July 1966
609
T\TOTSS
2-Thienyl p-Tolyl Sulfone.-Z-Lithiot hiophene wai formed by dehyde, and 2- and %thenaldehydes, have also shown metalation of thiophene with n-butyllithium.'a The yield has high antiviral activity.6 4-Bromo-3-niethylisothiazolebeen shown to be essentially q ~ a n t i t a t i v e . ' ~A solution of 25-carboxaldehyde thiosemicarbazone (11), when given lithiothiophene from 8.4 g (0.10 mole) of thiophene in etherorally, was found to protect mice infected intracerepentane-hexane solvent was maintained at room temperature during the addition (50 min) of 70.4 g (0.30 mole) of 2-chlorobrally with neuro~accinia.~Two thiosemicarbazones ethyl p-toluenesulfonate in 85 ml of ether. The mixture was derived from substituted pyrrolidine-2,3-diones (111, stirred for 3 hr a t room temperature, hydrolyzed with excess R = C2H5and CH2CH20H)demonstrated protection water, and extracted with ether in the usual fashion. Distillaagainst experimental influenza infection in n1ice.j tion of the extracts gave anreacted 2-chloroethyl p-toluenesulfon2-Keto-3-ethoxybutyraldehyde (kethoxal) has been ate and thiophene from unreacted 2-lithiothiophene as the only distillable products. The residual red oil was crystallized from shown to have antiviral activity in embryonated egg> acetone with charcoal treatment to yield 8.1 g (34%) of colorless infected with PR-8 influenza and Semcastle diseabe.' crystals, mp 120-121". Its bis(thiosemicarbazone) derivative (IV, IiTS) was Anal. Calcd for CllHL002S2:C, 55.40; H, 4.24; S, 26.90. Found: C, 55.36, 55.51; H, 4.20, 4.36; S, 26.71, 26.88. The infrared spectrum (KBr disk) of the sulfone showed strong bands a t approximately T.6 and 8 . i p whirh may be a ~ s i g n e d ' ~ to the sulfone gronp.
Acknowledgment.-The authors would like to express appreciation to the Sational Cancer Institute for pharmacological testing and for partial financial support under Public Health Service Research Grant S o . Ch-04068 from the National Cancer Institute. (13) D. 4 . Shirley and K. R . Barton, Tetrahedron, 22, 515 (1966). (14) L. J. Bellamp, "The Infrared Spectra of Complex Molecules," .John Wiley and Sons, Inc.. Y e n York, K,Y.,1958, pp 360-361.
Studies on hlethylglyoxal Bis(guany1hydrazone)l Analogs. V. 3 I e t h y l g l y o x a l Guanylhydrazone Thiosemicarbazones and Related Compounds2 EUGEKE G. PODREBARAC A N D C. C. CHEXG Midwest Research Institute, Kansas City, LVIZ'smirZ' 64110 Received January 1'7, 1966
Derivatives of benzaldehyde t hioseniicarbazone have been reported to be active tuberculostatic3 and antiviral4 agents. Additional work on thiosemicarbazone compounds led to the discovery of antiviral activity of isatin 3-thiosemicarbazone (I) (ITSC) against the pox group of viruses in human and type 2 polio in ERE( ce1ls.j A number of monocyclic thioseniicarbazones, such as derivatives of nicotinaldehyde, isonicotinalCH3rf.
I N,
H
I CH=NNHCSNHz
I1
I
I
R
____
I11
(1) According t o Chemical Abstracts, t h e name for this compound is 1.1'[ (methyl)ethanediylidenedinitrilo]diguanidine. (2) This investigation was supported b y t h e Cancer Chemotherapy Na-
tional Service Center (CCKSC), National Cancer Institute, Kational Institutes of Health, Public Health Service, Contract PH-43-65-94. (3) (a) G. Domagk, .?Taturwissenschaften, 33, 315 (1946); (b) R . Behnisch, F. Mietzsch, and H . Schmidt, Angeu;. Chem., 60, 113 (1948); (c) N. P. Buu-Hoi, M . Welsch. G. Dechamps, H. I,. Bihan, F. Binon, and K. D . S u o n g , J . O r g . C h e m . , 18, 121 (1953). (4) D. Hamre. J. Bernstein, and R. Donovick, Proe. Soc. Exptl. B i o l . X e d . , 79, 275 (1950). (5) C / . H. E . Whipple, Ed.. Ann. S . Y . A e a d . Sei., 130, 71 (1965).
I
H&=NNHC(=IGH)NH~ VI
found to be very effective when given orally or intraperitoneally to rats bearing the Walker 256 carcinosarcoma and S180.8 This activity pattern is similar to a closely related compound, niethylglyoxal bis(thiosen~icarbazone)~(V), but different from that of the guanylhydrazone analog (VI). The latter compound, the structural modifications of which have been systematically studied in our laboratories for the past 3 years,1° was found to be active in leukemia L1210 and Ca755 and is considered as one of the few agents clinically effective in the therapy of adult acute myelogenous leukemia." I n view of the antituberculous, antiviral, and antileukemic as well as other antitumor activities demonstrated by the thiosemicarbazone and guanylhydrazone derivatives, and the importance of the methylglyoxal moiety in cell growth,12 synthesis and biological evaluation of conipounds VI1 and VI11 are of pertinent interest.I3 (6) R . L. Thompson, S.A . Minton, ,Jr., J. E. Officer, and G. H. Hitchings, J . I m m u n o l . , 70, 229 (1953). (i) (a) G. E. Underwood and S. D. Weed, Proe. SOC.Ezptl. B i d . Med., 93, 421 (1956); (b) \V. F. h l c l i m a n s , G. E. Underwood, E. -1.Slater, E. V. Siem, J . I m m u n o l . , 78, 104 (1957). (8) H. G. Petering, H . H . Buskirk, and G. E. Cnderwood, Cancer Res., 24, 367 (1964). (9) (a) C. Neuberg, a n d RI. Kobel, Biochem. Z., 188, 215 (1927). (b) Testing information provided b y CCNYC. (10) (a) E . G. Podreharac, W.H . Nyberg, F. 4 . French, a n d C. C. Cheng. J . M e d . Chem., 6, 283 (1963); (h) F. Baiocchi, C. C. Cheng, \V. J. Haggerty, Jr., L. R . Lenis, T. K Liao, 15.. H. Nyberg, D . E. O'Brien, and E. G. Podrebarac, ibid.. 6, 431 (1963); (e) E. G. Podrebarac and C. C. Cheng, ibid., 7 , 806 (1964); (d) T. K. Liao, F. Baiocchi, and C. C. Cheng, J . O r g . Chem., SO, 560 (1965). (11) (a) B. L . Freedlander a n d F. A. French, Cancer R e s . , 18, 360 (1958); (12) E. J . Freireich and E. Frei, 111, Proc. Am. Assoc. Cancer R e s . , 3, 319 (1962); ( c ) E. J. Freireich, E. Frei, 111, and RI. Karon, Cancer Chemotherapy R e p t . , NO. 16, 183 (1962). (12) A. Szent-Gyorgyi [Science, 149, 34 (196511 recently stated t h a t substances which promote ("promine") or retard ("retine") cell growth m a y provide keys t o fundamental problems of cellular biology. Further study with t h e isolated "retine" indicated t h a t methylglyoxal, combined in some fashion u-ith a nitrogen-containing moiety, is the chief constituent. (13) According t o Thompson, et a1.,6 most thiosemicarbaoones possessing high antiviral activity are those in u hich t h e thiosemicarhazone group, = N K H C S N H ? , is separated b y two carbon atoms from a N or S atom. This statement has since been substantiated b y Furst" based on chelation studies. Our structure-activity study of t h e guanylhydrazone derivatives in antileukemic screenings indicated t h a t a similar relationship is also one of the fundamental requirements in t h e =XXHC(=NH)YHz series. (14) A. Furst, "Chemistry of Chelation in Cancer," Charles C Thomas, Sprinnfield, Ill., 1963, p 67.
