A common pharmacophore for cytotoxic natural products that stabilize microtubules.
Taxol (paclitaxel), a complex diterpene obtained from the Pacific yew, Taxus brevifolia, is arguably the most important new drug in cancer chemotherapy. The mechanism of cytotoxic action for paclitaxel-i.e., the stabilization of microtubules leading to mitotic arrest-is now shared by four recently identified natural products, eleutherobin, epothilones A and B, and discodermolide. Their ability to competitively inhibit [3H]paclitaxel binding to microtubules strongly suggests the existence of a common binding site. Recently, we have developed nonaromatic analogues of paclitaxel that maintain high cytotoxicity and tubulin binding (e.g., nonataxel). We now propose a common pharmacophore that unites paclitaxel, nonataxel, the epothilones, eleutherobin, and discodermolide, and rationalizes the extensive structure-activity relationship data pertinent to these compounds. Insights from the common pharmacophore have enabled the development of a hybrid construct with demonstrated cytotoxic and tubulin-binding activity.
Ojima
I
I
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA.
Chakravarty
S
S
Inoue
T
T
Lin
S
S
He
L
L
Horwitz
S B
SB
Kuduk
S D
SD
Danishefsky
S J
SJ
D000470:Alkaloids / Q000737:chemistry / Q000633:toxicity; D000473:Alkanes; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000633:toxicity; D002219:Carbamates; D003196:Computer Graphics; D004224:Diterpenes; D034261:Epothilones; D004852:Epoxy Compounds / Q000737:chemistry / Q000633:toxicity; D007783:Lactones / Q000737:chemistry / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008870:Microtubules / Q000187:drug effects*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000633:toxicity; D011753:Pyrones; D013844:Thiazoles / Q000737:chemistry / Q000633:toxicity
D000470:Alkaloids; D000473:Alkanes; D000972:Antineoplastic Agents, Phytogenic; D002219:Carbamates; D004224:Diterpenes; D034261:Epothilones; D004852:Epoxy Compounds; D007783:Lactones; D011753:Pyrones; D013844:Thiazoles; C109551:eleutherobin; C071229:discodermolide; D017239:Paclitaxel; C093788:epothilone B