Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors.
J Med Chem
; 51(18): 5494-7, 2008 Sep 25.
Article
in En
| MEDLINE
| ID: mdl-18800759
ABSTRACT
A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Biological Products
/
Genetic Engineering
/
Benzoquinones
/
HSP90 Heat-Shock Proteins
/
Lactams, Macrocyclic
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2008
Document type:
Article
Affiliation country:
Reino Unido