AT L1 Minor groove binders Flashcards
Name 3 covalent minor groove binders
PBDs
CPIs
Mitomycin C
Name 2 non-covalent minor groove binders
distamycin
netropsin
What is the shape of a minor groove binder
flat (planar) polyaromatic structures with a natural twist to fit minor groove
2 interaction of the minor groove binder and the DNA
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)
How could we modify non-covalent compounds do find new compounds
add alkylation moeties (mustards, epoxides)
how could we modify covalent compounds to find new compounds
link together to produce cross-linkers (inter and intra strand)
2 targets on the bases of the minor groove
NH2 of G
N3 of A
Overall mode of action of non-covalent minor groove binders
bind tightyly disrupting function and stiffeningthe duplex - more dfficult for strands to come appart
What site of alkylation of mitomycin C causes destbilisation
N2
What was the first CPI (cycloporpyrroloindole) based antitumour drug?
CC-1065
ethano bridges cause DNA to over-wind leading to dose limiting tox and death
What 2 further CPI based antitumour drugs were made?
Adozelosin - little advantage over other compounds
Bizelesin - 1000x more potent
Why is bizelasin more 1000 xpotent?
two warheads stuck together - problematic for repair as sterochemistry means it will always cross link DNA.
Therefore you are left with no repair template.
Problem with bizelain?
potent but virtually insoluble
What is a Hoogsteen base pair?
points on the back of the adenine bond - little idea of clinical significance.
Found where two adozelesin molecules overlap
Contrast binding of adozelosin and bizelasin
Adozelosin - two stands alkylated and not connected
Bizelesin - intrastrand cross links, less easily repaired as no template strand
Why is it good that bizelasin causes lots of Hoogsteen and open base pairs
makes it harder for repair molecules to recognise base pairs
CPI based tumour drugs regonise what series of base pairs?
series of adenine which is very stable and causes a kink
NAME 3 original: Pyrrolo(1,4)benzodiazepine (PBD) antitumor antibiotics
Tomayamycin
Anthramycin
Sibiromycin
Search for better PBD compounds lead to synth of…
DC81 and then dimers DSB-120 (easy to synth) AT-486 (difficult to synth) SJG-136 (current drug candidate)
What form of the PBD is widerly believed to react with DNA?
What is the mode of action
imine or carminolamine
C11 of PDB bonds with N2 of guanine (brought closer by non-covalent bonds)
Reaction between PBD and DNA is reversible so
PBD walks up and down the DNA looking for tastiest guanine
Mode of action of SJG-136
forms inter AND intra strand cross-links. Both are bad.
Stabilizes the duplex so the strand stiffens and won’t unwind for repair.
5 mechanisms of targetting DNA alkylation to the tumour
- pro-drugs
- size (based on increased permeability)
- hypoxia based targetting
- DNA specific structural targets (telomeres)
- antibody based taretting
How many base pairs would be needed to target a single place in the human genome
14-18 - however the dimers recongise 6 and are already pretty much insoluble
rational behind bizelasin design?
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