reagent deprotonating an organic molecule to create a new organometallic reagent.
What does Cisplatin work and what does it cause?
Cisplatin is activated in cells with low chloride ion concentration.
Once activated, 1 Chloro substituent is replaced with neutral water ligands, producing a positively charged species that binds to DNA in regions rich in guanine units, making Intrastrand links.
This causes localized unwinding of DNA double helix, inhibiting transcription
What is antisense therapy?
A form of treatment for genetic disorders
How does the mechanism of Cisplatin work?
- Cellular uptake of Cisplatin from the blood into the cytoplasm of the cell
- Aquation/activation: in Aquation, the 2 Cl- substiuients are turned into H2O ligands. In activation, Cisplatin then binds to the N7 and O6 of adjacent guanine molecules on guanine-cytosine base pairs.
- DNA platination: a 1,2-d(GpG) Intrastrand adduct is fromed as the major product. The H-bonds in G-C pair disrupted by the cross-links, causing localized unwinding of the DNA helix and inhibition of transcription, which dirupts:
- Cellular processing leading to apoptosis.
What are chain terminators?
Prodrugs used as antivirals
What is Acyclovir?
A chain terminating antiviral medication.
It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles.
What is the mechanism of Acyclovir?
ACV enters the cell and accumulates. Viral kinase (Thymidine kinase) adds a phosophate to the drug molecule. Cellular kinase comes along and adds 2 more phosophates for a total of 3.
ACV triphosphate incorporated into viral DNA via bonds to Cytosine. This causes an incomplete sugar by lacking the required OH at 3’ position which terminates the chain.
What are the chain termination requirements of Acyclovir?
- It must be recognized by the DNA template by interacting with a base on the template strand
- should have a triphosphate group to undergo the same reaction
- must make it impossible for any further building blocks to be added
What is Azidothymidine?
Azidothymidine (AZT) is a chain terminating prodrug used in the treatment of HIV
What is the mechanism of AZT?
AZT is phosphorylated to a triphosphate in the body which has two mechanisms of action:
- inhibits a viral enzyme (reverse transcriptase)
- is added to growing DNA chain and acts as chain terminator
How does antisense therapy work?
mRNA is intercepted by the antisense oligonucleotide, which makes it impossible for the mRNA to be translated into the protein.
The antisense oligonucleotide recognizes its complementary bases on mRNA and binds to them via H-bonding. This forms a duplex structure that act as a barrier to the translation process, blocking protein synthesis
The double helix is then destroyed by Ribonuclease H, which catalyzes the cleavage of RNA
What are the advantages of antisense therapy?
- Same effect as an enzyme inhibitor or receptor antagonist
- Smaller dose levels required compared to inhibitors or antagonists
because one mRNA leads to several copies of the same protein
• Potentially less side effects
What are the disadvantages of antisense therapy?
- ‘Exposed’ sections of mRNA which is a large molecule with secondary and tertiary structure must be targeted
- Short lifetime of oligonucleotides due to susceptibility to metabolism. Natural oligonucleotides are quickly degraded in the body by nucleases so they are not effective molecules.
- Poor absorption across cell membranes due their charge and polarity
The following compounds (i), (ii) and (iii) are antiviral drugs which mimic natural nucleosides. What nucleosides do they mimic?
i. DEOXYTHYMIDINE
ii. DEOXYGUANICINE
iii. DEOOXYCYTOSIDINE
Proflavine is an intercalating agent which was used to treat wounded soldiers in the second world war. Which of the following statements is false regarding proflavine?
a. It a useful systemic antibacterial agent.
b. Its planar shape is important to intercalation.
c. The primary amine groups are protonated and interact with phosphate groups of the DNA backbone.
d. When inserted into DNA, the tricyclic system can form van der Waals interactions with base pairs above and below it.
a. It a useful systemic antibacterial agent
Proflavine is too toxic to be used systemically since it does not distinguish between the DNA of host cells and those of an invading pathogen. It is used topically for the treatment of infected deep surface wounds.
