Journal of Medicinal Chemistry, 1970, Vol. 13, S o .
NOTES
4
769
TABLE I ACTIVITIES
OF
AROMSTIC SCHIFF BASESAGAINST
INTRAMVSCULAR
WALKER
SARCOMAa
R ’C,HaCH=X C gH rR
n
Reference
n’
hIax tolerated dose,b mg/kg
T/C a t t h e max tolerated doseC
xc
Zd
Za
z 7r’
Log ( C / T a t t h e max --tolerated dose)-Ohsd Calod
2-OH d 400 O..X 0.29 1.22 0.68 -0.54 0.236 0.224 2-OH e 400 0..59 -0.07 1. 2 L 0 51 -0.54 0 229 0.132 0.52 -0.d4 0.076 0.132 -0.17 1.22 0.84 2-OH 400 -0.34 0.137 0.128 1.22 -0.54 0.73 1.22 9 23 2-OH -0.54 1.22 0.22 -0.021 0.096 1..59 1.05 h 400 2-OH -0.33 -0.;i4 0.05.5 0.038 0.12 1.22 0.12 i 400 %-OH -0.04 -O..i4 0 013 0.004 -0.27 1.22 0.97 j 400 2-OH -0.23 -0.34 0.041 0 086 1.99 1.22 0.91 2-OH k 400 2-NOz 0.24 -0..54 -0.004 0.074 0.78 1.22 I 400 1.01 4-NO2 2-OH -0.30 -0.54 2.00 1.22 0.123 0.096 0,73 2-OH m 400 2-OH-4-NO2 2-OH-5-NO2 2-OH m 400 0.62 1.93 1.22 -0.43 -0.*54 0 208 0.120 -0..54 -0,041 -0 004 1.22 0.10 1.10 -0.83 n 500 4-N(CH,)z 2-OH 0.12 -O..i4 0.114 0.040 1.22 0.77 0.41 e 400 4-COyH 2-OH 0.00 0.00 0.22 -0.68 -0 088 1 . d9 1.17 H 0 400 2-OH-5-Cl 0.00 -0.083 -0.063 -0.43 1.93 0.00 0 400 1.21 2-OH-5-XOz H -0,155 -0.020 -0.61 -0.04 -0.37 -0.27 m 400 1.43 4-OH 4-OCHj 0.060 -0.024 0.22 -0 04 1.59 -0.27 m 400 0.87 2-OH-3-C1 4-OCH3 -0.43 -0.04 0.070 0 000 1.93 -0.27 Y 400 0. 2-OH-.i-N02 4-OCH3 -0.04.5 -0.024 -0.30 -0.04 2.00 -0.83 ?71 400 1.11 2-OH-4-XOy 4-OCHj -0.83 -0.54 0.33 -0.068 0.006 1.17 1.22 9 400 2-OH 4-X(CH3)y -0.047 0.33 0 081 0.83 0.10 -0.83 -0.49 4-S(CH3)? T ~ L 400 3-011 4-OH 4-N(CH3)2 p 400 0.98 -0.37 -0.83 -0.61 0.33 0.009 -0.022 0.33 -0.068 -0,026 -0.83 0.22 1.69 q 400 1.17 4-K(CH3), 2-OH-3-Cl 0.33 -0.045 -0,002 1.93 -0.83 0.43 9 400 1.11 4-N(CH3)2 2-OH-5-NOz a The screening data were supplied through the kindness of Dr. Harry B. Wood, Jr., of the Cancer Chemotherapy National Service Center, National Institutes of Health, Bethesda, Md. Assays were performed according to CCXSC specifications in Cancer Chemother. Effectiveness against intramuscular Walker sarcoma of the rat is measured by Rep., 25, 1 (1962). b One dose daily for 4 dags. weights of tumors of treated rats ( T )compared with the tumors of control rats (C); the value of T I C must’ be 0.53 or less for significant P. I. Schwab, Ber., 34,833 (1901). e A. Senier and F. G. Shepheard, J . Chem. SOC.,95, 1943 (1909). activity. d A. Hantzsch and 0. Ittyerah and K. C. Pandya, J . Indian Chem. SOC.,30, 717 (1953). 0 A. W. Baker and A. T. Shulgin, J . d m e r . Chem. Soc., 81, 1523 (1959). h J. Argauer and C. E. White, Anal. Chem., 36, 2141 (1964). A. Senier, F. G. Shepheard, and R. Clarke, J . Chem. Soc., 101, 1950 (1912). i A. Hantzsch and E. Wechsler, Justus Liebigs A n n . Chem., 325, 226 (1902). 11p 113.5-114’. dnal. (CI3Hl0E. SI. Hodnett and C. Capshew, Proc. Okla. dcad. Science, in press. N203) C , H, N. F. G. Pope, J . Chem. Soc., 93, 532 (1908). H. A. Torrey, Amer. Chem. J . , 34, 474 (1905). 0 L. C. Raiford and J . Linsk, J . Amer. Chem. Soc., 67, 878 (1945). p G. Smets and A . Delvau, Bull. Chim. Belges, 56, 106 (1947). L. Iluslin, W. Roth, and H. Erlenmeyer, Helv. Chim. Acta, 36,886 (1953). 2-CH3 3-CH3 4-CH3 2-OH 2-OH-5-C1 2-OCH3 4-OCH3
s
TABLE I1 C O N T R I B U ~ ~OF ON SUBSTITL-ESTS S TO ACTIVITY AGAINST INTRAYUSCULAR WILKER SARCOMA^ R’CeH4CH=?;CeH,R
R’ 2-H 2-OH
ab
CIT at maximum tolerated dose
-0,272 0.230
R
2-H 2-CH3 2-OH 4-H 15 -0.054 2-OCHj 4-OCHa 4 0.034 2-NOg 4-N(CH3)2 5 0.136 3-H 3-CH3 3-OH 4-H 4-CI13 4-OH 4-OCHa 4-XOa 4-N(CH3)r 4-COrH 5-H 5-NOn 5-c1 a The overall C/T a t rnaximum tolerated dose nrimber of compounds with each substituent. 11 13
nb
CiT at maximum tolerated dose
9 -0.178 1 0.315 12 0.10j 1 -0.06.5 1 -0.105 22 -0.051 1 0.612 1 0.521 13 -0.024 1 0.139 2 0.161 1 -0.021 3 -0.061 1 -0.142 1 0.249 16 -0.011 4 0.111 4 -0.066 is 1.116. The
some conclusions may be drawn from the results of this study. Better correlation of antitumor effects is obtained with substituents of the aldehyde moiety than with those of the amine group. This fact may indicate that the aldehyde group is more important to the antitumor value than the amine group is. Results of the correlation of antitumor activity of the Schiff bases from salicylaldehyde are somewhat better than those of the Schiff bases from all the aldehydes, but not as much as might be expected from the greater similarity of the Schiff bases from salicylaldehyde. The best correlation is obtained with r 2values; the biological meaning of this is not clear. Substituents with large values of T are desirable for antitumor activity. Increased antitumor activity is related to a large positive value of u ; electron withdrawal from the ring by the substituent group is desirable for antitumor activity. This fact may indicate that molecules containing such electron-withdrawing groups attach to receptor sites better or that stability of the Schiff base (increased by electron-wit hdraming groups) is a desirable factor for antitumor activity of the Schiff bases. Increased antitumor activity is related to large posi-
I
>I e
K! IIa. RI= K,= H h. R, = R1 = Me
J
c, R: = H;R? = hle d. R; = Me: RI= H
li
k.
IIIa. R, = R2= R, = H l\’:i, b.R,=R?=H; R,=C,;H; 11, c. R,= RL= Me; R,3= H c‘. d. R, = H; R2= Me; R3 = H e. R, = H; R2 = Me: R,3=C,,Hf , Rl = Me; R,= R,=
It, = R1 = H; R,,= SHI K , = R , = H ; R;=SH R = R,= Me: R, = NH,
K
=M
~R,;= H: R ; =
H
ePiiL1
H-X-K
&
(;I u
v
17
Glu =
Antineoplastic Research. 1. Pyrazole and Pyrimidine Derivatives of Dehydrocyclohexirnide Analogs’
Cycloheximide? (I),a product of S f r e p t o m y x s yi.iseus cultures, is well known for its ability t’o inhibit protein biosynthe~ie.~This biological action as well as that of emetine, anisomycin, and others is att,ributed to the stereochemical relationships between the S mid 0 atoms of the n i ~ l e c u l e . ~It has also been demonstrated that this relat’ionshipcan be affected by a change in the substitution pattern or stereochemistry at many of the other positions in the molecule.3 11) This work was aided Iiy Grant T-474 from t h e .\nierican C‘ancrs Society a n d Grant 6i-16 from its Illinois Division. (2) .‘ictidinne@. ( 3 ) For recent reports see 13. S. 13aliga. .\. IT. P r o n c z u k . a n d FI. S . Munro, .I. B i d . Chem., 244, 4480 (1969); 1.Geller, F. Robustelli, 6 . H. Barondes. €5. D. Cohen, a n d .\I. E.Jarvik. E a y c h o p h a r m n c o l o g i n , 14, 371 (1969): .J. A. I3urdman a n d L. J. .Journey, .I. .\‘eurochem., 16, 493 (1969); S. D. J. Y e l l a n d AI. Shils, Biochem. f’harmacd., 18, 1919 (1969). (4) ‘1. 1’. Grollrnan, Science, 157, 81 (1967): Proc. S a t . - < r ( i d . 56, 1867 (1966). ( 5 ) 11. I). Sisler and AI. 11. Siegel. in “.\ntih a n d 1’. I). Slmn.. Ed., Springer-Terlag. S e n Ilor
In order to estab1i.h lurthcr points about the structure-activity relationfhips of thefe molecules we have undertaken :t program directed toward the yynth several modified glutarimide antibiotic*. Durir courqe of the.? itudies we had occasion to prepare :I :I few dehydroc) cloheximide type compounds I1 which could :ilm be converted into a variety of heterocyclic compound,. through the 1,:S-diLetone system. € 3 7 ~ 1 1 though we would be destroying the essential iteroochemical feature-, the combination of the salient part. of cycloheximide with heterocjdic \ > . h t e r n \ :ippe:irod attractive for it- biological potential. Thc required 1,3-dihetone. I1 and 1’ n ere preparetl from the rnaminr~ of the appropriatelj 5ubstitutid ketont. :ml the :icid chloride of 2-(P-glutariniido)ac~,tic acid :iceording to the ac:.latioii procedure dewloped h j ,Johnion, rf al. ,fi in their elegant total \ynth+ih of c) cloheximide Though Struck :ind c0workt3r3~ h:d pr(1pared dibetone. I1:i.c.d by :I similar method, v t’ fourrtl the ,Johri~onmodific:ition. generally g a v ~much bettt.1 yields. Uehydrocyclolieximidr (IIb) was more prepared by the ,Tone\’ oxidation of cycloheuimi at ambient tenqxrature.’ The p? raxole derivative. 111 :ind V I were i > : i + i l ~ . formcd by t h r wtion of hydrazine and phenylhydrazint. o n the 1,3-clil\c.toiw- Although we have indicated the r l , u \ a h j \ C I’atun, a n d \ \ C’arlyon J 1866) T\ e h a \ e asslgned t h e ztereocllemi‘ti i a t C -2 a s depicted hecauqe of t h e argiiirient5 presented h \ these n o r h ~ r 5 (71 I1 F Struck. F1 3 scliaeffer A Krauth, R T Kernp 1 I hlieali, a n d J \ A l o n t y o m e n , J W e d Chem , 7 , 646 (1964) (8) l i e l d s n e r e generallj 70-80V0 decidedl\ better t h a n t h e CrOs-I10 \c niethod ongmall) used h g h C. Iiornheld I1 G Jones, a n d T 1 P a r k e [I $ m e r Chem SOC 71, 1 5 0 (194911
r
