468
Q. Li et al. / Bioorg. Med. Chem. Lett. 12 (2002) 465–469
A-289099 exhibits reasonably good physicochemical
properties. Its solubilities in 0.1 M HCl and pH 7.4 phos-
phate buffer are 1.27 mg/mL and 0.7 mg/mL, respec-
tively. A-289099 has a logD of 3.94 and p Ka of 5.0.
In conclusion, a series of indole containingoxazolines
has been discovered as a result of structural modifica-
tions of the lead compound A-105972. The compounds
exert their anticancer activity through inhibition of
tubulin polymerization by bindingat the colchicine site.
A-289099 was identified as an orally active antimitotic
agent active against various cancer cell lines, including
those that express the MDR phenotype.
Figure 1. Effect of A-289099 on microtubule depolymerization in
HCT-15 cells. Left: control cells. Right: cells treated with 44 nM
A-289099 for 4 h. Green: microtubules, Blue: nuclear DNA.
References and Notes
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157.
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13. A-289099 (5b-S) has [a]2D5 of +195.7ꢀ (c=1.04, CH2Cl2)
(99% ee) and 5b-R has [a]2D5 of À184.5ꢀ (c=1.04, CH2Cl2)
(98% ee). The ee was determined by HPLC on a Chirapack
AS column elutingwith 15% ethanol in hexane.
Figure 2. Stereoview of the superimposed structures of A-289099
(green) and Combretastatin A4 (yellow). Their geometries were opti-
mized usingDISCOVER force field (CFF98).
Table 5. Pharmacokinetic properties of the two enantiomers of 5b
Species
Mousea
PK
5b-S
(A-289099)
5b-R
t1/2 (h)
AUC (mgh/mL)
F (%)
1.1
5.69
15.1
1.3
0.40
21.0
Ratb
t1/2 (h)
AUC (mgh/mL)
F (%)
2.1
7.18
17.1
1.3
3.04
44.0
Dogb
t1/2 (h)
AUC (mgh/mL)
F (%)
3.3
0.16
6.5
2.9
0.33
7.0
Monkeyb
t1/2 (h)
AUC (mgh/mL)
F (%)
1.3
1.75
18.6
1.4
0.89
16.2
aA single 10 mg/kg dose.
bA single 5 mg/kg dose.
Table 6. In vivo efficacy6b of A-289099 in comparison with E7010
against M5076 murine ovarian sarcoma in mice (PO, QD, d1-28)
Compd
Dose
(mg/kg/day)
Mean tumor delay
to 1 g(day)
ILSa (%)
A-289099
E7010
50
100b
50
150b
19.0
28.4
6.4
139
206
47
27.4
201
aIncrease in life span.
bMaximum tolerated dose.
tumor model. When dosed QD, d1-28, at the maximum
tolerated dose, A-289099 achieved 206% increase in life
span and an impressive 28 day delay to 1 gtumor
volume in mice with M5076 murine ovarian sarcoma.
This efficacy is comparable to that of a previously
reported antimitotic agent, E701016 (Table 6).