AT L1 Minor groove binders

Question 1

Name 3 covalent minor groove binders

Answer 1

PBDs
CPIs
Mitomycin C

Question 2

Name 2 non-covalent minor groove binders

Answer 2

distamycin

netropsin

Question 3

What is the shape of a minor groove binder

Answer 3

flat (planar) polyaromatic structures with a natural twist to fit minor groove

Question 4

2 interaction of the minor groove binder and the DNA

Answer 4

alkylation center at a base of the minor groove

secondary non-covalent interactions important in covalent binfing (won’t react without this holding them in close contact)

Question 5

How could we modify non-covalent compounds do find new compounds

Answer 5

add alkylation moeties (mustards, epoxides)

Question 6

how could we modify covalent compounds to find new compounds

Answer 6

link together to produce cross-linkers (inter and intra strand)

Question 7

2 targets on the bases of the minor groove

Answer 7

NH2 of G

N3 of A

Question 8

Overall mode of action of non-covalent minor groove binders

Answer 8

bind tightyly disrupting function and stiffeningthe duplex - more dfficult for strands to come appart

Question 9

What site of alkylation of mitomycin C causes destbilisation

Answer 9

N2

Question 10

What was the first CPI (cycloporpyrroloindole) based antitumour drug?

Answer 10

CC-1065

ethano bridges cause DNA to over-wind leading to dose limiting tox and death

Question 11

What 2 further CPI based antitumour drugs were made?

Answer 11

Adozelosin - little advantage over other compounds

Bizelesin - 1000x more potent

Question 12

Why is bizelasin more 1000 xpotent?

Answer 12

two warheads stuck together - problematic for repair as sterochemistry means it will always cross link DNA.
Therefore you are left with no repair template.

Question 13

Problem with bizelain?

Answer 13

potent but virtually insoluble

Question 14

What is a Hoogsteen base pair?

Answer 14

points on the back of the adenine bond - little idea of clinical significance.
Found where two adozelesin molecules overlap

Question 15

Contrast binding of adozelosin and bizelasin

Answer 15

Adozelosin - two stands alkylated and not connected

Bizelesin - intrastrand cross links, less easily repaired as no template strand

Question 16

Why is it good that bizelasin causes lots of Hoogsteen and open base pairs

Answer 16

makes it harder for repair molecules to recognise base pairs

Question 17

CPI based tumour drugs regonise what series of base pairs?

Answer 17

series of adenine which is very stable and causes a kink

Question 18

NAME 3 original: Pyrrolo(1,4)benzodiazepine (PBD) antitumor antibiotics

Answer 18

Tomayamycin
Anthramycin
Sibiromycin

Question 19

Search for better PBD compounds lead to synth of…

Answer 19

DC81 
and then dimers
DSB-120 (easy to synth)
AT-486 (difficult to synth)
SJG-136 (current drug candidate)

Question 20

What form of the PBD is widerly believed to react with DNA?

What is the mode of action

Answer 20

imine or carminolamine

C11 of PDB bonds with N2 of guanine (brought closer by non-covalent bonds)

Question 21

Reaction between PBD and DNA is reversible so

Answer 21

PBD walks up and down the DNA looking for tastiest guanine

Question 22

Mode of action of SJG-136

Answer 22

forms inter AND intra strand cross-links. Both are bad.

Stabilizes the duplex so the strand stiffens and won’t unwind for repair.

Question 23

5 mechanisms of targetting DNA alkylation to the tumour

Answer 23

• pro-drugs
• size (based on increased permeability)
• hypoxia based targetting
• DNA specific structural targets (telomeres)
• antibody based taretting

Question 24

How many base pairs would be needed to target a single place in the human genome

Answer 24

14-18 - however the dimers recongise 6 and are already pretty much insoluble

Question 25

rational behind bizelasin design?

Answer 25

remove ethano bridges from CC1065 to stop tox and death producing Adozelosin. Bizelesin is a dimer, 1000x times more potent as sterochem means it must cross link DNA