Potent cytotoxic C-11 modified geldanamycin analogues.
17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.
Tian
Zong-Qiang
ZQ
Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, California 94545, USA.
Wang
Zhan
Z
MacMillan
Karen S
KS
Zhou
Yiqing
Y
Carreras
Christopher W
CW
Mueller
Thomas
T
Myles
David C
DC
Liu
Yaoquan
Y
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004952:Esters; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D016227:Benzoquinones; D004952:Esters; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011355:Prodrugs; C112765:tanespimycin; C001277:geldanamycin