TY - JOUR
T1 - A common pharmacophore for cytotoxic natural products that stabilize microtubules
AU - Ojima, Iwao
AU - Chakravarty, Subrata
AU - Inoue, Tadashi
AU - Lin, Songnian
AU - He, Lifeng
AU - Horwitz, Susan Band
AU - Kuduk, Scott D.
AU - Danishefsky, Samuel J.
PY - 1999/4/13
Y1 - 1999/4/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033551046&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033551046&partnerID=8YFLogxK
U2 - 10.1073/pnas.96.8.4256
DO - 10.1073/pnas.96.8.4256
M3 - Article
C2 - 10200249
AN - SCOPUS:0033551046
SN - 0027-8424
VL - 96
SP - 4256
EP - 4261
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
ER -