247
Notes Nucleosides. XXXV. 1-~-u-Arabinofuranosyl-5-methy1cytosine1
CHART
1
11~1sL. D(IEIW,JOHN F. C O D ~ K G T O A NN D, J.ICI< J. Fox
l)it,ision OJ Biological Chmzistry, Sloan-Kelferiny Ins!z'lule Jor C'unwv IZeseaxh, Noun-Kettering Division oj Cornell C'niversily Jfeclical College, .Yew York 21, .\-ew York
Pyrimidine nucleosides containing the 1-p-D-arabinofurariosyl moiety have exhibited interesting biological properties. Anioiig t8hese compounds are 1-(p-D-arabinofuranosy1)cytosirie (CA)z which is active against' several experimental tum01-s;~1-p-D-arabinofuranosyl3-iodouracil n-hich is active against herpes and vaccinia virus in cell c.ultures;j 1-p-D-arabinofuranosyl-S-fluorouracil (I;UA)6 xvhich is active against leukemia B82 mid Sarcoma 180; and finally 1-0-D-arabinofuranosyl5-fluorocytosine (FCA)4 which is active against Sarvonia, 180 and leukeniias P388, P81.5, and L1210, as well us against, the 5-fluorouracil-resistant strains of the latter two. Both C,A and FCA are currently undergoing r linicd t ri als.718 These biological data suggested the synthesis of 1(p-D-arabinofuranosy1)-5-methylcytosine (VII, N C h , see Chart I) because of its st.ructura1 similarity to C h arid FCAA. 1-(5-0-Trityl-/3-D-ribofuranosy1)thymine (I) was converted directly into the 2,2'-anhydroarabino derivative (11)911 (67%) by use of the t'hionocarbonate p r o c ~ e ~ l u r developed e~~'~ for nucleosides. Detritylation of I1 by anhydrous hydrogen chloride in ether gave the crystalline hydrochloride of III9') in quantitative yield which was subsequently converted to nucleoside 111 (92yo). Refluxing the 2,2'-anhydronucleoside 111 in 1 N sulfuric acid for 1 hr yielded 1-p-D-arabinofuranosylthymine in 88% yield." The arabiriosyl nucleoside (IT) was ronverted to :\ICA\ (VII) by modification of the thiatiori process previously reported for pyrimidine nucleosides.12 Acetylation of IT' gave a 94yo yield of the tri-0-acetate (V) which was thiated with phosphorus peritasulfide in pyridine to the 4-thione (VI) in quantitative yield.
I1
I
Received J u l y 28, 1966
1
HO
1
IV
,
AcO
I11
'
I
I
AcO
V
VI
y' Ac Tr = triphenylrnethyl acetyl
PH3 I
H O H z C q
HO VI1,MCA
Reaction of the thione (VI) with liquid ammonia at 55' overnight gave -1ICA (VII) iii 80y0yield. Preliminary Screening Studies.-At dose5 of 100 nig/kg ip daily for ten doses, ,\lCA was inactive in ull experiments agairist m o u e leukemia P815. -\lCh was administered intraperitoneally to Sarcoma, 180 tumor-bearing mice twice daily starting with the day following tumor implantation. With ;\ICA$, tumor hosts showed no toxic. signs after 13 injections of 123 nig/kg/day. The ratio of the average diameter of treated tumors to the average diameter of the control tumors (T/C) n a s 1.0 indicating no retardation of growth of tumors over the controls by _\ICL\. Experimental Sectioni3 2,Z'-Anhydro-1-(5-O-trityl-P-~-arabinofuranosyl)thymine
(1) This investigation n a s ruppurted in part by funds from the National
Cancer Institute, Piational Institutes of Health, U. 8 . Public Health Service (Grant S o . C.\ O S i 4 8 ) . Dekker, I ' r o c . C h e m . SOL.., 12) 11. R . \Valn-ick, \\'. I
