Abstract
Development of the DNA gyrase inhibitor, novobiocin, into a selective Hsp90 inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit ∼700-fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other cancer cell lines. Utilization of structure-activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest midnanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Anti-Bacterial Agents / chemistry
-
Anti-Bacterial Agents / pharmacology
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Carbohydrates / chemistry
-
Cell Line, Tumor
-
Cell Proliferation / drug effects*
-
Coumarins / chemistry*
-
Coumarins / pharmacology
-
Drug Design*
-
Female
-
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
-
HSP90 Heat-Shock Proteins / chemistry
-
HSP90 Heat-Shock Proteins / metabolism
-
Humans
-
Male
-
Molecular Structure
-
Molecular Targeted Therapy
-
Neoplasms / drug therapy*
-
Novobiocin / analogs & derivatives*
-
Novobiocin / chemistry
-
Novobiocin / pharmacology
-
Structure-Activity Relationship
Substances
-
Anti-Bacterial Agents
-
Antineoplastic Agents
-
Carbohydrates
-
Coumarins
-
HSP90 Heat-Shock Proteins
-
Novobiocin