HO OH
RO OR V, R= COCHJ
c1
SH
RO OR VIa, R = H b, R = COCH,
HO OH VI1
1 R I
I
S-R I
might he inweased if this reaction could be iuhibited or eliminated. It is of irit'erest that tuberridin demonstrated a coinplete resistarice to these three deaminases under the same conditioris and, therefore, by analogy VIa might well resist enzymatic dechlorination by adenosine dea.minase. Treatment of VIa with aqueous thiourea produced i - ( p - D - ribofuranosyl) pyrrolo [2,3- d ]pyrimidine - 4-thiol (VII) which was identical in all respects with the same compound previously preparedl20 from the t'hiation of V with l'& followed by renioval of the blocking groups 011 the cwhohydratc moiet'y. 4-I3eiizylt'hio-i-(P-urihofuraiiosyl) pyrrolo [2,~-d]pyriniidirie(IXh) d u c d when VI1 was treated with benzyl chloride iii dilute aqueous ammonia. I t is of considerable interest that 6-methylthiopurine ribonucleoside has been postulat,edl6to act as a substrate for adenosine kinase which converts it, to the nucleotide form in mouse tissues, Ehrlich ascites carcinoma cells in vivo, arid tumor cells in vitro. 6-llethylthiopurine ribonucleoside has also d e n ~ o n s t r a t e dsignificant ~~ in vivo activity against leukemia L1210 which had become resistant to 6-mercaptopurine therapy. This activit,y has prompted an investigation to determine if a correlation (16) I. C. Caldwell, .J. F. Henderson. and .4. R. P. I'atpraon, Can. .I. Biochem., 4 4 , 229 (1986). (17) L. L. Bennett. Jr., R . JY. Brockman, H. P. Schneb;i, R. Ctiumley, G . J. 1)ixon. F. h l . Schabel, ,Jr., E. A . Dulmadge, H. E. Skipper, J. .A. AIontgorners, and H. J. Thomas, .Vature, 205, 1 2 i 6 (196.5).
between the ring nitrogelis a i d cytotoxicit'y might exist. While it has beeii determined that S-deaza-6inethylthiopuririe ribonucleoside1s possesses far greater activity than does 1-deaza-6-niethylthiopuririe riboriucleoside, l 9 neither compound compares favorably with the parerit compound, 6-niethylthiopurine ribonucleoside. The only remaining deaza nucleoside derivat'ive is the (*ompound. +niethylthio-i-(P-r)ribofuranosyl) pyrrolo [L'.3 4 ] pyri iiiidiiie (IXa) which was prepared in our laboratory by alkylat'ion of T'II with methyl iodide. Dehalogenation of 1 3 wit,h hydrogen and I'd-C: catalyst has result'ed in the preparation of i-(p-Dribofurariosy1)pyrrolo [",3-d]pyrimidine (YIIId, i-deazanebularine) . This compound is of interest sin r e thc active coristituent from Jyai.icus riebuluris 13at(*h has bccri isolated'" and 1at)ei. ca1i:u.acterjzeds1 LIS the nucleoside antibiotic 9-(p-~-ri13ofuranosyl)puri11e (ncbulariiie) . Sebularine has also beeii isolated*?from Sfrept o m yces yofiosukaensis and has d e n i o n ~ t r a t e dsome ~~ activity in tissue cultures. In fact' it has been recently suggested24 that 7-deazanebularine (YIId) should be synt'hesized arid its biochemical behavior compared with that of riebularine. Sucleophilica displace~neiit~ of t'he 4-chloro group of \-Ia in refluxing sodium iiiethoxide afforded 4-methoxyi-(p-i~-ribofur~~~osyl)pyrrolo [2~,3-tI]pyriniidine(\-IIIa). Treatnieiit of T'Ia with dimethylamine and piyeridhie under anhydrous conditions produced 4-dimethylaminoi-(P-i)-ribofuraiiosyl)pyrrolo [',S-tl]pyriniidirie (T'IIIh) and 4- (l-piperidyl)-i-(p-D-ribofuraiiosyl)pyrrolo[2,3-d]pyrimidine (T'IIIc), respectively. It is of interest that the corresponding purine ribonucleoside, 6- (1-piperidyl)9-(p-n-ribofuranosyl)purine possesses25significant antitumor activity against Walker 7 5 3 and 7.56 carcinoma and inhibits the growt,h of Vicia juba. Treat,merit of \'Ia with niet'hariolic ammonia at 150' resulted in a displacenieiit of the cahloro group t o produce 4-amino7-(p-u-ribofurariosy1)pyrrolo [:!,S-[(]pyrimidi~le(I,t,ubercidin). .lctually this provides t'hc first total chemical synthesis of tubercidin since 'i-(p-D-ribofuraiiosyl) pyrrolo[2,3-d]-4-pyrimidone has been previously prepared'*" by chemical synthesis. :\lethylation of tubercidin (I) Ivith methyl iodide in dimethylacetaniide (Chart 11) furnished a morioniethyl derivat,ive as the iodide salt, which was assumed tu be 4-amino- 3 -methyl-'i-(p-1~-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (X). The pnir spect8runi indirated that alliylatioii of :t rhig nitrogen had ocwrred s i i i w t,lie :ibsorption pculi observed for the iiiet'hyl group \vas a singlet atid it has been previously shown26that under similar reaction conditions adenosine undergoes alkylation on the ring nitrogen adjacent to the exocyclic (18) J . .\, Montgumery and I r o c , A\utl. d i i i d . Sii. 1.. S., 63, Y79 ( l Y ( i 8 ) . T . Schleicti acti J. Goldstein, Science, 160, 1168 (19053. (4) R. 9. H a y n a r d ani1 S. 13. \\-eiss, Proc. S a i l . A c a d . Sca., 1. S.,55, 1161 (1966). ( 5 ) S . Sueoka and T. Kano-Sueoka, ibzd., 52, l5X5 (1964). ( 6 ) AI. N. Lipsett and A . Peterkofsky i b d . . 65, 1169 (1966). ( 7 ) 1 3 . Goeliler and It. H. Doi, ibid., 66, 1017 (1866). (8) R. I. 1%. Francki and R . E. F. AIattliews, i.iralagj{, 17, : 1 6 i (1962). (9) P. I
