Minor groove recognition

1
Minor groove recognition
Major groove widefits proteins better also
hydrophilic
Minor groove narrow, small linear molecules fit
more snugly along groove. The spine of
hydration is displaced
Minor groove hydrophobic, lined with sugar C atoms
Opportunities for all types of interaction Van
der Waals H-bonding Electrostatic p-p stacking
Minor groove binding
2
Minor groove recognition sites for H-bonding
Drugs prefer AT rich regions because amino of G
projects into groove, clashing with drugs
3
Distamycin and Netropsin
Oligopeptide-like Antivirals
Naturally curved, fit groove
Cationic charge at one or both ends,
electrostatic to phosphate or charged H-bonds to
bases. Amidine is delocalised cation
4
11 complex
21 complex
5
Retrosynthesis of Distamycin
Modified oligopeptide
Unnatural amino acid unit
6
Synthesis of Distamycin I
Activating and directing
7
Synthesis of Distamycin II
8
Synthesis of Distamycin III
9
Synthesis of Distamycin IV
Distamycin
Mild formylation under neutral conditions
10
Combine minor groove recognition with alkylation
chemistry
Antitumour agents
11
Synthetic polyamides (Dervan et al)
G
Synthetic polayamides designed to bind to
block expression of genes in cells