Synthesis and biological evaluation of coumarin replacements of novobiocin as Hsp90 inhibitors.
Since Hsp90 modulates all six hallmarks of cancer simultaneously, it has become an attractive target for the development of cancer chemotherapeutics. In an effort to develop more efficacious compounds for Hsp90 inhibition, novobiocin analogues were prepared by replacing the central coumarin core with naphthalene, quinolinone, and quinoline surrogates. These modifications allowed for modification of the 2-position, which was previously unexplored. Biological evaluation of these compounds suggests a hydrophobic pocket about the 2-position of novobiocin. Anti-proliferative activities of these analogues against multiple cancer cell lines identified 2-alkoxyquinoline derivatives to exhibit improved activity.
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, KS 66045-7563, USA.
Bhaskar Reddy
BR
Kusuma
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, KS 66045-7563, USA.
Anuj
A
Khandelwal
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, KS 66045-7563, USA.
Wen
W
Gu
Department of Urology, The University of Kansas Medical Center, 3901 Rainbow Blvd., Mail Stop 1016, Kansas City, KS 66160, USA.
Douglas
D
Brown
Department of Urology, The University of Kansas Medical Center, 3901 Rainbow Blvd., Mail Stop 1016, Kansas City, KS 66160, USA.
Weiya
W
Liu
Department of Urology, The University of Kansas Medical Center, 3901 Rainbow Blvd., Mail Stop 1016, Kansas City, KS 66160, USA.
George
G
Vielhauer
Department of Urology, The University of Kansas Medical Center, 3901 Rainbow Blvd., Mail Stop 1016, Kansas City, KS 66160, USA.
Jeffrey
J
Holzbeierlein
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, KS 66045-7563, USA. Electronic address: bblagg@ku.edu.
Brian S J
BS
Blagg
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D009281:Naphthalenes / Q000737:chemistry; D009675:Novobiocin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000737:chemistry
D000970:Antineoplastic Agents; D003374:Coumarins; D018841:HSP90 Heat-Shock Proteins; D009281:Naphthalenes; D011804:Quinolines; D009675:Novobiocin; C031721:naphthalene; C030123:coumarin; C037219:quinoline
Anti-cancer; Chaperone; Hsp90; Novobiocin