Sovember 1909
XOTEH
c*oiitiniied. When the temperatiire i'ose t o 15-20', all of the irihc~liible material went, iiito solutioii. The clear solution was poured int,o 500 ml of H20 and the mixture wa. adjusted to pH 5 . The product was removed by filtration, washed with deionized H20, and dried overnight at i o " . The crude product melted a t 219-220' dec. Bisi7-fluoro-5-nitro-8-quinolinolato)copper (11) (IIa).-Two soIritions containing 0.41 g (0.0018 mole) of i-fluoro-5-nitro-8quiiiolitiol in 10 ml of MeOH and 0.21 g (0.0010 mole) of Cli(OAc,),.H?Oi n 20 nil of 75qi aqueoria 1teOH were mixed and $tined for 1 hr. The product was removed by filtration, boiled i i i 1)lIF .*everal times, and t.he insoluble material was washed with acetone arid dried lindei, vnciium a t 100" overnight. The componitd was FiifYiciently pure for anal! 7-Chloro-5-nitro-8-quinolinol (Ib).-Tu 400 ml of H20 xvas added 5 . i g 10.028 mole) of 5-iritro-8-quirioliiio14and 1.8 g 10.026 mole) of 85c; ROH. Soliitioir was effected by stirring and heatiiig. After cooling t o 30", 50 ml of SaOC1 ( 5 . 2 5 % ) \vas added :tiid stirring was contiillled 1 hr loiiger. The mixture was brought to pH 5 with 25 ml of AcOH. The pt,odiict was obtained by tilt,ratioii, wishing with deionized H20, arid dryiiig at i o " over-
guanosine disulfide was also found to be a more potent inhibitor on a molar basis than either 2 or thioguanosine. Despite these rather intriguing results there does not appear to have been any further study upon the effects of disulfide formation on biological activity in 6-t hiopurinyl nucleosides. In an effort to explore this aspect further we have prepared the disulfides of several 6-t hiopurinyl nucleosides. The candidates chosen for conversion to their disulfideb were a- and P-9-(2-deoxy-u-erythro-pentofuranosy1)-9H-purine-6-thio12 (3), a- and P-2-amino-9-(2deoxy-i)-eryth ro-pent ofuranosy1)-9H-purine-6-thiol6 (4), 9-B-1)-arahinofurariosyl-9H-purine-G-thiol~ ( 5 ) , and 2amino-9-(3-deoxy-p-r, -erythro-pentofuranosyl) -9H- purine-&thiol8 (6). All of the compounds chosen with the exception of a-3 have previously demonstrated significant activity in the leukemia L1210 test system" (Table I).
tiight.
1117
6,6'-L)ithiobispurinyl Nucleosides' ---SH" Dose,
FREDKELLER.\SD JAMES E. B ~ K E K .Ilrtlicinal ChPmistr?/ SPction, Chrniical Research DepaifmPnt, lii?iPr Laboratories, Division of Dart Industries, Inc., Sorth ridge, Ca 1ijorn ia 91324 X i w i w t l Fcbruaiii 5, 1969
rl number of nucleosides of purine-6-t'hiol (1) and 2-aminopurine-6-thiol (2) have been prepared in an effort to modify the toxicity of these clinically useful :inticancer agerit,s and to provide drugs for use against 1- and 2-resistant cancer st,rains. A serious problem which has presented itself in t'he use of these new drug cartdidat'es i R their rapid elimination and metabolism by oxidative pathways to therapeutically inactive products. The metabolism of (%mercaptopurine and some of its deriv:itives hws been the subject of :I recent review.Y 111:LI~ attempt to provide :I "reservoir" source of 1 arid 2 :is well a s their 8-i)-ribofurnnosides, Doerr, ef a/.,4 prepared the disulfides of these compounds using an adaptation of the iodine-buffer procedure of AIiller, et d.: The disulfides could he envisioned as reverting to the corresponding thiol and sulfenic acid through chemical means by the attack of base,4 or alternately an enzymatic system such as that regulating the oxidation and reduction of glut:ithione could prevail t o reduce the disulfide to the thiol. The earlier paper4 did riot record any metabolic data to support directly the "reservoir" hypothesis but did note that the :ictivity of the disulfide of t,hioinosine in the Sarcoma 180 tem was greater than that of 1 while thc corrc~spontlingthiol \v:w in:ictivc. Tlrc thio( 1 1 -\lost of tliir \vork w a a uerfulctied rirldrr the a u s u i c e r uf r l j r ('alicrr
Chemotherapy National Service Center. Xational Institutes of Health, Put)lie Health Ssrvice. under Contract PH-43-66404. T h e views expressed in this paper are those of the authors and d o not necessarily reflect those of t h e ('CNSC. (2) See R. H. Iwamoto. E. .\I. h c t o n , and L. Goodman, J . Org. Ckem.. 27, R94Y (19621, and leading references therein for a discussion of t h e rationale for tlie preparation of these compounds. ( : ( I C,. B. Elion. Frrirr,iti,jrb T'rm., 26, 898 ( 1 H t i i ) . (-1) I . I.. I)ocrr. I . \Vein[~eri,L). .i. ('larke, a n d J. .J. 1:o.r. .I. O r y . Cltem.. 26, 3.101 IlYlil). c.5) \V. I{. XIiller. R. 0. Rol)lin, J r . . and E. I%..\stmood. J . A m . Chem. S o c . , 6 7 , 2201 (1945).
Compound
my,'kg
,--s-sh
g,-
ILS, 70
ff-3
3-3 ff-4
200 1.i 20 400 200
36
J)ose, mdkg
400 4-600 400 150 400 to-150
---_
93 Y9 3-.i 63 !3-6 89 Optimal dose. Optimal dose not determined; tered iiitraperitorieally in saline stispension. 13-4
--
ILS, '/c
16 30 47 3% 40 33 adminis-
The thiols were smoothly converted to disulfides 111 good yields upon treatment in the iodine-buff er i y + With the exception of a- arid p-3 all oi the nucleohide disulfideq proved t o be quite water insoluble and were recovered by filtration of the reaction mixture and conveniently purified by recrystallization from DlIF-H20 (method -4). The 2-deoxynucleoside disulfides (a- arid 6-3) had significant water solubility :ind were best recovered by lyophilization of the oxidation mixture and recrystallization of the residueq from a minimum of H20 (method R). The physical constant5 of the new compounds are listed in Table 11. -111 of the disulfides exhibited the characteristic uv spectra described prev i o u ~ l ylo. ~ Biological Testing.-The preliminary screening resulth in the 1,1210 system for the neu disulfides are li*ted in Table I along with the optimal dose> for the parent thiol*.$ It n-ould appear from theye data that all of the ( 6 ) R . 11. Iwamoto. E . AI, .leton. and 1,. Goodman, .I. M e , / . C h e m . . 6 , 081 (19fi3). ( T I 1.; .I. Ileist. .\. l%enitv/,I.. G o d m a n , 13. K. Ilaker. ancl \\'. \\ . 1 . w
./. Or
