Chemsitry E-Learning package; Intro and Alkylating Agents

Question 1

Which drugs target DNA in order to have anti-cancer properties?

Answer 1

Doxirubicin
Irinotecan
Bendmustine
Cyclosphosphamide

Question 2

Which bases are purine?

Answer 2

Guanine

Alanine

Question 3

Which bases are pyrimidine?

Answer 3

Cytosine

Thymine

Question 4

Which enzyme is used to initially “unzip” the DNA helix during replication?

Answer 4

Helicase

Question 5

What are the two strands of DNA referred to when they have been unzipped?

Answer 5

Leading and lagging (scumbag) strands

Question 6

How is the leading 5 prime to 3 prime strand replicated?

Answer 6

DNA polymerase facilitates the addition of complementary bases

Question 7

How is the lagging 3 prime to 5 prime strand replicated?

Answer 7

RNA primase attaches at random to the strand acting as a primer and allowing DNA polymerase to begin the replication process, lots of little fragments of the strand are made this way. They are known as OKAZAKI fragments. DNA ligase then connect all of these fragments to make a complementary copied strand.

Question 8

In order for a strand to be complimentary it must be what?

Answer 8

Complementary and antiparallell!

Question 9

Which atoms in adenine can be targeted by alkylation?

Answer 9

N1 and N3 in the benzene ring

Question 10

Which atoms in guanine can be targeted by alkylation

Answer 10

N7 in the 5 carbon ring and O6 off the benzene ring

Question 11

Which atoms in cysteine can be targeted by alkylation

Answer 11

N3 in the benzene ring

Question 12

In this context, what is a lesion? (Noll et al)

Answer 12

Modifications to the DNA in the form of changes to phosphate groups and or base pairs, that lead to mutation or cell death.

Question 13

What is the difference between a monofunctional and a bifunctional akylating agent?

Answer 13

A bifunctional alkylating agent causes interstrand cross-linking (and tumour formation?)
Monofunctional alkylating agents largely
produce point mutations that are readily explained by the
type of alkylation product formed.
The bifunctional cross-linking agents cause chromosomal alterations consistent with DNA strand breakage and hyper-recombination.

Question 14

What is the difference between an intrastrand, and an interstrand, cross-link?

Answer 14

Intrastrand is cross links within the same DNA strand whereas interstrand linking is between the two strands of the DNA helix.

Question 15

Why are interstrand cross links particularly cytotoxic?

Answer 15

Cross strand interlinking gives a physical constraint to the DNA helix, in order to repair this lesion both strands of the DNA must be repaired

Question 16

What is the difference between mutagenic and clastogenic agents?

Answer 16

Cross-linking agents are typically clastogenic rather than
mutagenic. Clastogens are agents that cause damage at the chromosomal level rather than at the DNA sequence level; i.e., a clastogen produces the gain, loss, or rearrangement of chromosomal segments and/or causes sister chromatid exchanges.

Question 17

Interstrand cross-links formed by nitrogen mustards distort the DNA structure, e.g. they may bend it. Can you explain why?

Answer 17

Interstrand cross-link formation occurs almost exclusively
with guanine residues in 5′-GNC-3′ sequences in DNA.49-53
The minimal distance between the guanines in this sequence
is approximately 6.8 Å in B-form DNA, which is more than
the 5.1 Å distance that can be spanned by the five atoms
that comprise the cross-link.27 This constraint would be
expected to produce a distortion of the helix in the region
of the cross-link.

Question 18

Clincially relevant nitrogen mustards?

Where are they derived from?

Answer 18

The metabolism of the drug cyclophosphamide
Produces ; chlorambucil (1), mechlorethamine (2) and
phosphamide mustard (3)