title: Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti-proliferative agents.
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.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045-7563, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.forename: Alison C
authors.initials: AC
authors.lastname: Donnelly
authors.forename: Bhaskar R
authors.initials: BR
authors.lastname: Kusuma
authors.forename: Gary E L
authors.initials: GE
authors.lastname: Brandt
authors.forename: Douglas
authors.initials: D
authors.lastname: Brown
authors.forename: Roger A
authors.initials: RA
authors.lastname: Rajewski
authors.forename: George
authors.initials: G
authors.lastname: Vielhauer
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Holzbeierlein
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002241:Carbohydrates / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002241:Carbohydrates; D003374:Coumarins; D018841:HSP90 Heat-Shock Proteins; D009675:Novobiocin