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Evaluation of N-haloacyl Analogs of α,α-diphenyl-4-piperidinemethanol Against Ehrlich Ascites Carcinoma in Mice
Evaluation of N-Haloacyl Analogs of a,a-Diphenyl-4-piperidinemethano1 Against Ehrlich Ascites Carcinoma in Mice By WIUIAM D. ROLL The antitumor activity of 8 haloamide derivatives of n,a-diphenyl-4-piperidinemethanol was studied in C3H agouti mice against the Ehrlich ascites carcinoma. The preliminary screening studies would seem t o indicate that the chemotherapeutic effect of these compounds is potentially significant. There seems t o be a definite correlation between structure and activity within the propionamide and acetamide analogs i n that within each group of compounds the iodoamides have the highest order of activity; the bromoamides have intermediate activity; and the chloroamides have the least activity. T h e haloacetamide analogs seem t o be more toxic than the corresponding halopropionamide derivatives.
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TABLE DERIVATIVES OF ol,a-DIPHESYL-4paper (1) the synthesis and potential PIPERIDINEMETHANOL antitumor activity of a series of N-haloacyl derivat.ives of a,a-dipheny1-4-piperidinemethanol Compd. wcrc reported. A continuation of the antitumor screening study shows that the compounds (Table I ) 1-(3-Chloropropionyl)-a,a-diphenyl-4-piperidincmethanol ( I ) have significant activity against Ehrlich ascites 1-(2-Chloropropionyl)-a,~-diphenyl-4-piperidi~etumor in C3H mice. methanol (11) l-Chloroacctyl-~,~-diphenyl-4-piperidir~e~1iethanol EXPERIMENTAL' (111) Experiments were performed on 5-10-week-old 1-(3-Bromopropionyl)-~~,a-diphcnyl-4-pipcridincC3H agouti mice purchased from the K. B. Jackson methanol (11') Memorial Laboratory, Bar Harbor, Maine. The I-(2-Bromopropionyl)-a,a-diphenyl-4-piperidincmethanol (17) testing procedure used was similar to that described l-Bromoacetyl-a,a-diphenyt-4-piperidin~m~t~~a~ol by Linder (2) and Hauschka et al. ( 3 ) . (VI) Transplantation of the tumor was carried out by 1-(3-Iodopropionyl)-a, ru-diplicnyl-4-piperidincaseptically withdrawing ascites fluid from a donor methanol ( V I I ) mouse bearing a 7-day ascites tumor. Each expcri1-Iodoacetyl-or,~-dipIienyl-4-piperidi1iemethaiiol mental animal was inoculated i.p. with 2 X lo6 (VIII) ascites cells. Ten animals were used as controls and 10 animals for treatment. Mice were distributed into groups of comparable weight and treatment TABLE II.-RESULTS OF SCREENING TESTSVersus was begun 24 hr. after tumor implantation. The THE EHRLICH ASCITES CARCINOMA" compouuds were administered in peanut oil (1yo) ~and control animals received Corresponding volumes GI-owth of peanut oil alone. Change in body weight was Dosage, Mortality Av. Wt. Inhibimr.,f'Kg.,f' Treated Change, tion noted as a measurc of the accumulation of tumor T I C . Gm. Katio" Compd. Day" Group cells and ascitic fluid. Cell counts were used as a 1.9/4.5 5:l I 20 0/l0 measure of the inhibition of tumor cell growth. 2:l 20 0/10 0.5/4.4 I1 The dosages recorded in Table I1 were administered 111 10 0/10 -l.T/3.5 3:1 in single intraperitoneal injections per day com3 2/5 3 2O:l Iv 20 0/10 mencing 24 hr. after transplantation of the tumor v 20 0/10 - 1 .6 / 4 .5 13:l and continuing for 3 days. The results recorded -3.6/4.1 32:l vI 10 2/10 T5:l 20 0/10 0.6/4 5 VII in Table I1 were determined on the sixth day after 27:l 10 0/10 --2.1/4.2 VIII intrapcritoiieal transplantation of the tumor. N A PREVIOUS
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RESULTS
The chemotherapeutic activity of the halopropionamide analogs ( I , I V , VTI) against ascites tumor showed that the iodopropionyl derivative (VII) exhibited the greatest inhibition, and the relative activity within this group of compounds was VII > I V > I. Thc same ordcr of activity was Received December 20, 1965, from the College of I'harmacy. TJniversity of Toledo, Toledo, Ohio. Accepted for publication January 13, 1966. This investigation was supported by a prant from t h e College of Pharmacy Research Fund, University of Toledo, and Maumee Valley Hospital, Toledo, Ohio. 1 The author wishes to thank Dr. Robert J. Schlembach and members of the staff of Maumee Valley Hospital, Toledo, Ohio, for their assistance in the testing of these componnds; and Dr. Dante Scarpelli, Ohio State University. fnr providing us with the original donor animals.
a T = treated group. C = contiol group. Katio o f the total number of turnor' cells in control mice t o number in treated animals. Represents one-half the I.Dso as determined in C3H mice.
noted with regard to thc haloacetamidc analogs: iodoacetamide > bromoacctamidc > chloroacctamide. The toxicity of haloacetyl dcrivatives was greater than that of the halopropionyl analogs. (See Footnote I;,Table 11.) REFERENCES (1) Roll, W. D., J. Phnvm. S c i . , 5 4 , 269(196.5). ( 2 ) Lindei-, A,, Concrv Rps., 19, 189(1959). (3) Hauschka, T. S Patt, H. M . , Sassenrath, E. N.. and Tarnowski, G. S.. C&eiit K e s . Cancer C h e n m l h e r a p y , Repol-t No. 8 , 19.56, p. 23.
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TABLE DERIVATIVES OF ol,a-DIPHESYL-4paper (1) the synthesis and potential PIPERIDINEMETHANOL antitumor activity of a series of N-haloacyl derivat.ives of a,a-dipheny1-4-piperidinemethanol Compd. wcrc reported. A continuation of the antitumor screening study shows that the compounds (Table I ) 1-(3-Chloropropionyl)-a,a-diphenyl-4-piperidincmethanol ( I ) have significant activity against Ehrlich ascites 1-(2-Chloropropionyl)-a,~-diphenyl-4-piperidi~etumor in C3H mice. methanol (11) l-Chloroacctyl-~,~-diphenyl-4-piperidir~e~1iethanol EXPERIMENTAL' (111) Experiments were performed on 5-10-week-old 1-(3-Bromopropionyl)-~~,a-diphcnyl-4-pipcridincC3H agouti mice purchased from the K. B. Jackson methanol (11') Memorial Laboratory, Bar Harbor, Maine. The I-(2-Bromopropionyl)-a,a-diphenyl-4-piperidincmethanol (17) testing procedure used was similar to that described l-Bromoacetyl-a,a-diphenyt-4-piperidin~m~t~~a~ol by Linder (2) and Hauschka et al. ( 3 ) . (VI) Transplantation of the tumor was carried out by 1-(3-Iodopropionyl)-a, ru-diplicnyl-4-piperidincaseptically withdrawing ascites fluid from a donor methanol ( V I I ) mouse bearing a 7-day ascites tumor. Each expcri1-Iodoacetyl-or,~-dipIienyl-4-piperidi1iemethaiiol mental animal was inoculated i.p. with 2 X lo6 (VIII) ascites cells. Ten animals were used as controls and 10 animals for treatment. Mice were distributed into groups of comparable weight and treatment TABLE II.-RESULTS OF SCREENING TESTSVersus was begun 24 hr. after tumor implantation. The THE EHRLICH ASCITES CARCINOMA" compouuds were administered in peanut oil (1yo) ~and control animals received Corresponding volumes GI-owth of peanut oil alone. Change in body weight was Dosage, Mortality Av. Wt. Inhibimr.,f'Kg.,f' Treated Change, tion noted as a measurc of the accumulation of tumor T I C . Gm. Katio" Compd. Day" Group cells and ascitic fluid. Cell counts were used as a 1.9/4.5 5:l I 20 0/l0 measure of the inhibition of tumor cell growth. 2:l 20 0/10 0.5/4.4 I1 The dosages recorded in Table I1 were administered 111 10 0/10 -l.T/3.5 3:1 in single intraperitoneal injections per day com3 2/5 3 2O:l Iv 20 0/10 mencing 24 hr. after transplantation of the tumor v 20 0/10 - 1 .6 / 4 .5 13:l and continuing for 3 days. The results recorded -3.6/4.1 32:l vI 10 2/10 T5:l 20 0/10 0.6/4 5 VII in Table I1 were determined on the sixth day after 27:l 10 0/10 --2.1/4.2 VIII intrapcritoiieal transplantation of the tumor. N A PREVIOUS
~~
~
RESULTS
The chemotherapeutic activity of the halopropionamide analogs ( I , I V , VTI) against ascites tumor showed that the iodopropionyl derivative (VII) exhibited the greatest inhibition, and the relative activity within this group of compounds was VII > I V > I. Thc same ordcr of activity was Received December 20, 1965, from the College of I'harmacy. TJniversity of Toledo, Toledo, Ohio. Accepted for publication January 13, 1966. This investigation was supported by a prant from t h e College of Pharmacy Research Fund, University of Toledo, and Maumee Valley Hospital, Toledo, Ohio. 1 The author wishes to thank Dr. Robert J. Schlembach and members of the staff of Maumee Valley Hospital, Toledo, Ohio, for their assistance in the testing of these componnds; and Dr. Dante Scarpelli, Ohio State University. fnr providing us with the original donor animals.
a T = treated group. C = contiol group. Katio o f the total number of turnor' cells in control mice t o number in treated animals. Represents one-half the I.Dso as determined in C3H mice.
noted with regard to thc haloacetamidc analogs: iodoacetamide > bromoacctamidc > chloroacctamide. The toxicity of haloacetyl dcrivatives was greater than that of the halopropionyl analogs. (See Footnote I;,Table 11.) REFERENCES (1) Roll, W. D., J. Phnvm. S c i . , 5 4 , 269(196.5). ( 2 ) Lindei-, A,, Concrv Rps., 19, 189(1959). (3) Hauschka, T. S Patt, H. M . , Sassenrath, E. N.. and Tarnowski, G. S.. C&eiit K e s . Cancer C h e n m l h e r a p y , Repol-t No. 8 , 19.56, p. 23.
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