New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models.
During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.
Szczepankiewicz
B G
BG
Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. bruce.g.szczepankiewicz@abbott.com
Liu
G
G
Jae
H S
HS
Tasker
A S
AS
Gunawardana
I W
IW
von Geldern
T W
TW
Gwaltney
S L
SL
Wu-Wong
J R
JR
Gehrke
L
L
Chiou
W J
WJ
Credo
R B
RB
Alder
J D
JD
Nukkala
M A
MA
Zielinski
N A
NA
Jarvis
K
K
Mollison
K W
KW
Frost
D J
DJ
Bauch
J L
JL
Hui
Y H
YH
Claiborne
A K
AK
Li
Q
Q
Rosenberg
S H
SH
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003078:Colchicine / Q000737:chemistry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C442803:A 259745; D000970:Antineoplastic Agents; D010080:Oxazoles; D003078:Colchicine