Communications to the Editor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3305
Ta ble 1. Effects of Compounds 1-5 on PI-PLC and
and 4 was begun 4 days after tumor inoculation in
groups of 8 mice as 4 daily intraperitoneal injections of
the compounds suspended in 3% EtOH, 3% Tween 20,
0.9% NaCl. Tumor volume was measured with calipers
on day 10. As shown in Table 2, compound 1 was lethal
at a daily dose of 500 mg/kg and exhibited no antitumor
activity at one-half this dose. Compound 4 was not toxic
at the highest dose tested of 150 mg/kg/day and inhib-
ited tumor growth by 67%. There was no antitumor
activity at doses of 100 and 50 mg/kg/day.
PI-3-kinase Activity and Growth Inhibition of HT-29 in Vitro
IC50 (µM)
compd
PI-PLC
PI-3-K
growth inhibition HT-29
1
2
3
4
5
N/Ab
8
>250a
30
35a
37
N/Ab
19.9
10
N/Ab
2.5
10
2.1
45
5.3
a
b
Reported in ref 16. N/A, not active, with <20% inhibition at
100 µM.
In summary, we present the synthesis and the bio-
activity of several rationally designed phosphatidyli-
nositol analogues. Further studies of these compounds
in animals using other tumor xenografts will be reported
in due course.
Ta ble 2. Antitumor Activity of 1 and 4 against HT-29 Human
Colon in Scid Mice
compd dose
(mg/kg)
tumor volb on
day 10 (cm3)
schedulea
T/C (%)
Pc
control
1
500
250
4
0.27 ( 0.04
Ack n ow led gm en t. This work was supported by the
National Institute of Health Grants No. CA61015 and
CA42286.
ip, qd 4-5
ip, qd 4-7
lethal
0.30 ( 0.06
111.1
NS
150
100
50
ip, qd 4-7
ip, qd 4-7
ip, qd 4-7
0.09 ( 0.07
0.32 ( 0.09
0.28 ( 0.05
33.3
118.0
103.7
<0.05
NS
NS
Refer en ces
a
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e.g., 250 mg/kg ip, qd 4-7 means that the 250 mg/kg dose was
given as an intraperitoneal injection each day from days 4 to 7 (4
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b
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group; 0.05 is usually the maximum value for significance. NS,
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Final hydrogenation furnished the desired phosphonate
5.
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Preliminary studies of in vivo antitumor activity were
conducted in scid (severe combined immunodeficient)
mice implanted subcutaneously with 107 HT-29 human
colon adenocarcinoma cells. Injection of compounds 1