Synthesis and Antitumor Activity of Nonsymmetric Phosphoric Acid Triamides
527
Compound IV. Yield, 3.20 g (42%); m.p., 104 – 106°C
(ether); C13H26N3O3P; 1H NMR spectrum (d, ppm):
0.50 – 2.10 (m, 9H, C5H9-cyclohexyl), 1.17 (t, 3H,
CH3CH2), 1.97 (d, 4H, aziridine); 2.24 (bm, 1H, NH), 2.66
(d, 6H, CH3NCH3), 3.00 (m, 1H, CHN), 4.03 (q, 2H, CH2O).
Yields and physicochemical characteristics of com-
pounds I – XII were reported elsewhere [5, 6].
inhibited the growth of sarcoma M-1. Moderate antitumor ef-
fect was observed for compounds I – III on the Pliss
lymphosarcoma model and for compounds II, V, and VI on
the sarcoma 180 model. At the same time all these com-
pounds weakly affected the growth of other tumors and the
average lifetime. In comparison with the most active
triamides, the reference drug thiophosphamide exhibited a
lower antitumor activity with respect to Walker’s carcinosar-
coma (W-256), but more actively inhibited the growth of sar-
coma 180 and lymphoid leukosis (L-1200).
EXPERIMENTAL BIOLOGICAL PART
Thus, the results of our experiments showed that the
antitumor activity of nonsymmetric phosphoric acid triami-
des is determined for the most part by the nature of amide re-
sidues attached at the phosphorus atom. The antitumor effect
can be varied within a broad range by changing this residue,
the maximum antitumor activity being inherent in non-
symmetric triamides containing the ethyleneimine residue.
The acute toxicity of the synthesized compounds was
studied upon single intraperitoneal injections with 1% starch
jelly to male ICR mice weighing 20 – 22 g [7]. The toxicity
parameters were estimated according to the Litch-
field – Wilcoxon method. The data were statistically pro-
cessed in terms of the Student t-criterion [8].
The antitumor activity was studied on rats (90 – 110 g)
inoculated with strains of Walker’sascites carcinosarcoma
(W-256), sarcoma M-1 (SM-1), and Pliss lymphosarcoma
(PLS) and on C57BP and DBA12 mice inoculated with sar-
coma 180 (S-180), epidermoid Lewis lung carcinoma (LLC),
and lymphoid leukemia (L-1210). The strains of experimen-
tal tumor models were obtained from the Blokhin Oncologic
Research Center (Russian Academy of Sciences, Moscow).
The tumors were transplanted by conventional methods [9].
The compounds to be tested were intraperitoneally injected
at a single daily therapeutic dose (TD) over a period of 5
days. The antitumor activity was evaluated either by the per-
centage tumor growth inhibition (TGI) determined on the
seventh day after termination of treatment or by the percent-
age lifetime increase (LTI) in the test groups relative to un-
treated control. The animals were kept under standard condi-
tions recommended in the literature [9 – 12]. The acute tox-
icity and antitumor activity of the test compounds were
compared to the analogous data for thiophosphamide (TPP).
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RESULTS AND DISCUSSION
10. Guide for the Care and Use of Laboratory Animals, D. C.,
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11. European Convention for the Protection of Vertebrate Animals
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As seen from the experimental data presented in Table 1,
all the tested compounds I – XII possess a lower antitumor
activity as compared to that of the reference drug thiophos-
phamide. Compounds I – III, V, and VI showed a pro-
nounced antitumor effect with respect to Walker’s carcino-
sarcoma (W-256), and compounds I – III, VI, XII strongly
12. Euthanasia of Experimental Animals, European Commission
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