Antimetabolites Flashcards
What is the difference between nucleosides and nucleotides?
What is the difference between DNA and RNA?
nucleoside - base + sugar
nucleotide - base + sugar + phosphate (at C5 or C3)
RNA nucleotide
- has ribose sugar (2 x OH are cis)
DNA nucleotide
- has 2-deoxyribose sugar (1 x OH + 1 x H)
Why are nucleosides used as antivirals and nucleotides as antimetabolites?
nucleosides
- do not have charged phosphate groups so can cross the cell membranes
How and why does RNA undergo alkaline hydrolysis?
alkaline hydrolysis
- phosphate is deprotonated and substituted at the 3 position
RNA is easily cleaved, synthesised when needed and degraded once it has served its purpose vs DNA is preserved
Which bases are pyrimidines and which are purines?
pyrimidines
- cytosine (C), thymine (T) and uracil (U)
purines
- adenosine (A) and guanine (G)
How are DNA and RNA synthesised?
new nucleotides are added at the 3 end with 5-3 direction growth
- each time a nucleotide is added, a diphosphate is expelled
OH on the base at the 3 position undergoes nucleophilic substitution by attacking the 5 position on the next nucleotide
DNA is synthesised by enzymes called DNA polymerase
RNA is synthesised by enzymes called RNA polymerase
What is the primary structure of DNA/RNA?
nucleotides are held together by phosphate ester linkages
- phosphate esters link 3 position OH of one ribose with the 5 position OH of another
makes the nucleic acid a long unbranched chain with a backbone of sugar and phosphate units with heterocyclic bases protruding from the chains at regular intervals
- for a DNA double helix, bases are on the inside with sugar + phosphate on the outside
What are the features of the DNA double helix?
DNA strands are twisted into a helix around a common axis
bases are planar and parallel to each other on the inside of the helix
sugar+phosphate backbone are wrapped around the bases
have favourable Van der Waals interactions between mutually induced dipoles of adjacent base pairs
- are known as stacking interactions
= contribute to the stability of the double helix
What is the effect of having phosphate in the DNA double helix?
phosphate OH group has a pKa of 2
- at physiological pH, it is in its basic form
= negatively charged
repels nucleophiles thereby preventing phosphate linkages from cleavage
- DNA remains intact/preserved
How is DNA replicated?
DNA polymerase adds nucleotides to the chain
DNA ligase forms phosphodiester bonds
What is fludarabine? What is it used to treat?
is an analogue of adenosine monophosphate (AMP)
- AMP contains ribose sugar vs fludarabine contains arabinose sugar
- contains fluorine to help with partitioning across BBB and cell membranes as it has polar hydrophobicity
ionises at physiological pH due to phosphates allowing trapping in the blood but fluorine aids partitioning
used to treat chronic lymphocytic leukaemia
What is the mechanism of action of fludarabine?
interferes with DNA polymerase
- acts as a substrate for incorporation into DNA which inhibits further DNA synthesis
polar phosphate ion partitions the drug into the blood stream
5-nucleotidase cleaves the phosphate converting it to a nucleoside
nucleoside enters the endothelial cell of a blood vessel tumour via nucleoside specific transport carrier (NSTC)
CDK phosphorylates the nucleoside at the 5 position forming a triphosphate
the triphosphate is incorporated into DNA/RNA at the 3 position
- electron withdrawing F interferes with pi stacking interaction and hydrogen bonding is not as effective
= breaks the secondary structure apart preventing further addition to the chain
What is gemcitabine? What is it used to treat?
is a nucleoside
- has two fluorine at the 3 position
- is hydrophilic
treats
- pancreatic cancer, metastatic bladder cancer, metastatic non-small cell lung cancer
How does gemcitabine work?
mimics cytidine and is incorporated into DNA after three phosphorylations to give dF-dCTP (deoxyfluorine deoxycytidine phosphate)
- creates irreparable error which inhibits further DNA synthesis
