.itc near the active center the 2,4,6-triamino-5-arylazol)yrirnidines may be binding in conformatioil X X I I I . In this conforniation the alkylating A SUI)-
7"""
COOEt
I
CICH2CH2(Et>N(CH2),NH
,& N'
H N
NH(C H2)n N( Et )CH,C
"2
H2C I
ssI I1R
"2
SSlII
htitueiit would be able to bridge to the same general :irw on the enzyme as the corresponding substituent as i i i XXI. In the case of XXII ionic repulsion between t hc J-l-imino substituent and the enzyme was considered to force it5 adoption of conformation X X I I a : presumably the same repulsion factor would be operative for the L',~,G-trianiitiopyriiiiidiiies but since there :ire
:mino groups a t the 4 :~ndt j 1)osition. i-epulsioii will probably be :q~proximittely equivalent regardless of whether conforniation XXIII or XXIIla is xdoptcd. Such speculation affords an explanation of the irreversible iriactivatiiig properties of ti-S-w-(S-ethyl-2-chloroethyl)alky1-2,4,G-trianiino - 3 - (4 -'carbet hoxj phenyliizo) 1)yrimidinesand also of their relatively low potency. Acknowledgment.-This n-ork was supported by it grant (CA 06645) from the S:ttional Cancer In+titutc, Satioiial Iiistitutes of Health, I-. S. Public Health Service.
Peptides of Pyrimidine Amino Acids'
The a-amino-p-( 2-mel.capto-6-oso)-4-pyrinlidylpropi~)tlicacids were fouiid to be pheiiylalaiiine antagonials. A number of dipeptides of these amino acids have been synthedized and tested as inhibitors of growth and prot ein synthesis iii Ehrlich ascites carcinoma in mice. Glyryl-, or~-phenylalanyl-,and ~,-phenylalanyl-ol-:rnliiioa-(~--mercapto-6-oxo-3-methyl)-4-pyrimidylpropio1lic acid showed an enhanced :ict.ivit,y over n-:imiiio-p-( 2-mercapto-6-oxo3-methyl)-4-pyrimidylpropionic acid.
liesenrch efforts within recent years have resulted in the synthesis of many antimetabolites of pyrimidines, l)urities, amino acids, vita,niins, and other met'abolites :IS I)oteiitinl anticancer agents. One of tlie major t w k s of cancer chemotheraiiy is to search for antitumor diugs n i t h diverse and select spectra of action. In ordcr t o get better selectivity arid transport' into the cell iritcrior large numbers of antitumor drugs h:tve heeii y . t i t hcsized in which cytotoxic groups have been ititroduced into natur:il carrier^.^ ;Iniong the natural c:irriers. the amino acids and peptides have been shon-11 t o ~)I:LJ. important roles. The best example of such ii usc of :in :imino acid or a peptide is found in the work of I k ~ g e l:ind St0clq~8-c Im-ionov and S ~ p h i n a ,and ~~ Sol)hiii:t, et uL3e They have synthesized DL-, L-, and ~~-~~-di(L'-chloroet~liyl)iinii~iophenylala~~i~ie and their pep( l i 'l'tii.* inreiriration wab supported 1j.v l'ulilic Health Service Itesearcli ( : r a n t s ('.\-0636-1-0-1 and CA-0636-1-05 irorn tlie Kational Cancer Inscitilte. ( 2 ) Tu I\ liom iniluiries sliorild be sent. 4)la) F, Bergel and J. .I, Stock, J . Cheni. Soc., 2409 (1954); (b) F. I , V . (', E. Burnop, and J . .\, Stock, ibid., 1223 (19.55); ( e ) F. Bergel, ,I. \ . S t u c k , and K. \Vade, "Bii,logical .lgproaclies t o Cancer Cliernother" .\riuIeinic P r e ~ s Inc., New Y o r k , N. Y., 1961, 11 125; (11) I,.F. 1,ariiin o v and %. 1'. Sopiiiina. IJohI. . 4 1 j ~ d ..I'uuk SSSIZ, 114, 1070 (1857); ( e ) %. 1'. S
