Synthesis and biological evaluation of C-3'-modified analogs of 9(R)-dihydrotaxol.
Taxol (1) is considered a most exciting new drug in cancer chemotherapy. The promising antitumor activity of 9(R)-dihydrotaxol (3) encouraged us to further explore the structure-activity relationship of this new member of the taxane family. Studies indicated that the C-13 side chain of taxol is indispensable for antitumor activity and that the natural substitution pattern of a 2'(R)-hydroxy and a 3'(S)-acylamino group might be optimal. However, relatively little is known about the effects of the 3'-phenyl ring on activity. The synthesis and biological evaluation of analogs of 3 modified at the C-3' position are described. This study revealed that the 3'-phenyl ring was not required for activity and identified several compounds which had equal or greater in vitro and in vivo activity than taxol.
Li
L
L
Anti-Infective Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500.
Thomas
S A
SA
Klein
L L
LL
Yeung
C M
CM
Maring
C J
CJ
Grampovnik
D J
DJ
Lartey
P A
PA
Plattner
J J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D007202:Indicators and Reagents; D008175:Lung Neoplasms / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D043823:Taxoids
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D043823:Taxoids; C088970:9-dihydrotaxol; D017239:Paclitaxel