1120 Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11
NOT1.5
product formed a ppt it' was filt'ered off a i d recryst,d from either c6H6 or CHCl3-hexaiie. (b) When t,he product reniaiiied iii sohi the EtOH was removed in vacuo and the resiilting foam was dissolved in CHC13 and added dropwise, with stirring t o 1 0 vol i i f hexane. The ppt was filtered off aiid furt,her purified by a secoiid pptn. Yields varied between 50 aiid XOC;.;,. Tetrabenzylgentamicin CZ (111j.---NaBlf4 (0.43 g ) \viis added t o a refluxing soln of peiitabeiizylidiiie geiitamiciii C, (0.66 g) iii abs EtOH (25 ml). Refluxiiig was coiitd f o r 3.5 hr. The solii was cooled and acidified t o p H 1.5 with 1S I12S04-31eOlT. After I hr at room temp the so111was poiired into dil S I I 4 0 I I (2 -V, 200 1111) and extd with CHCl, (2 X 100 mlj. The est \vas washed with 5:? NaTTS03 and HzO, dried (hIgSOa), filtered, aiid evapd to yield a colorless foam. Tlc (silica gcl, rh)droc:iprcwm\-ciii s ~ i o \ec1 \ iiimrptioii :it A,,,, 256 (E::;,) -i s,) m d Xln,, 163 t i i n (E;:;, 74) in H20, in coiitru\t t o the. iibsorptioii of rnpreom) cin complc\; itself, 3X (E;;&260) 111 HzO. Thc 111111' spwt r:t of both perhydroviomycin and perhydrocapreoinycirr \\-ere similar to the spectr:i of thc. parent compounds except that in each cme, the absorptioii a t T 1.9 i i i both viomycin arid capreom) ciii h:td disappeared The biological activities of pf.rhydroviomycin arid p r h j drocq)reom>cin \\-ere measured by the zone inhibition met hod using Bacillus subtilis. I'erh? drovioniyciii I \ : L ~found t o be approsimatelv 30% a i activr. :is viom) cin, wid perrhydrocapreoniyciii 4 3 7 as :LctivC 219 caprrom) Clll I n order t o denmilstrate homogeneity, the prrh? droviomycin nus chromatographed using a 550 cni X 1.9 cni Sephadex G-15 column. -1total recolery of 92% n a s achieved from thcl column. .I I\ t curv(1 of 111dividual fractions \\-a5plotted, 11hich revealed that !13%1 of the. material rrcovercd T\ as homogeneous, giviiig a Gaussian pe:ili in the curve. Bioassay of each fraction in the peal, revealed an average activity of 300: of the activit 1 of rommerci:Ll viomyciii.
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 11
NOTES Tlc of perhydrocapreomycin using 1-BAWAA revealed only one ninhydrin-positive spot, which has the same Rr value of capreomycin. Bioassay revealed perhydrocapreomycin to be 4370 as active as capreomycin itself.
Acknowledgment.-The authors are indebted to Dr. Paul D. Shaw and Mr. Ren6 deBus, University of Illinois, Urbana, Ill., for the bioassays, and to Parke, Davis and Company and Eli Lilly and Company for their generous gifts of viomycin and capreomycin, resp.
Cobalt Chelates of Schiff Bases of Aromatic Amines as Antitumor Agents ERNEST M. HODNETT,* CHARLES H. MOORE, Department of Chemistry, Oklahoma, State University, Stillwater, Oklahoma 74074 AND
FREDERIC A. FRENCH'
Chemotherapy Research Laboratory, M t . Zion Hospital and Medical Center, Sun Francisco, California 94116 Received M a y 17, 1071
Some metal chelates have shown activity against tumors of experimental ani mal^.^-^ We have therefore
1121
ious Schiff bases. We have found that good yields of pure compounds are obtained from the amine, salicylaldehyde, and CO(OAC)~.Analysis of each compound for Co indicates that 2 molecules of ligand have combined with each C O + except ~ for 111, which has only 1 molecule of ligand for each Co2+. The properties of 12 of these compounds are shown in Table I. The metal chelates are dark-colored solids with limited solubility in organic solvents; 4 dissolve to a small extent in dioxane and in benzene. Their stabilities in aq soln were unknown as were their mode of action in biological systems. The toxicities of these compounds to mice were determined for 2 routes of administration: ip injection and gavage. Postmortem examination of the animals receiving ip injections showed no drug deposit a t the site of injection although the chelates have practically no solubility in HzO. The antitumor activities of these chelates were evaluated against L1210 leukemia, sarcoma 180 ascites, and the Lewis lung carcinoma using both ip and gavage routes of administration. The results of these tests are shown in Table 11. While none of these compounds meet or exceed the CCNSC criteria of significant activity, several of the reported activities are sufficiently close to the borderline to be of possible extrapolative value for further studies. This might be done through a multiple parametric approach.
TABLE I PREPARATION AND PROPERTIES OF COBALT DERIVATIVES OF SCHIFFBASES Name
-
Formula'"
MP, OC
Color
Yield, %
188-192b~C Reddish yellow 52 C~JLOCONZOZ Cobalt, bis [o-(N-phenylformimidoyl)phenolato] Red 95 C28HzaCONz0z 195. 5-197d Cobalt(II), bis [o-(N-o-tolylformimidoy1)phenolato] Cobalt(II), bis [o-(N-p-tolylformimidoy1)Cz~HzaCONz0z 183-184 Reddish purple 82 phenolatolC Z ~ H Z O C O N Z ~ ~ S>Z300 Brown-black 51 Cobalt(II), bis [o- [iV-(0-mercaptopheny1)formimidoyl]phenolato] Cobalt(II), [NV-salicy1idenenanthranilato(2-)]CiaH9CoN03 196 Brownish orange 68 CzsHzoCoN& >300 Mustard yellow 95 Cobalt (II), bis [ p-(salicylideneamino)benzoato]Yellow 87 ClaHioCoO4.2H2Oe >300 Cobalt(II), bis(salicylaldehydato), dihydrate Red 98 C26HzoCONz0~ 277-280 Cobalt (11),bis [o- [N-(p-hydroxypheny1)formimidoyl]phenolato] 288-291 Reddish purple 96 CzsHiaC~NzOa~ Cobalt (I1), bis [o- [N-(0-methoxypheny1)formimidoyl]phenolato] Red-purple 84 CzsHz4C0N204 185.5-186.5 Cobalt(II), bis[o-(,V-(p-methoxyphenyl)formimidoyl] phenolato]Cobalt(I1 ), bis [o- [ N -[p-(dimethy1amino)phenyl) C ~ O H ~ O C O N ~ O ~ 265-267 Purple 95 formimidoyl] phenolato] Cobalt(II), bis [o- [N-(0-nitro)formimidoyl] CzsHisCoNaOs >300 Light brown 70 phenolatolE. $1. Hodnett and a All compds were analyzed for Co. The Co content agreed with the theoretical value within acceptable limits. H . Nishikawa and S. Yamada, W. Willie, Proc. Okla. Acad. Sci., 46, 107 (1966). c B. West, J . Chem. SOC.,3115 (1952); no mp given. Bull. Chem. SOC.Jap., 38,1506 (1965). e R. H. Bailes and M. Calvin, J.Amer. Chem. SOC.,69,1886 (1947).
-
prepared some Co derivatives of the Schiff bases of salicylaldchyde and various aromatic amines and have determined their activities against ~ 1 2 1 0leukemia, ascitic sarcoma 180, and Lewis lung carcinoma in mice. Similar metal derivatives have been prepared by Bailes and Calvin5 as 0 carriers, using Co salts and varThe biological phase of this work was conducted under Grant Chfrom the National Cancer Institute. E. M. Hodnett and W.Willie, Proc. Okla. Acad. Scz., 46, 107 (1966). E. M . Hodnett and William J. Dunn, 111, t o be published. (4) S. Kirschner, Y.-K. Wei, D . Francis, and J. G. Bergman, J. M e d . Chrm., 9, 369 (1966). ( 5 ) R . H. Bailes and M . Calvin, J . A m e r . Chem. Soc., 69, 1886 (1947).
(1) 03287 (2) (3)
Experimental Section General Synthesis.-Co(OL4c)~ (25 "ales) was placed in a 500-ml flask equipped with an N, inlet. Solvent (generally 40 ml of EtOH) was added to the metal acetate and stirred magnetically until the acetate had dissolved. A primary amine (50 mmoles) and 100 mmoles of anhyd Na2C03were added to the flask with continuous stirring. Salicylaldehyde (50 mmoles), dissolved in 40 ml of the solvent, was placed in the addition funnel. The system flushed with N,, and the soln of salicylaldehyde was added with stirring to the mixt. The reaction mixt was warmed until CO, evoln ceased and then held somewhat below the bp of the solvent for 15-20 min. The ppt which formed was filtered from the reaction mixt, washed wlth distd H20, and with EtOH, and dried under vacuum a t room temp.
